Platelets are small anucleate blood cells supporting vascular function. They circulate in a quiescent state monitoring the vasculature for injuries. Platelets adhere to injury sites and can be rapidly activated to secrete granules and to form platelet/platelet aggregates. These responses are controlled by signalling networks that include G proteins and their regulatory guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Recent proteomics studies have revealed the complete spectrum of G proteins, GEFs, and GAPs present in platelets. Some of these proteins are specific for platelets and very few have been characterised in detail. GEFs and GAPs play a major role in setting local levels of active GTP-bound G proteins in response to activating and inhibitory signals encountered by platelets. Thus, GEFs and GAPs are highly regulated themselves and appear to integrate G protein regulation with other cellular processes. This review focuses on GAPs of small G proteins of the Arf, Rab, Ras, and Rho families, as well as of heterotrimeric G proteins found in platelets.

Platelets circulate in the bloodstream supporting vascular integrity, haemostasis, immune defence, and tissue repair [1]. Platelets are anucleate and have a lifespan of around 10 days. Core structural components include an open canalicular system which is continuous with the plasma membrane and a dense tubular system involved in Ca2+ storage. Platelets contain 50–80 alpha granules, 3–8 dense granules, and 1–3 lysosomal granules, as well as 5–8 mitochondria [2,3]. Each granule type carries specific regulatory molecules which upon exocytosis stimulate a positive feedback loop recruiting more platelets to lesion sites and supporting their activation. Platelet alpha granules contain more than 300 different proteins while dense granules contain ATP, ADP, Ca2+ ions, and pyrophosphates which are essential for normal haemostasis [9]. Activated platelets change their shape, they adhere to sites of vascular injury and bind to each other to form aggregates [4]. These processes require rapid and extensive remodelling of the cytoskeleton. Furthermore, activated platelets alter the composition of the outer layer of their plasma membrane by exposing phosphatidylserine thus supporting binding and activation of clotting factors leading to extracellular fibrin fibre formation [5]. Platelet functions are tightly controlled by activating and inhibitory signalling networks (Figure 1) [6].

Overview of platelet signalling

Figure 1
Overview of platelet signalling

Platelet can be activated by von Willebrand factor (vWF) binding to the glycoprotein (GP) complex GPIb/V/IX, collagen binding to GPVI, and podoplanin binding to the C-type lectin-like receptor (CLEC-2) which activate tyrosine kinase signalling leading to activation of phospholipase C (PLC), formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP2), activation of protein kinase C (PKC), and release of Ca2+ ions from intracellular stores. Thromboxane A2 (TXA2), thrombin, and adenosine-diphosphate (ADP) activate TP, protease-activated receptors (PAR1, PAR4 in humans), and purinergic P2Y1 and P2Y12 G-protein coupled receptors leading to activation of α and βγ subunits of heterotrimeric G proteins by exchange of Gα-bound guanosine-5'-diphosphate, GDP, by guanosine-5'-triphoshate, GTP followed by PLC activation and Ca2+ signalling, activation of guanine-nucleotide exchange factors (GEF) of the small G protein RhoA, activation of phosphatidylinositol 3-kinase (PI3K), or inhibition of adenylate cyclase (AC), as indicated, and platelet activation. Gα-GTP is turned into inactive Gα-GDP by regulator of G protein signalling proteins (RGS). RhoA-GTP triggers a range of cytoskeletal rearrangements and RhoA-GTP is turned into inactive RhoA-GDP by GTPase-activation proteins (RhoGAP). Endothelium-derived prostacyclin (PGI2) inhibits platelets through activation of the IP receptor coupled to the stimulatory Gαs protein leading to formation of 3'5'-cyclic adenosine monophosphate (cAMP) from adenosine-5'-triphosphate (ATP), activation of protein kinase A (PKA) and phosphorylation of a wide range of substrate proteins. In parallel, endothelial nitric oxide (NO) diffuses through the plasma membrane and activates NO-sensitive guanylate cyclase (GC) to generate 3'5'-cyclic guanosine monophosphate (cGMP) which activates protein kinase G (PKG) to phosphorylate substrates leading to platelet inhibition. Platelet activation and inhbition pathways interact at multiple levels. Platelet activation leads to activation of the Rap1 G protein which enables the transition of inactive to active integrin αIIbβ3IIbβ3) leading to fibrinogen binding, platelet aggregation, and further platelet activation. Rap1 is regulated by specific GEF and GAP proteins. Arf family G proteins are involved in endocytosis of integrin αIIbβ3 and in the regulation of the cytoskeleton, and in other membrane and vesicle transport processes. Rab family G proteins are required for the generation, transport and release of platelet granules, and are probably involved in many other membrane and vesicle transport processes as well as in endocytosis. Arf and Rab proteins are controlled by dedicated GEFs and GAPs. Created with Biorender.com.

Figure 1
Overview of platelet signalling

Platelet can be activated by von Willebrand factor (vWF) binding to the glycoprotein (GP) complex GPIb/V/IX, collagen binding to GPVI, and podoplanin binding to the C-type lectin-like receptor (CLEC-2) which activate tyrosine kinase signalling leading to activation of phospholipase C (PLC), formation of inositol 1,4,5-triphosphate (IP3) and 1,2-diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP2), activation of protein kinase C (PKC), and release of Ca2+ ions from intracellular stores. Thromboxane A2 (TXA2), thrombin, and adenosine-diphosphate (ADP) activate TP, protease-activated receptors (PAR1, PAR4 in humans), and purinergic P2Y1 and P2Y12 G-protein coupled receptors leading to activation of α and βγ subunits of heterotrimeric G proteins by exchange of Gα-bound guanosine-5'-diphosphate, GDP, by guanosine-5'-triphoshate, GTP followed by PLC activation and Ca2+ signalling, activation of guanine-nucleotide exchange factors (GEF) of the small G protein RhoA, activation of phosphatidylinositol 3-kinase (PI3K), or inhibition of adenylate cyclase (AC), as indicated, and platelet activation. Gα-GTP is turned into inactive Gα-GDP by regulator of G protein signalling proteins (RGS). RhoA-GTP triggers a range of cytoskeletal rearrangements and RhoA-GTP is turned into inactive RhoA-GDP by GTPase-activation proteins (RhoGAP). Endothelium-derived prostacyclin (PGI2) inhibits platelets through activation of the IP receptor coupled to the stimulatory Gαs protein leading to formation of 3'5'-cyclic adenosine monophosphate (cAMP) from adenosine-5'-triphosphate (ATP), activation of protein kinase A (PKA) and phosphorylation of a wide range of substrate proteins. In parallel, endothelial nitric oxide (NO) diffuses through the plasma membrane and activates NO-sensitive guanylate cyclase (GC) to generate 3'5'-cyclic guanosine monophosphate (cGMP) which activates protein kinase G (PKG) to phosphorylate substrates leading to platelet inhibition. Platelet activation and inhbition pathways interact at multiple levels. Platelet activation leads to activation of the Rap1 G protein which enables the transition of inactive to active integrin αIIbβ3IIbβ3) leading to fibrinogen binding, platelet aggregation, and further platelet activation. Rap1 is regulated by specific GEF and GAP proteins. Arf family G proteins are involved in endocytosis of integrin αIIbβ3 and in the regulation of the cytoskeleton, and in other membrane and vesicle transport processes. Rab family G proteins are required for the generation, transport and release of platelet granules, and are probably involved in many other membrane and vesicle transport processes as well as in endocytosis. Arf and Rab proteins are controlled by dedicated GEFs and GAPs. Created with Biorender.com.

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Platelet activation can be initiated by subendothelial collagen exposed at injury sites providing a binding site for von Willebrand factor (vWF). vWF binding to the glycoprotein (GP) receptor complex GPIb-V-IX establishes platelet tethering but cannot support stable adhesion. Instead, it facilitates platelet binding to collagen via the tyrosine kinase linked GPVI receptor [7]. GPVI is covalently bound to the Fc gamma receptor (FcRγ) and binding of collagen to GPVI induces phosphorylation of an immunoreceptor tyrosine-based activation motif (ITAM) in FcRγ by Src family kinases (Figure 1). This phosphorylation activates the tyrosine kinase Syk leading to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C γ2 (PLCγ2) resulting in the second messengers 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG activates protein kinase C (PKC) whereas IP3 increases intracellular Ca2+ both leading to platelet activation and granule release [8]. ADP, a dense granule component, binds to and activates the G-protein coupled receptors (GPCR) P2Y12 and P2Y1 leading to amplified platelet activation through reduced cyclic adenosine monophosphate (cAMP) synthesis, phosphatidylinositol 3-kinase (PI3K) activation and through increased Ca2+ signalling (Figure 1, see chapter on heterotrimeric G proteins below for further details). Other amplifiers of platelet activation include thromboxane A2 (TXA2) which activates the thromboxane-prostanoid (TP) GPCR and thrombin, produced in the clotting cascade, which activates platelets through PAR1 and PAR4 GPCRs [9]. Platelet activation leads to a conformational change in the abundant fibrinogen receptor at the plasma membrane, integrin αIIbβ3, which mediates platelet aggregation.

Platelet inhibition is maintained predominantly by the activation of two cyclic nucleotide signalling pathways, one involving cAMP which is activated by endothelium-derived prostacyclin (PGI2), and the other cyclic guanosine monophosphate (cGMP) activated by endothelial nitric oxide (NO) (Figure 1). These pathways are likely to be constitutively active due to the continuous production and release of PGI2 and NO from the endothelium. PGI2 binds to the IP receptor, a GPCR coupled to Gαs which activates adenylate cyclase (AC). AC uses ATP to synthesise cAMP which binds to the regulatory subunit of protein kinase A (PKA) allowing the catalytic subunits to phosphorylate numerous substrate proteins and inhibit platelet activation. NO activates the cGMP pathway following its diffusion through the membrane and subsequent binding to NO-dependent guanylate cyclase which activates protein kinase G (PKG). There is significant overlap between the substrates phosphorylated by PKG and PKA. The inhibitory effects of these pathway are so potent that activation of either pathway can reverse platelet aggregation resulting in dissolution of pre-existing platelet aggregates [10].

Activating and inhibitory pathways converge on guanine-nucleotide binding proteins (G proteins or GTPases) of the Ras superfamily which exert their functions through interactions of the GTP-bound G proteins with downstream effector proteins (Figure 1) [11]. G proteins require guanine nucleotide exchange factors (GEFs) to allow GTP to replace GDP in the active centre. GTPase-activating proteins (GAPs) play a critical role in activating the low endogenous GTPase activities of many G proteins by turning the active GTP-bound forms into their inactive GDP-bound versions. Thus, GAPs effectively serve as off-switches of G protein signalling [12]. This review will provide a broad overview of GAPs of Ras superfamily small G proteins and of alpha subunits of heterotrimeric (αβγ) G proteins found in human platelets. A few GAPs will be described in more detail focusing on available platelet data. Emerging roles of GAPs beyond G protein regulation will be highlighted. Information on platelet GEFs of the Rho family, a member of the Ras superfamily, is included in other reviews [13–16].

The Ras superfamily of small G proteins encompasses Arf, Rab, Ras, and Rho family proteins and each family has its dedicated GAPs. Similarly, the activity of heterotrimeric (αβγ) G proteins is controlled by regulator of G protein signalling (RGS) proteins. Comprehensive proteomics mapping [17,18] has revealed the G proteins and GAPs expressed by human platelets including protein copy numbers per platelet (Tables 1 and 2). G protein specificities have only been established for a few GAPs and even fewer studies have investigated platelet specific roles of GAPs. GAPs have been identified that regulate Rap1, RhoA, Rac1, and Gαi and Gαq in platelets; however, many orphan G proteins are still present, especially in the Arf and Rab families. Almost all ArfGAPs encoded by the human genome, except ADAPs [19], and most Ras/RapGAPs are expressed in platelets. In contrast, platelets express only about half of the encoded RabGAPs, RhoGAPs, and RGSs. Similar numbers of Arf, Ras and Gα proteins and their GAPs can be found, whereas more Rabs and fewer Rhos compared to their GAPs are expressed. A low Rho/RhoGAP ratio might indicate that individual Rho proteins are targeted by more than one RhoGAP possibly contributing to the creation of diverse zones of local Rho protein activity [20,21]. G protein expression levels vary more than 10-fold with certain G proteins ranging between 10,000 up to above 100,000 copies per platelet. In contrast, GAP copy numbers are generally below 10,000 copies per platelet [18]. A comparison of tissue expression patterns suggests that the G proteins Rab27B, Rab32, Rab37, RhoF, Gα13, Gαq (Table 1), and the GAP family members RASA3, Rap1GAP2, RhoGAP6, RhoGAP18, and RGS18 are particularly highly expressed in platelets possibly indicating platelet specific functions (Table 2).

Table 1
Overview of G proteins and their expression in human platelets
UniProtGene NameProtein nameProtein copy number per plateletPlatelet specificityPlatelet studies
Arf family 
P84077 ARF1 ADP-ribosylation factor 1 49771   
P61204 ARF3 ADP-ribosylation factor 3 44255   
P18085 ARF4 ADP-ribosylation factor 4 33268   
P84085 ARF5 ADP-ribosylation factor 5 36244  
P62330 ARF6 ADP-ribosylation factor 6 6370  22916275
26738539 
Q13795 ARFRP1 ADP-ribosylation factor-related protein 1 1495   
P40616 ARL1 ADP-ribosylation factor-like protein 1 2274   
P36404 ARL2 ADP-ribosylation factor-like protein 2 922   
P36405 ARL3 ADP-ribosylation factor-like protein 3 3335   
P40617 ARL4A ADP-ribosylation factor-like protein 4A   
P56559 ARL4C ADP-ribosylation factor-like protein 4C   
P49703 ARL4D ADP-ribosylation factor-like protein 4D   
Q9Y689 ARL5A ADP-ribosylation factor-like protein 5A Detected   
Q96KC2 ARL5B ADP-ribosylation factor-like protein 5B Detected   
A6NH57 ARL5C Putative ADP-ribosylation factor-like protein 5C   
Q9H0F7 ARL6 ADP-ribosylation factor-like protein 6 Detected   
Q96BM9 ARL8A ADP-ribosylation factor-like protein 8A 4977   
Q9NVJ2 ARL8B ADP-ribosylation factor-like protein 8B 5894   
Q6T311 ARL9 ADP-ribosylation factor-like protein 9   
Q8N8L6 ARL10 ADP-ribosylation factor-like protein 10   
Q969Q4 ARL11 ADP-ribosylation factor-like protein 11   
Q5H913 ARL13A ADP-ribosylation factor-like protein 13A   
Q3SXY8 ARL13B ADP-ribosylation factor-like protein 13B Detected   
Q8N4G2 ARL14 ADP-ribosylation factor-like protein 14   
Q9NXU5 ARL15 ADP-ribosylation factor-like protein 15 1838   
Q0P5N6 ARL16 ADP-ribosylation factor-like protein 16   
Q8IVW1 ARL17A ADP-ribosylation factor-like protein 17   
Rab family 
P62820 RAB1A Ras-related protein Rab-1A 24879   
Q9H0U4 RAB1B Ras-related protein Rab-1B Detected 29632235 
P61019 RAB2A Ras-related protein Rab-2A 11553   
Q8WUD1 RAB2B Ras-related protein Rab-2B 7403   
P20336 RAB3A Ras-related protein Rab-3A 3735   
P20337 RAB3B Ras-related protein Rab-3B   
Q96E17 RAB3C Ras-related protein Rab-3C 4173   
O95716 RAB3D Ras-related protein Rab-3D Detected   
P20338 RAB4A Ras-related protein Rab-4A 6013  10938270 
P61018 RAB4B Ras-related protein Rab-4B 6242   
P20339 RAB5A Ras-related protein Rab-5A 6189  34732055 
P61020 RAB5B Ras-related protein Rab-5B 7661   
P51148 RAB5C Ras-related protein Rab-5C 12138   
P20340 RAB6A Ras-related protein Rab-6A 20898   
Q9NRW1 RAB6B Ras-related protein Rab-6B 27455   
Q9H0N0 RAB6C Ras-related protein Rab-6C   
Q53S08 RAB6D Ras-related protein Rab-6D   
P51149 RAB7A Ras-related protein Rab-7a 18761   
Q96AH8 RAB7B Ras-related protein Rab-7b   
O14966 RAB29 Ras-related protein Rab-7L1 Detected   
P61006 RAB8A Ras-related protein Rab-8A 17938 23140275 
Q92930 RAB8B Ras-related protein Rab-8B 16055   
P51151 RAB9A Ras-related protein Rab-9A 1737   
Q9NP90 RAB9B Ras-related protein Rab-9B 2464   
P61026 RAB10 Ras-related protein Rab-10 23418   
P62491 RAB11A Ras-related protein Rab-11A 27698   
Q15907 RAB11B Ras-related protein Rab-11B 25996   
Q6IQ22 RAB12 Ras-related protein Rab-12 2122   
P51153 RAB13 Ras-related protein Rab-13 11203   
P61106 RAB14 Ras-related protein Rab-14 23180   
P59190 RAB15 Ras-related protein Rab-15 8452   
Q9H0T7 RAB17 Ras-related protein Rab-17   
Q9NP72 RAB18 Ras-related protein Rab-18 4663   
A4D1S5 RAB19 Ras-related protein Rab-19   
Q9NX57 RAB20 Ras-related protein Rab-20 1462   
Q9UL25 RAB21 Ras-related protein Rab-21 5612   
Q9UL26 RAB22A Ras-related protein Rab-22A 1906   
Q9ULC3 RAB23 Ras-related protein Rab-23 Detected   
Q969Q5 RAB24 Ras-related protein Rab-24 885   
P57735 RAB25 Ras-related protein Rab-25   
Q9ULW5 RAB26 Ras-related protein Rab-26   
P51159 RAB27A Ras-related protein Rab-27A 7688  12070017 
O00194 RAB27B Ras-related protein Rab-27B 35939 ++ 17384153 
P51157 RAB28 Ras-related protein Rab-28 Detected   
Q15771 RAB30 Ras-related protein Rab-30 4724  
Q13636 RAB31 Ras-related protein Rab-31 2157  35839075 
Q13637 RAB32 Ras-related protein Rab-32 8860 ++ 31399401 
Q14088 RAB33A Ras-related protein Rab-33A 1964   
Q9H082 RAB33B Ras-related protein Rab-33B 1589   
Q9BZG1 RAB34 Ras-related protein Rab-34 Detected   
Q15286 RAB35 Ras-related protein Rab-35 5614   
O95755 RAB36 Ras-related protein Rab-36   
Q96AX2 RAB37 Ras-related protein Rab-37 9153 ++  
P57729 RAB38 Ras-related protein Rab-38 4450 31399401 
Q14964 RAB39A Ras-related protein Rab-39A Detected   
Q96DA2 RAB39B Ras-related protein Rab-39B Detected   
Q8WXH6 RAB40A Ras-related protein Rab-40A   
Q12829 RAB40B Ras-related protein Rab-40B   
Q96S21 RAB40C Ras-related protein Rab-40C   
P0C0E4 RAB40AL Ras-related protein Rab-40A-like   
Q5JT25 RAB41 Ras-related protein Rab-41   
Q8N4Z0 RAB42 Ras-related protein Rab-42   
Q86YS6 RAB43 Ras-related protein Rab-43 Detected   
Q7Z6P3 RAB44 Ras-related protein Rab-44   
Q5HYI8 RABL3 Rab-like protein 3 1041   
Q3YEC7 RABL6 Rab-like protein 6 1360   
Q8IZ41 RASEF Ras and EF-hand domain-containing protein   
Q9UBK7 RABL2A Rab-like protein 2A   
Q9UNT1 RABL2B Rab-like protein 2B Detected   
Ras family 
Q9NYS0 NKIRAS1 NF-kappa-B inhibitor-interacting Ras-like protein 1   
Q9NYR9 NKIRAS2 NF-kappa-B inhibitor-interacting Ras-like protein 2 Detected   
P11233 RALA Ras-related protein Ral-A 3363  29437579 
P11234 RALB Ras-related protein Ral-B 6791 29437579 
P62834 RAP1A Ras-related protein Rap-1A 124810  30131434 
P61224 RAP1B Ras-related protein Rap-1b 154326 30131434 
P10114 RAP2A Ras-related protein Rap-2a 2921   
P61225 RAP2B Ras-related protein Rap-2b 6248 18582561 
Q9Y3L5 RAP2C Ras-related protein Rap-2c 3054   
Q7Z444 ERAS GTPase ERas   
P01112 HRAS GTPase HRas Detected   
P01116 KRAS GTPase KRas 6581   
Q9NYN1 RASL12 Ras-like protein family member 12   
O14807 MRAS Ras-related protein M-Ras   
P01111 NRAS GTPase NRas 6581   
Q9H628 RERGL Ras-related and estrogen-regulated growth inhibitor-like protein   
Q96A58 RERG Ras-related and estrogen-regulated growth inhibitor   
Q92963 RIT1 GTP-binding protein Rit1 1415   
Q99578 RIT2 GTP-binding protein Rit2   
P62070 RRAS2 Ras-related protein R-Ras2 Detected  29883056 
P10301 RRAS Ras-related protein R-Ras 2648   
Q92737 RASL10A Ras-like protein family member 10A   
Q96S79 RASL10B Ras-like protein family member 10B   
Q6T310 RASL11A Ras-like protein family member 11A   
Q9BPW5 RASL11B Ras-like protein family member 11B   
Rho family 
P60953 CDC42 Cell division control protein 42 homolog 27939  20139097 
P63000 RAC1 Ras-related C3 botulinum toxin substrate 1 32870  16195235
18704480 
P15153 RAC2 Ras-related C3 botulinum toxin substrate 2 27923  16195235 
P60763 RAC3 Ras-related C3 botulinum toxin substrate 3 Detected   
O94844 RHOBTB1 Rho-related BTB domain-containing protein 1   
Q9BYZ6 RHOBTB2 Rho-related BTB domain-containing protein 2   
P61586 RHOA Transforming protein RhoA 31315  22045984 
P62745 RHOB Rho-related GTP-binding protein RhoB Detected   
P08134 RHOC Rho-related GTP-binding protein RhoC 25384   
O00212 RHOD Rho-related GTP-binding protein RhoD   
Q9HBH0 RHOF Rho-related GTP-binding protein RhoF 5257 ++ 23359340 
P84095 RHOG Rho-related GTP-binding protein RhoG 5498  24106270 
Q15669 RHOH Rho-related GTP-binding protein RhoH   
Q9H4E5 RHOJ Rho-related GTP-binding protein RhoJ   
P17081 RHOQ Rho-related GTP-binding protein RhoQ Detected   
Q7L0Q8 RHOU Rho-related GTP-binding protein RhoU   
Q96L33 RHOV Rho-related GTP-binding protein RhoV   
Q92730 RND1 Rho-related GTP-binding protein Rho6   
P52198 RND2 Rho-related GTP-binding protein RhoN   
P61587 RND3 Rho-related GTP-binding protein RhoE   
Galpha family 
P29992 GNA11 Guanine nucleotide-binding protein subunit alpha-11 Detected   
Q03113 GNA12 Guanine nucleotide-binding protein subunit alpha-12 Detected   
Q14344 GNA13 Guanine nucleotide-binding protein subunit alpha-13 6145 ++ 14528298
15326177 
O95837 GNA14 Guanine nucleotide-binding protein subunit alpha-14   
P30679 GNA15 Guanine nucleotide-binding protein subunit alpha-15 Detected   
P63096 GNAI1 Guanine nucleotide-binding protein G(i) subunit alpha-1 10226   
P04899 GNAI2 Guanine nucleotide-binding protein G(i) subunit alpha-2 14795  20852125 
P08754 GNAI3 Guanine nucleotide-binding protein G(i) subunit alpha-3 8712   
P38405 GNAL Guanine nucleotide-binding protein G(olf) subunit alpha   
P09471 GNAO1 Guanine nucleotide-binding protein G(o) subunit alpha Detected   
P50148 GNAQ Guanine nucleotide-binding protein G(q) subunit alpha 14839 ++ 9296496
15326177 
Q5JWF2 GNAS1 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas   
P63092 GNAS2 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short 2874  18812479
32647264 
P11488 GNAT1 Guanine nucleotide-binding protein G(t) subunit alpha-1 Detected   
P19087 GNAT2 Guanine nucleotide-binding protein G(t) subunit alpha-2   
A8MTJ3 GNAT3 Guanine nucleotide-binding protein G(t) subunit alpha-3   
P19086 GNAZ Guanine nucleotide-binding protein G(z) subunit alpha 4436  
UniProtGene NameProtein nameProtein copy number per plateletPlatelet specificityPlatelet studies
Arf family 
P84077 ARF1 ADP-ribosylation factor 1 49771   
P61204 ARF3 ADP-ribosylation factor 3 44255   
P18085 ARF4 ADP-ribosylation factor 4 33268   
P84085 ARF5 ADP-ribosylation factor 5 36244  
P62330 ARF6 ADP-ribosylation factor 6 6370  22916275
26738539 
Q13795 ARFRP1 ADP-ribosylation factor-related protein 1 1495   
P40616 ARL1 ADP-ribosylation factor-like protein 1 2274   
P36404 ARL2 ADP-ribosylation factor-like protein 2 922   
P36405 ARL3 ADP-ribosylation factor-like protein 3 3335   
P40617 ARL4A ADP-ribosylation factor-like protein 4A   
P56559 ARL4C ADP-ribosylation factor-like protein 4C   
P49703 ARL4D ADP-ribosylation factor-like protein 4D   
Q9Y689 ARL5A ADP-ribosylation factor-like protein 5A Detected   
Q96KC2 ARL5B ADP-ribosylation factor-like protein 5B Detected   
A6NH57 ARL5C Putative ADP-ribosylation factor-like protein 5C   
Q9H0F7 ARL6 ADP-ribosylation factor-like protein 6 Detected   
Q96BM9 ARL8A ADP-ribosylation factor-like protein 8A 4977   
Q9NVJ2 ARL8B ADP-ribosylation factor-like protein 8B 5894   
Q6T311 ARL9 ADP-ribosylation factor-like protein 9   
Q8N8L6 ARL10 ADP-ribosylation factor-like protein 10   
Q969Q4 ARL11 ADP-ribosylation factor-like protein 11   
Q5H913 ARL13A ADP-ribosylation factor-like protein 13A   
Q3SXY8 ARL13B ADP-ribosylation factor-like protein 13B Detected   
Q8N4G2 ARL14 ADP-ribosylation factor-like protein 14   
Q9NXU5 ARL15 ADP-ribosylation factor-like protein 15 1838   
Q0P5N6 ARL16 ADP-ribosylation factor-like protein 16   
Q8IVW1 ARL17A ADP-ribosylation factor-like protein 17   
Rab family 
P62820 RAB1A Ras-related protein Rab-1A 24879   
Q9H0U4 RAB1B Ras-related protein Rab-1B Detected 29632235 
P61019 RAB2A Ras-related protein Rab-2A 11553   
Q8WUD1 RAB2B Ras-related protein Rab-2B 7403   
P20336 RAB3A Ras-related protein Rab-3A 3735   
P20337 RAB3B Ras-related protein Rab-3B   
Q96E17 RAB3C Ras-related protein Rab-3C 4173   
O95716 RAB3D Ras-related protein Rab-3D Detected   
P20338 RAB4A Ras-related protein Rab-4A 6013  10938270 
P61018 RAB4B Ras-related protein Rab-4B 6242   
P20339 RAB5A Ras-related protein Rab-5A 6189  34732055 
P61020 RAB5B Ras-related protein Rab-5B 7661   
P51148 RAB5C Ras-related protein Rab-5C 12138   
P20340 RAB6A Ras-related protein Rab-6A 20898   
Q9NRW1 RAB6B Ras-related protein Rab-6B 27455   
Q9H0N0 RAB6C Ras-related protein Rab-6C   
Q53S08 RAB6D Ras-related protein Rab-6D   
P51149 RAB7A Ras-related protein Rab-7a 18761   
Q96AH8 RAB7B Ras-related protein Rab-7b   
O14966 RAB29 Ras-related protein Rab-7L1 Detected   
P61006 RAB8A Ras-related protein Rab-8A 17938 23140275 
Q92930 RAB8B Ras-related protein Rab-8B 16055   
P51151 RAB9A Ras-related protein Rab-9A 1737   
Q9NP90 RAB9B Ras-related protein Rab-9B 2464   
P61026 RAB10 Ras-related protein Rab-10 23418   
P62491 RAB11A Ras-related protein Rab-11A 27698   
Q15907 RAB11B Ras-related protein Rab-11B 25996   
Q6IQ22 RAB12 Ras-related protein Rab-12 2122   
P51153 RAB13 Ras-related protein Rab-13 11203   
P61106 RAB14 Ras-related protein Rab-14 23180   
P59190 RAB15 Ras-related protein Rab-15 8452   
Q9H0T7 RAB17 Ras-related protein Rab-17   
Q9NP72 RAB18 Ras-related protein Rab-18 4663   
A4D1S5 RAB19 Ras-related protein Rab-19   
Q9NX57 RAB20 Ras-related protein Rab-20 1462   
Q9UL25 RAB21 Ras-related protein Rab-21 5612   
Q9UL26 RAB22A Ras-related protein Rab-22A 1906   
Q9ULC3 RAB23 Ras-related protein Rab-23 Detected   
Q969Q5 RAB24 Ras-related protein Rab-24 885   
P57735 RAB25 Ras-related protein Rab-25   
Q9ULW5 RAB26 Ras-related protein Rab-26   
P51159 RAB27A Ras-related protein Rab-27A 7688  12070017 
O00194 RAB27B Ras-related protein Rab-27B 35939 ++ 17384153 
P51157 RAB28 Ras-related protein Rab-28 Detected   
Q15771 RAB30 Ras-related protein Rab-30 4724  
Q13636 RAB31 Ras-related protein Rab-31 2157  35839075 
Q13637 RAB32 Ras-related protein Rab-32 8860 ++ 31399401 
Q14088 RAB33A Ras-related protein Rab-33A 1964   
Q9H082 RAB33B Ras-related protein Rab-33B 1589   
Q9BZG1 RAB34 Ras-related protein Rab-34 Detected   
Q15286 RAB35 Ras-related protein Rab-35 5614   
O95755 RAB36 Ras-related protein Rab-36   
Q96AX2 RAB37 Ras-related protein Rab-37 9153 ++  
P57729 RAB38 Ras-related protein Rab-38 4450 31399401 
Q14964 RAB39A Ras-related protein Rab-39A Detected   
Q96DA2 RAB39B Ras-related protein Rab-39B Detected   
Q8WXH6 RAB40A Ras-related protein Rab-40A   
Q12829 RAB40B Ras-related protein Rab-40B   
Q96S21 RAB40C Ras-related protein Rab-40C   
P0C0E4 RAB40AL Ras-related protein Rab-40A-like   
Q5JT25 RAB41 Ras-related protein Rab-41   
Q8N4Z0 RAB42 Ras-related protein Rab-42   
Q86YS6 RAB43 Ras-related protein Rab-43 Detected   
Q7Z6P3 RAB44 Ras-related protein Rab-44   
Q5HYI8 RABL3 Rab-like protein 3 1041   
Q3YEC7 RABL6 Rab-like protein 6 1360   
Q8IZ41 RASEF Ras and EF-hand domain-containing protein   
Q9UBK7 RABL2A Rab-like protein 2A   
Q9UNT1 RABL2B Rab-like protein 2B Detected   
Ras family 
Q9NYS0 NKIRAS1 NF-kappa-B inhibitor-interacting Ras-like protein 1   
Q9NYR9 NKIRAS2 NF-kappa-B inhibitor-interacting Ras-like protein 2 Detected   
P11233 RALA Ras-related protein Ral-A 3363  29437579 
P11234 RALB Ras-related protein Ral-B 6791 29437579 
P62834 RAP1A Ras-related protein Rap-1A 124810  30131434 
P61224 RAP1B Ras-related protein Rap-1b 154326 30131434 
P10114 RAP2A Ras-related protein Rap-2a 2921   
P61225 RAP2B Ras-related protein Rap-2b 6248 18582561 
Q9Y3L5 RAP2C Ras-related protein Rap-2c 3054   
Q7Z444 ERAS GTPase ERas   
P01112 HRAS GTPase HRas Detected   
P01116 KRAS GTPase KRas 6581   
Q9NYN1 RASL12 Ras-like protein family member 12   
O14807 MRAS Ras-related protein M-Ras   
P01111 NRAS GTPase NRas 6581   
Q9H628 RERGL Ras-related and estrogen-regulated growth inhibitor-like protein   
Q96A58 RERG Ras-related and estrogen-regulated growth inhibitor   
Q92963 RIT1 GTP-binding protein Rit1 1415   
Q99578 RIT2 GTP-binding protein Rit2   
P62070 RRAS2 Ras-related protein R-Ras2 Detected  29883056 
P10301 RRAS Ras-related protein R-Ras 2648   
Q92737 RASL10A Ras-like protein family member 10A   
Q96S79 RASL10B Ras-like protein family member 10B   
Q6T310 RASL11A Ras-like protein family member 11A   
Q9BPW5 RASL11B Ras-like protein family member 11B   
Rho family 
P60953 CDC42 Cell division control protein 42 homolog 27939  20139097 
P63000 RAC1 Ras-related C3 botulinum toxin substrate 1 32870  16195235
18704480 
P15153 RAC2 Ras-related C3 botulinum toxin substrate 2 27923  16195235 
P60763 RAC3 Ras-related C3 botulinum toxin substrate 3 Detected   
O94844 RHOBTB1 Rho-related BTB domain-containing protein 1   
Q9BYZ6 RHOBTB2 Rho-related BTB domain-containing protein 2   
P61586 RHOA Transforming protein RhoA 31315  22045984 
P62745 RHOB Rho-related GTP-binding protein RhoB Detected   
P08134 RHOC Rho-related GTP-binding protein RhoC 25384   
O00212 RHOD Rho-related GTP-binding protein RhoD   
Q9HBH0 RHOF Rho-related GTP-binding protein RhoF 5257 ++ 23359340 
P84095 RHOG Rho-related GTP-binding protein RhoG 5498  24106270 
Q15669 RHOH Rho-related GTP-binding protein RhoH   
Q9H4E5 RHOJ Rho-related GTP-binding protein RhoJ   
P17081 RHOQ Rho-related GTP-binding protein RhoQ Detected   
Q7L0Q8 RHOU Rho-related GTP-binding protein RhoU   
Q96L33 RHOV Rho-related GTP-binding protein RhoV   
Q92730 RND1 Rho-related GTP-binding protein Rho6   
P52198 RND2 Rho-related GTP-binding protein RhoN   
P61587 RND3 Rho-related GTP-binding protein RhoE   
Galpha family 
P29992 GNA11 Guanine nucleotide-binding protein subunit alpha-11 Detected   
Q03113 GNA12 Guanine nucleotide-binding protein subunit alpha-12 Detected   
Q14344 GNA13 Guanine nucleotide-binding protein subunit alpha-13 6145 ++ 14528298
15326177 
O95837 GNA14 Guanine nucleotide-binding protein subunit alpha-14   
P30679 GNA15 Guanine nucleotide-binding protein subunit alpha-15 Detected   
P63096 GNAI1 Guanine nucleotide-binding protein G(i) subunit alpha-1 10226   
P04899 GNAI2 Guanine nucleotide-binding protein G(i) subunit alpha-2 14795  20852125 
P08754 GNAI3 Guanine nucleotide-binding protein G(i) subunit alpha-3 8712   
P38405 GNAL Guanine nucleotide-binding protein G(olf) subunit alpha   
P09471 GNAO1 Guanine nucleotide-binding protein G(o) subunit alpha Detected   
P50148 GNAQ Guanine nucleotide-binding protein G(q) subunit alpha 14839 ++ 9296496
15326177 
Q5JWF2 GNAS1 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas   
P63092 GNAS2 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short 2874  18812479
32647264 
P11488 GNAT1 Guanine nucleotide-binding protein G(t) subunit alpha-1 Detected   
P19087 GNAT2 Guanine nucleotide-binding protein G(t) subunit alpha-2   
A8MTJ3 GNAT3 Guanine nucleotide-binding protein G(t) subunit alpha-3   
P19086 GNAZ Guanine nucleotide-binding protein G(z) subunit alpha 4436  

G protein family members were obtained from UniProt and compared with platelet proteome data. Shown are all proteins encoded by the human genome. Protein copy numbers per platelet are given as far as available. ‘Detected’ indicates expressed proteins where a copy number has not yet been determined. All found proteins have also been confirmed at the transcriptome level of megakaryocytes or platelets. ‘-’ indicates that proteins could not be detected in platelets. Platelet specificity was determined as high expression in platelets compared to other human tissues according to https://www.proteomicsdb.org and http://www.humanproteomemap.org (‘+’ indicates within the top 5 highly expressing tissues, ‘++’ indicates platelets as highest expressing tissue in both databases). References for platelet studies on G proteins are given as PubMed ID numbers (PMID).

Table 2
Overview of GAPs and their expression in human platelets
UniProtGeneProtein nameProtein copy number per plateletPlatelet specificityPhospho sitesG-protein specificity (cell-based assays)Functions and regulation (platelet studies)
ArfGAP, PS50115 
Q15027 ACAP1 Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 1150  Arf6 (11062263)  
Q15057 ACAP2 Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 2 1057  13 Arf6 (11062263)  
Q96P50 ACAP3 Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3 Detected    
O75689 ADAP1 Arf-GAP with dual PH domain-containing protein 1     
Q9NPF8 ADAP2 Arf-GAP with dual PH domain-containing protein 2     
Q9UPQ3 AGAP1 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 1 Detected    
Q99490 AGAP2 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 1199  15   
Q96P47 AGAP3 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 3 Detected    
Q96P64 AGAP4 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 4     
A6NIR3 AGAP5 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 5     
Q5VW22 AGAP6 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 6     
Q5VUJ5 AGAP7 Putative Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 7     
Q5VTM2 AGAP9 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 9     
P52594 AGFG1 Arf-GAP domain and FG repeat-containing protein 1 1825  10   
O95081 AGFG2 Arf-GAP domain and FG repeat-containing protein 2 Detected    
Q96P48 ARAP1 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 3061  17   
Q8WZ64 ARAP2 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 2     
Q8WWN8 ARAP3 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3     
Q8N6T3 ARFGAP1 ADP-ribosylation factor GTPase-activating protein 1 Detected  17 Arf1 (19015319, 36513395)  
Q8N6H7 ARFGAP2 ADP-ribosylation factor GTPase-activating protein 2 899  13 Arf1 (19015319, 36513395)  
Q9NP61 ARFGAP3 ADP-ribosylation factor GTPase-activating protein 3 Detected  21 Arf1, Arl1 (19015319, 33715220)  
Q9ULH1 ASAP1 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 3588 18  Binds Crkl and to focal adhesions (12522101) 
O43150 ASAP2 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 4132 10   
Q8TDY4 ASAP3 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3 Detected    
Q9Y2X7 GIT1 ARF GTPase-activating protein GIT1 3149  30 Arf1, Arf6 (28981399) Binds RhoGEF6 and RhoGEF7, interacts with integrin αIIbβ3 (26507661, 18211801) 
Q14161 GIT2 ARF GTPase-activating protein GIT2 1071  28   
Q8IYB5 SMAP1 Stromal membrane-associated protein 1 890    
Q8WU79 SMAP2 Stromal membrane-associated protein 2 1717    
TBC_RabGAP, PS50086 
Q96CN4 EVI5L EVI5-like protein 648    
O60447 EVI5 Ecotropic viral integration site 5 protein homolog     
Q5TC63 GRTP1 Growth hormone-regulated TBC protein 1 Detected    
Q5R372 RABGAP1L Rab GTPase-activating protein 1-like 615    
Q9Y3P9 RABGAP1 Rab GTPase-activating protein 1 1619    
Q2NKQ1 SGSM1 Small G protein signalling modulator 1     
O43147 SGSM2 Small G protein signalling modulator 2     
Q96HU1 SGSM3 Small G protein signalling modulator 3     
Q86TI0 TBC1D1 TBC1 domain family member 1 Detected  24   
Q9BYX2 TBC1D2 TBC1 domain family member 2A     
Q9UPU7 TBC1D2B TBC1 domain family member 2B Detected  10   
Q8IZP1 TBC1D3 TBC1 domain family member 3     
A6NDS4 TBC1D3B TBC1 domain family member 3B     
Q6IPX1 TBC1D3C TBC1 domain family member 3C     
A0A087WVF3 TBC1D3D TBC1 domain family member 3D     
A0A087X179 TBC1D3E TBC1 domain family member 3E     
A6NER0 TBC1D3F TBC1 domain family member 3F     
Q6DHY5 TBC1D3G TBC1 domain family member 3G     
P0C7X1 TBC1D3H TBC1 domain family member 3H     
A0A087WXS9 TBC1D3I TBC1 domain family member 3I     
A0A087X1G2 TBC1D3K TBC1 domain family member 3K     
B9A6J9 TBC1D3L TBC1 domain family member 3L     
O60343 TBC1D4 TBC1 domain family member 4 Detected  42 Rab10 (33175605)  
Q92609 TBC1D5 TBC1 domain family member 5 1046  27 Rab7B (30111580)  
Q9P0N9 TBC1D7 TBC1 domain family member 7 Detected    
O95759 TBC1D8 TBC1 domain family member 8     
Q0IIM8 TBC1D8B TBC1 domain family member 8B Detected    
Q6ZT07 TBC1D9 TBC1 domain family member 9 Detected    
Q66K14 TBC1D9B TBC1 domain family member 9B 1012  18   
Q9BXI6 TBC1D10A TBC1 domain family member 10A Detected  14 Rab35 (28566286)  
Q4KMP7 TBC1D10B TBC1 domain family member 10B 827  22 Rab27b (23671284)  
Q8IV04 TBC1D10C Carabin Detected    
O60347 TBC1D12 TBC1 domain family member 12     
Q9NVG8 TBC1D13 TBC1 domain family member 13 2656 Rab35 (22762500)  
Q9P2M4 TBC1D14 TBC1 domain family member 14 Detected    
Q8TC07 TBC1D15 TBC1 domain family member 15 2534  14   
Q8TBP0 TBC1D16 TBC1 domain family member 16     
Q9HA65 TBC1D17 TBC1 domain family member 17 Detected  Rab8 (22854040)  
Q8N5T2 TBC1D19 TBC1 domain family member 19     
Q96BZ9 TBC1D20 TBC1 domain family member 20 1069  Rab1A (22854043)  
Q8IYX1 TBC1D21 TBC1 domain family member 21     
Q8WUA7 TBC1D22A TBC1 domain family member 22A 1138    
Q9NU19 TBC1D22B TBC1 domain family member 22B Detected    
Q9NUY8 TBC1D23 TBC1 domain family member 23 1187    
Q3MII6 TBC1D25 TBC1 domain family member 25 Detected    
Q86UD7 TBC1D26 TBC1 domain family member 26     
Q9UFV1 TBC1D29P Putative TBC1 domain family member 29     
Q9Y2I9 TBC1D30 TBC1 domain family member 30     
Q96DN5 TBC1D31 TBC1 domain family member 31     
Q8TEA7 TBCK TBC domain-containing protein kinase-like protein Detected    
P35125 USP6 Ubiquitin carboxyl-terminal hydrolase 6     
Q92738 USP6NL USP6 N-terminal-like protein Detected  26   
RasGAP, PS50018 
Q5VWQ8 DAB2IP Disabled homolog 2-interacting protein     
Q14C86 GAPVD1 GTPase-activating protein and VPS9 domain-containing protein 1 1283  34   
P46940 IQGAP1 Ras GTPase-activating-like protein IQGAP1 1040  17 No GAP activity, Cdc42/Rac1 effector (34830479) Inhibits alpha granule release (15026422) 
Q13576 IQGAP2 Ras GTPase-activating-like protein IQGAP2 8102 19 No GAP activity, Cdc42/Rac1 effector (34830479) Interacts with arp3 and actin (12515716) 
Q86VI3 IQGAP3 Ras GTPase-activating-like protein IQGAP3     
P21359 NF1 Neurofibromin 628  20 HRas (9668168)  
O95294 RASAL1 RasGAP-activating-like protein 1     
Q9UJF2 RASAL2 Ras GTPase-activating protein nGAP Detected  26   
Q86YV0 RASAL3 RAS protein activator like-3 573  25   
C9J798 RASA4B Ras GTPase-activating protein 4B     
P20936 RASA1 Ras GTPase-activating protein 1 2921   
Q15283 RASA2 Ras GTPase-activating protein 2 Detected    
Q14644 RASA3 Ras GTPase-activating protein 3 8293 ++ 12 Rap1, H-Ras (16431904) Reduces Rap1-GTP, inhibits platelet adhesion and aggregation, binds PIP3, linked to P2Y12 receptor via PI3K (24967784, 25705885, 27903653) 
O43374 RASA4 Ras GTPase-activating protein 4     
Q96PV0 SYNGAP1 Ras/Rap GTPase-activating protein SynGA     
RapGAP, PS50085 
Q5VVW2 GARNL3 GTPase-activating Rap/Ran-GAP domain-like protein 3     
Q6GYQ0 RALGAPA1 Ral GTPase-activating protein subunit alpha-1 669  28   
Q2PPJ7 RALGAPA2 Ral GTPase-activating protein subunit alpha-2 Detected  12   
Q86X10 RALGAPB Ral GTPase-activating protein subunit beta 884  RalA (29915037)  
P47736 RAP1GAP Rap1 GTPase-activating protein 1     
Q684P5 RAP1GAP2 Rap1 GTPase-activating protein 2 2327 ++ 22 Rap1 (15632203) Inhibited by S9 phosphorylation, activated by PKA/PKG mediated S7 phosphorylation, binds 14-3-3, binds Slp1 and stimulates dense granule release (15632203, 18039662, 19528539) 
O43166 SIPA1L1 Signal-induced proliferation-associated 1-like protein 1 Detected  65   
Q9P2F8 SIPA1L2 Signal-induced proliferation-associated 1-like protein 2     
O60292 SIPA1L3 Signal-induced proliferation-associated 1-like protein 3     
Q96FS4 SIPA1 Signal-induced proliferation-associated protein 1 Detected  12   
P49815 TSC2 Tuberin 593  35   
RhoGAP, PS50238 
Q9Y3L3 SH3BP1 SH3 domain-binding protein 1 595  14   
Q12979 ABR Active breakpoint cluster region-related protein Detected  Rac1 (32203420)  
Q96P48 ARAP1 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 3061  17 Rac1, Cdc42 (32203420)  
Q8WZ64 ARAP2 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 2     
Q8WWN8 ARAP3 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3     
P11274 BCR Breakpoint cluster region protein 793  47 Rac1 (32203420)  
Q6ZT62 BARGIN Bargin     
P15882 CHN1 N-chimaerin     
P52757 CHN2 Beta-chimaerin     
Q8WUY9 DEPDC1B DEP domain-containing protein 1B     
O94988 FAM13A Protein FAM13A     
Q9NYF5 FAM13B Protein FAM13B     
Q9P107 GMIP GEM-interacting protein 1228  17 RhoA, Rac1, Cdc42 (32203420)  
P32019 INPP5B Type II inositol 1,4,5-trisphosphate 5-phosphatase 1629    
B2RTY4 MYO9A Unconventional myosin-IXa Detected  14   
Q13459 MYO9B Unconventional myosin-IXb 1428  40 RhoA (33268376) Activated by PKA/PKG mediated S1354 phosphorylation (32692911) 
Q01968 OCRL Inositol polyphosphate 5-phosphatase OCRL 850  RhoA (33528045) Reduces RhoA-GTP, augments Rac1-GTP and myosin light chain phosphorylation, inhibits filopodia, stimulates spreading, clot retraction and thrombus formation (33528045, 36176266) 
O60890 OPHN1 Oligophrenin-1 1527  RhoA, Rac1, Cdc42 (25556321) Reduces RhoA-GTP, Rac1-GTP, and Cdc42-GTP, inhibits adhesion and granule release (25556321) 
P27986 PIK3R1 Phosphatidylinositol 3-kinase regulatory subunit alpha 1904  17   
O00459 PIK3R2 Phosphatidylinositol 3-kinase regulatory subunit beta Detected  12   
Q15311 RALBP1 RalA-binding protein 1 785  14 Rac1 (32203420)  
Q9H0H5 RACGAP1 Rac GTPase-activating protein 1     
Q07960 ARHGAP1 Rho GTPase-activating protein 1 9290 RhoA, Cdc42 (32203420)  
P98171 ARHGAP4 Rho GTPase-activating protein 4 1400  Rac1 (32203420)  
Q13017 ARHGAP5 Rho GTPase-activating protein 5 Detected  16 RhoA (32203420)  
O43182 ARHGAP6 Rho GTPase-activating protein 6 4151 ++ RhoA (32203420) Binds COPD and COPI vesicles, might regulate protein transport (37409526) 
Q96QB1 DLC1 Rho GTPase-activating protein 7     
P85298 ARHGAP8 Rho GTPase-activating protein 8     
Q9BRR9 ARHGAP9 Rho GTPase-activating protein 9 Detected  Rac1 (32203420)  
A1A4S6 ARHGAP10 Rho GTPase-activating protein 10 1114  RhoA (32203420)  
Q6P4F7 ARHGAP11A Rho GTPase-activating protein 11A     
Q3KRB8 ARHGAP11B Inactive Rho GTPase-activating protein 11B     
Q8IWW6 ARHGAP12 Rho GTPase-activating protein 12 Detected  23 Rac1 (32203420)  
Q53QZ3 ARHGAP15 Rho GTPase-activating protein 15 833  11 Rac1 (32203420, 32839212)  
Q68EM7 ARHGAP17 Rho GTPase-activating protein 17 1603  21 Rac1, RhoA (22975681) Regulated by tyrosine phosphorylation (22975681), activated by PKA/PKG mediated S702 phosphorylation (26507661) 
Q8N392 ARHGAP18 Rho GTPase-activating protein 18 7100 ++ RhoC (25425145), RhoA (32016689)  
Q14CB8 ARHGAP19 Rho GTPase-activating protein 19     
Q9P2F6 ARHGAP20 Rho GTPase-activating protein 20     
Q5T5U3 ARHGAP21 Rho GTPase-activating protein 21 886  46 RhoA (32203420, 33727037), Cdc42 (33727037) Inhibits alpha granule release and aggregation (33727037) 
        
Q7Z5H3 ARHGAP22 Rho GTPase-activating protein 22     
Q9P227 ARHGAP23 Rho GTPase-activating protein 23     
Q8N264 ARHGAP24 Rho GTPase-activating protein 24     
P42331 ARHGAP25 Rho GTPase-activating protein 25 1054  11 Rac1 (36190314)  
Q9UNA1 ARHGAP26 Rho GTPase-activating protein 26 Detected  RhoA (32203420)  
Q6ZUM4 ARHGAP27 Rho GTPase-activating protein 27 Detected  11 Rac1 (32203420)  
Q9P2N2 ARHGAP28 Rho GTPase-activating protein 28     
Q52LW3 ARHGAP29 Rho GTPase-activating protein 29     
Q7Z6I6 ARHGAP30 Rho GTPase-activating protein 30 Detected  15 RhoA, Rac1, Cdc42 (32203420)  
Q2M1Z3 ARHGAP31 Rho GTPase-activating protein 31     
A7KAX9 ARHGAP32 Rho GTPase-activating protein 32 Detected  40   
O14559 ARHGAP33 Rho GTPase-activating protein 33     
Q9NRY4 ARHGAP35 Rho GTPase-activating protein 35 783  23 RhoA, Rac1 (32203420)  
Q6ZRI8 ARHGAP36 Rho GTPase-activating protein 36     
Q9C0H5 ARHGAP39 Rho GTPase-activating protein 39     
Q5TG30 ARHGAP40 Rho GTPase-activating protein 40     
A6NI28 ARHGAP42 Rho GTPase-activating protein 42     
Q17R89 ARHGAP44 Rho GTPase-activating protein 44     
Q92619 ARHGAP45 Rho GTPase-activating protein 45 (HMHA1) 3891  25   
Q7Z6B7 SRGAP1 SLIT-ROBO Rho GTPase-activating protein 1 Detected  Rac1 (32203420)  
O75044 SRGAP2 SLIT-ROBO Rho GTPase-activating protein 2 Detected  23 Rac1, Cdc42 (32203420, 31880824)  
O43295 SRGAP3 SLIT-ROBO Rho GTPase-activating protein 3     
Q9Y3M8 STARD13 StAR-related lipid transfer protein 13 Detected  RhoA (32203420)  
Q92502 STARD8 StAR-related lipid transfer protein 8 Detected  RhoA, Cdc42 (32203420, 25673874)  
Q6ZW31 SYDE1 Rho GTPase-activating protein SYDE1     
Q5VT97 SYDE2 Rho GTPase-activating protein SYDE2     
Q8N103 TAGAP T-cell activation Rho GTPase-activating protein     
RGS, PS50132 
Q08116 RGS1 Regulator of G-protein signalling 1     
P41220 RGS2 Regulator of G-protein signalling 2     
P49796 RGS3 Regulator of G-protein signalling 3 Detected  Gαi, Gαo (33007266)  
P49798 RGS4 Regulator of G-protein signalling 4     
O15539 RGS5 Regulator of G-protein signalling 5     
P49758 RGS6 Regulator of G-protein signalling 6 2434 Gαo (32513692, 33007266)  
P49802 RGS7 Regulator of G-protein signalling 7     
P57771 RGS8 Regulator of G-protein signalling 8     
O75916 RGS9 Regulator of G-protein signalling 9     
O43665 RGS10 Regulator of G-protein signalling 10 4608 Gαq, Gαi, Gαo (30150297, 33007266) Inhibits Gαq and Gαi signalling, aggregation, granule release, regulated by spinophilin and 14-3-3 (27829061, 30150297) 
O94810 RGS11 Regulator of G-protein signalling 11     
O14924 RGS12 Regulator of G-protein signalling 12     
O14921 RGS13 Regulator of G-protein signalling 13     
O43566 RGS14 Regulator of G-protein signalling 14 Detected  12 Gαi1 (30093406, 33007266)  
O15492 RGS16 Regulator of G-protein signalling 16     
Q9UGC6 RGS17 Regulator of G-protein signalling 17     
Q9NS28 RGS18 Regulator of G-protein signalling 18 4463 ++ Gαi, Gαq (33007266) Inhibits Gαi and Gαq signalling, regulated by spinophilin and 14-3-3, inhibited by S49/S218 phosphorylation, activated by PKA/PKG mediated S216 phosphorylation (22210881, 26407691, 22234696, 24244663) 
P49795 RGS19 Regulator of G-protein signalling 19 1086  Gαz (33007266)  
O76081 RGS20 Regulator of G-protein signalling 20     
Q2M5E4 RGS21 Regulator of G-protein signalling 21     
Q8NE09 RGS22 Regulator of G-protein signalling 22     
Q15835 GRK1 Rhodopsin kinase GRK1     
P25098 GRK2 Beta-adrenergic receptor kinase 1 1409    
P35626 GRK3 Beta-adrenergic receptor kinase 2 Detected    
P32298 GRK4 G protein-coupled receptor kinase 4     
P34947 GRK5 G protein-coupled receptor kinase 5 1557  Inhibits PAR1 receptor signalling (34581777)  
P43250 GRK6 G protein-coupled receptor kinase 6 2005  Inhibits PAR1 and P2Y12 receptor signalling (31899801)  
Q8WTQ7 GRK7 Rhodopsin kinase GRK7     
O15085 ARHGEF11 Rho guanine nucleotide exchange factor 11     
O15169 AXIN1 Axin-1 Detected    
Q9Y2T1 AXIN2 Axin-2     
Q9Y5W8 SNX13 Sorting nexin-13 Detected    
Q9Y5W7 SNX14 Sorting nexin-14 Detected    
Q9H3E2 SNX25 Sorting nexin-25     
O43572 AKAP10 A-kinase anchor protein 10, mitochondrial 819  Rab4, Rab11 (19797056)  
UniProtGeneProtein nameProtein copy number per plateletPlatelet specificityPhospho sitesG-protein specificity (cell-based assays)Functions and regulation (platelet studies)
ArfGAP, PS50115 
Q15027 ACAP1 Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 1 1150  Arf6 (11062263)  
Q15057 ACAP2 Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 2 1057  13 Arf6 (11062263)  
Q96P50 ACAP3 Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3 Detected    
O75689 ADAP1 Arf-GAP with dual PH domain-containing protein 1     
Q9NPF8 ADAP2 Arf-GAP with dual PH domain-containing protein 2     
Q9UPQ3 AGAP1 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 1 Detected    
Q99490 AGAP2 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2 1199  15   
Q96P47 AGAP3 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 3 Detected    
Q96P64 AGAP4 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 4     
A6NIR3 AGAP5 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 5     
Q5VW22 AGAP6 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 6     
Q5VUJ5 AGAP7 Putative Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 7     
Q5VTM2 AGAP9 Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 9     
P52594 AGFG1 Arf-GAP domain and FG repeat-containing protein 1 1825  10   
O95081 AGFG2 Arf-GAP domain and FG repeat-containing protein 2 Detected    
Q96P48 ARAP1 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 3061  17   
Q8WZ64 ARAP2 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 2     
Q8WWN8 ARAP3 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3     
Q8N6T3 ARFGAP1 ADP-ribosylation factor GTPase-activating protein 1 Detected  17 Arf1 (19015319, 36513395)  
Q8N6H7 ARFGAP2 ADP-ribosylation factor GTPase-activating protein 2 899  13 Arf1 (19015319, 36513395)  
Q9NP61 ARFGAP3 ADP-ribosylation factor GTPase-activating protein 3 Detected  21 Arf1, Arl1 (19015319, 33715220)  
Q9ULH1 ASAP1 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 3588 18  Binds Crkl and to focal adhesions (12522101) 
O43150 ASAP2 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 2 4132 10   
Q8TDY4 ASAP3 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 3 Detected    
Q9Y2X7 GIT1 ARF GTPase-activating protein GIT1 3149  30 Arf1, Arf6 (28981399) Binds RhoGEF6 and RhoGEF7, interacts with integrin αIIbβ3 (26507661, 18211801) 
Q14161 GIT2 ARF GTPase-activating protein GIT2 1071  28   
Q8IYB5 SMAP1 Stromal membrane-associated protein 1 890    
Q8WU79 SMAP2 Stromal membrane-associated protein 2 1717    
TBC_RabGAP, PS50086 
Q96CN4 EVI5L EVI5-like protein 648    
O60447 EVI5 Ecotropic viral integration site 5 protein homolog     
Q5TC63 GRTP1 Growth hormone-regulated TBC protein 1 Detected    
Q5R372 RABGAP1L Rab GTPase-activating protein 1-like 615    
Q9Y3P9 RABGAP1 Rab GTPase-activating protein 1 1619    
Q2NKQ1 SGSM1 Small G protein signalling modulator 1     
O43147 SGSM2 Small G protein signalling modulator 2     
Q96HU1 SGSM3 Small G protein signalling modulator 3     
Q86TI0 TBC1D1 TBC1 domain family member 1 Detected  24   
Q9BYX2 TBC1D2 TBC1 domain family member 2A     
Q9UPU7 TBC1D2B TBC1 domain family member 2B Detected  10   
Q8IZP1 TBC1D3 TBC1 domain family member 3     
A6NDS4 TBC1D3B TBC1 domain family member 3B     
Q6IPX1 TBC1D3C TBC1 domain family member 3C     
A0A087WVF3 TBC1D3D TBC1 domain family member 3D     
A0A087X179 TBC1D3E TBC1 domain family member 3E     
A6NER0 TBC1D3F TBC1 domain family member 3F     
Q6DHY5 TBC1D3G TBC1 domain family member 3G     
P0C7X1 TBC1D3H TBC1 domain family member 3H     
A0A087WXS9 TBC1D3I TBC1 domain family member 3I     
A0A087X1G2 TBC1D3K TBC1 domain family member 3K     
B9A6J9 TBC1D3L TBC1 domain family member 3L     
O60343 TBC1D4 TBC1 domain family member 4 Detected  42 Rab10 (33175605)  
Q92609 TBC1D5 TBC1 domain family member 5 1046  27 Rab7B (30111580)  
Q9P0N9 TBC1D7 TBC1 domain family member 7 Detected    
O95759 TBC1D8 TBC1 domain family member 8     
Q0IIM8 TBC1D8B TBC1 domain family member 8B Detected    
Q6ZT07 TBC1D9 TBC1 domain family member 9 Detected    
Q66K14 TBC1D9B TBC1 domain family member 9B 1012  18   
Q9BXI6 TBC1D10A TBC1 domain family member 10A Detected  14 Rab35 (28566286)  
Q4KMP7 TBC1D10B TBC1 domain family member 10B 827  22 Rab27b (23671284)  
Q8IV04 TBC1D10C Carabin Detected    
O60347 TBC1D12 TBC1 domain family member 12     
Q9NVG8 TBC1D13 TBC1 domain family member 13 2656 Rab35 (22762500)  
Q9P2M4 TBC1D14 TBC1 domain family member 14 Detected    
Q8TC07 TBC1D15 TBC1 domain family member 15 2534  14   
Q8TBP0 TBC1D16 TBC1 domain family member 16     
Q9HA65 TBC1D17 TBC1 domain family member 17 Detected  Rab8 (22854040)  
Q8N5T2 TBC1D19 TBC1 domain family member 19     
Q96BZ9 TBC1D20 TBC1 domain family member 20 1069  Rab1A (22854043)  
Q8IYX1 TBC1D21 TBC1 domain family member 21     
Q8WUA7 TBC1D22A TBC1 domain family member 22A 1138    
Q9NU19 TBC1D22B TBC1 domain family member 22B Detected    
Q9NUY8 TBC1D23 TBC1 domain family member 23 1187    
Q3MII6 TBC1D25 TBC1 domain family member 25 Detected    
Q86UD7 TBC1D26 TBC1 domain family member 26     
Q9UFV1 TBC1D29P Putative TBC1 domain family member 29     
Q9Y2I9 TBC1D30 TBC1 domain family member 30     
Q96DN5 TBC1D31 TBC1 domain family member 31     
Q8TEA7 TBCK TBC domain-containing protein kinase-like protein Detected    
P35125 USP6 Ubiquitin carboxyl-terminal hydrolase 6     
Q92738 USP6NL USP6 N-terminal-like protein Detected  26   
RasGAP, PS50018 
Q5VWQ8 DAB2IP Disabled homolog 2-interacting protein     
Q14C86 GAPVD1 GTPase-activating protein and VPS9 domain-containing protein 1 1283  34   
P46940 IQGAP1 Ras GTPase-activating-like protein IQGAP1 1040  17 No GAP activity, Cdc42/Rac1 effector (34830479) Inhibits alpha granule release (15026422) 
Q13576 IQGAP2 Ras GTPase-activating-like protein IQGAP2 8102 19 No GAP activity, Cdc42/Rac1 effector (34830479) Interacts with arp3 and actin (12515716) 
Q86VI3 IQGAP3 Ras GTPase-activating-like protein IQGAP3     
P21359 NF1 Neurofibromin 628  20 HRas (9668168)  
O95294 RASAL1 RasGAP-activating-like protein 1     
Q9UJF2 RASAL2 Ras GTPase-activating protein nGAP Detected  26   
Q86YV0 RASAL3 RAS protein activator like-3 573  25   
C9J798 RASA4B Ras GTPase-activating protein 4B     
P20936 RASA1 Ras GTPase-activating protein 1 2921   
Q15283 RASA2 Ras GTPase-activating protein 2 Detected    
Q14644 RASA3 Ras GTPase-activating protein 3 8293 ++ 12 Rap1, H-Ras (16431904) Reduces Rap1-GTP, inhibits platelet adhesion and aggregation, binds PIP3, linked to P2Y12 receptor via PI3K (24967784, 25705885, 27903653) 
O43374 RASA4 Ras GTPase-activating protein 4     
Q96PV0 SYNGAP1 Ras/Rap GTPase-activating protein SynGA     
RapGAP, PS50085 
Q5VVW2 GARNL3 GTPase-activating Rap/Ran-GAP domain-like protein 3     
Q6GYQ0 RALGAPA1 Ral GTPase-activating protein subunit alpha-1 669  28   
Q2PPJ7 RALGAPA2 Ral GTPase-activating protein subunit alpha-2 Detected  12   
Q86X10 RALGAPB Ral GTPase-activating protein subunit beta 884  RalA (29915037)  
P47736 RAP1GAP Rap1 GTPase-activating protein 1     
Q684P5 RAP1GAP2 Rap1 GTPase-activating protein 2 2327 ++ 22 Rap1 (15632203) Inhibited by S9 phosphorylation, activated by PKA/PKG mediated S7 phosphorylation, binds 14-3-3, binds Slp1 and stimulates dense granule release (15632203, 18039662, 19528539) 
O43166 SIPA1L1 Signal-induced proliferation-associated 1-like protein 1 Detected  65   
Q9P2F8 SIPA1L2 Signal-induced proliferation-associated 1-like protein 2     
O60292 SIPA1L3 Signal-induced proliferation-associated 1-like protein 3     
Q96FS4 SIPA1 Signal-induced proliferation-associated protein 1 Detected  12   
P49815 TSC2 Tuberin 593  35   
RhoGAP, PS50238 
Q9Y3L3 SH3BP1 SH3 domain-binding protein 1 595  14   
Q12979 ABR Active breakpoint cluster region-related protein Detected  Rac1 (32203420)  
Q96P48 ARAP1 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 3061  17 Rac1, Cdc42 (32203420)  
Q8WZ64 ARAP2 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 2     
Q8WWN8 ARAP3 Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3     
P11274 BCR Breakpoint cluster region protein 793  47 Rac1 (32203420)  
Q6ZT62 BARGIN Bargin     
P15882 CHN1 N-chimaerin     
P52757 CHN2 Beta-chimaerin     
Q8WUY9 DEPDC1B DEP domain-containing protein 1B     
O94988 FAM13A Protein FAM13A     
Q9NYF5 FAM13B Protein FAM13B     
Q9P107 GMIP GEM-interacting protein 1228  17 RhoA, Rac1, Cdc42 (32203420)  
P32019 INPP5B Type II inositol 1,4,5-trisphosphate 5-phosphatase 1629    
B2RTY4 MYO9A Unconventional myosin-IXa Detected  14   
Q13459 MYO9B Unconventional myosin-IXb 1428  40 RhoA (33268376) Activated by PKA/PKG mediated S1354 phosphorylation (32692911) 
Q01968 OCRL Inositol polyphosphate 5-phosphatase OCRL 850  RhoA (33528045) Reduces RhoA-GTP, augments Rac1-GTP and myosin light chain phosphorylation, inhibits filopodia, stimulates spreading, clot retraction and thrombus formation (33528045, 36176266) 
O60890 OPHN1 Oligophrenin-1 1527  RhoA, Rac1, Cdc42 (25556321) Reduces RhoA-GTP, Rac1-GTP, and Cdc42-GTP, inhibits adhesion and granule release (25556321) 
P27986 PIK3R1 Phosphatidylinositol 3-kinase regulatory subunit alpha 1904  17   
O00459 PIK3R2 Phosphatidylinositol 3-kinase regulatory subunit beta Detected  12   
Q15311 RALBP1 RalA-binding protein 1 785  14 Rac1 (32203420)  
Q9H0H5 RACGAP1 Rac GTPase-activating protein 1     
Q07960 ARHGAP1 Rho GTPase-activating protein 1 9290 RhoA, Cdc42 (32203420)  
P98171 ARHGAP4 Rho GTPase-activating protein 4 1400  Rac1 (32203420)  
Q13017 ARHGAP5 Rho GTPase-activating protein 5 Detected  16 RhoA (32203420)  
O43182 ARHGAP6 Rho GTPase-activating protein 6 4151 ++ RhoA (32203420) Binds COPD and COPI vesicles, might regulate protein transport (37409526) 
Q96QB1 DLC1 Rho GTPase-activating protein 7     
P85298 ARHGAP8 Rho GTPase-activating protein 8     
Q9BRR9 ARHGAP9 Rho GTPase-activating protein 9 Detected  Rac1 (32203420)  
A1A4S6 ARHGAP10 Rho GTPase-activating protein 10 1114  RhoA (32203420)  
Q6P4F7 ARHGAP11A Rho GTPase-activating protein 11A     
Q3KRB8 ARHGAP11B Inactive Rho GTPase-activating protein 11B     
Q8IWW6 ARHGAP12 Rho GTPase-activating protein 12 Detected  23 Rac1 (32203420)  
Q53QZ3 ARHGAP15 Rho GTPase-activating protein 15 833  11 Rac1 (32203420, 32839212)  
Q68EM7 ARHGAP17 Rho GTPase-activating protein 17 1603  21 Rac1, RhoA (22975681) Regulated by tyrosine phosphorylation (22975681), activated by PKA/PKG mediated S702 phosphorylation (26507661) 
Q8N392 ARHGAP18 Rho GTPase-activating protein 18 7100 ++ RhoC (25425145), RhoA (32016689)  
Q14CB8 ARHGAP19 Rho GTPase-activating protein 19     
Q9P2F6 ARHGAP20 Rho GTPase-activating protein 20     
Q5T5U3 ARHGAP21 Rho GTPase-activating protein 21 886  46 RhoA (32203420, 33727037), Cdc42 (33727037) Inhibits alpha granule release and aggregation (33727037) 
        
Q7Z5H3 ARHGAP22 Rho GTPase-activating protein 22     
Q9P227 ARHGAP23 Rho GTPase-activating protein 23     
Q8N264 ARHGAP24 Rho GTPase-activating protein 24     
P42331 ARHGAP25 Rho GTPase-activating protein 25 1054  11 Rac1 (36190314)  
Q9UNA1 ARHGAP26 Rho GTPase-activating protein 26 Detected  RhoA (32203420)  
Q6ZUM4 ARHGAP27 Rho GTPase-activating protein 27 Detected  11 Rac1 (32203420)  
Q9P2N2 ARHGAP28 Rho GTPase-activating protein 28     
Q52LW3 ARHGAP29 Rho GTPase-activating protein 29     
Q7Z6I6 ARHGAP30 Rho GTPase-activating protein 30 Detected  15 RhoA, Rac1, Cdc42 (32203420)  
Q2M1Z3 ARHGAP31 Rho GTPase-activating protein 31     
A7KAX9 ARHGAP32 Rho GTPase-activating protein 32 Detected  40   
O14559 ARHGAP33 Rho GTPase-activating protein 33     
Q9NRY4 ARHGAP35 Rho GTPase-activating protein 35 783  23 RhoA, Rac1 (32203420)  
Q6ZRI8 ARHGAP36 Rho GTPase-activating protein 36     
Q9C0H5 ARHGAP39 Rho GTPase-activating protein 39     
Q5TG30 ARHGAP40 Rho GTPase-activating protein 40     
A6NI28 ARHGAP42 Rho GTPase-activating protein 42     
Q17R89 ARHGAP44 Rho GTPase-activating protein 44     
Q92619 ARHGAP45 Rho GTPase-activating protein 45 (HMHA1) 3891  25   
Q7Z6B7 SRGAP1 SLIT-ROBO Rho GTPase-activating protein 1 Detected  Rac1 (32203420)  
O75044 SRGAP2 SLIT-ROBO Rho GTPase-activating protein 2 Detected  23 Rac1, Cdc42 (32203420, 31880824)  
O43295 SRGAP3 SLIT-ROBO Rho GTPase-activating protein 3     
Q9Y3M8 STARD13 StAR-related lipid transfer protein 13 Detected  RhoA (32203420)  
Q92502 STARD8 StAR-related lipid transfer protein 8 Detected  RhoA, Cdc42 (32203420, 25673874)  
Q6ZW31 SYDE1 Rho GTPase-activating protein SYDE1     
Q5VT97 SYDE2 Rho GTPase-activating protein SYDE2     
Q8N103 TAGAP T-cell activation Rho GTPase-activating protein     
RGS, PS50132 
Q08116 RGS1 Regulator of G-protein signalling 1     
P41220 RGS2 Regulator of G-protein signalling 2     
P49796 RGS3 Regulator of G-protein signalling 3 Detected  Gαi, Gαo (33007266)  
P49798 RGS4 Regulator of G-protein signalling 4     
O15539 RGS5 Regulator of G-protein signalling 5     
P49758 RGS6 Regulator of G-protein signalling 6 2434 Gαo (32513692, 33007266)  
P49802 RGS7 Regulator of G-protein signalling 7     
P57771 RGS8 Regulator of G-protein signalling 8     
O75916 RGS9 Regulator of G-protein signalling 9     
O43665 RGS10 Regulator of G-protein signalling 10 4608 Gαq, Gαi, Gαo (30150297, 33007266) Inhibits Gαq and Gαi signalling, aggregation, granule release, regulated by spinophilin and 14-3-3 (27829061, 30150297) 
O94810 RGS11 Regulator of G-protein signalling 11     
O14924 RGS12 Regulator of G-protein signalling 12     
O14921 RGS13 Regulator of G-protein signalling 13     
O43566 RGS14 Regulator of G-protein signalling 14 Detected  12 Gαi1 (30093406, 33007266)  
O15492 RGS16 Regulator of G-protein signalling 16     
Q9UGC6 RGS17 Regulator of G-protein signalling 17     
Q9NS28 RGS18 Regulator of G-protein signalling 18 4463 ++ Gαi, Gαq (33007266) Inhibits Gαi and Gαq signalling, regulated by spinophilin and 14-3-3, inhibited by S49/S218 phosphorylation, activated by PKA/PKG mediated S216 phosphorylation (22210881, 26407691, 22234696, 24244663) 
P49795 RGS19 Regulator of G-protein signalling 19 1086  Gαz (33007266)  
O76081 RGS20 Regulator of G-protein signalling 20     
Q2M5E4 RGS21 Regulator of G-protein signalling 21     
Q8NE09 RGS22 Regulator of G-protein signalling 22     
Q15835 GRK1 Rhodopsin kinase GRK1     
P25098 GRK2 Beta-adrenergic receptor kinase 1 1409    
P35626 GRK3 Beta-adrenergic receptor kinase 2 Detected    
P32298 GRK4 G protein-coupled receptor kinase 4     
P34947 GRK5 G protein-coupled receptor kinase 5 1557  Inhibits PAR1 receptor signalling (34581777)  
P43250 GRK6 G protein-coupled receptor kinase 6 2005  Inhibits PAR1 and P2Y12 receptor signalling (31899801)  
Q8WTQ7 GRK7 Rhodopsin kinase GRK7     
O15085 ARHGEF11 Rho guanine nucleotide exchange factor 11     
O15169 AXIN1 Axin-1 Detected    
Q9Y2T1 AXIN2 Axin-2     
Q9Y5W8 SNX13 Sorting nexin-13 Detected    
Q9Y5W7 SNX14 Sorting nexin-14 Detected    
Q9H3E2 SNX25 Sorting nexin-25     
O43572 AKAP10 A-kinase anchor protein 10, mitochondrial 819  Rab4, Rab11 (19797056)  

Proteins containing GAP domains were obtained from UniProt and compared with platelet proteome data. Shown are all proteins encoded by the human genome. Protein copy numbers per platelet are given as far as available. ‘Detected’ indicates expressed proteins where a copy number has not yet been determined. All found proteins have also been confirmed at the transcriptome level of megakaryocytes or platelets. ‘-’ indicates that proteins could not be detected in platelets. Platelet specificity was determined as high expression in platelets compared to other human tissues according to https://www.proteomicsdb.org and http://www.humanproteomemap.org (‘+’ indicates within the top 5 highly expressing tissues, ‘++’ indicates platelets as highest expressing tissue in both databases). Phosphorylation (Phospho) sites refers to sites identified by proteomics and by low throughput studies. Shown are numbers of phosphorylation sites found in any cell type with a minimum of at least 5 references according to PhosphoSite (https://www.phosphosite.org/). References for G protein specificities of GAPs are given as PubMed ID numbers (PMID). Detailed studies refers to platelet data, listed are PMIDs.

GAPs are defined as proteins that contain catalytic GAP domains and GAP domain profiles have been defined and are accessible through the Prosite database (ARFGAP, PS50115; TBC_RABGAP, PS50086; RAS_GTPASE_ACTIV_2, PS50018; RAPGAP, PS50085; RHOGAP, PS50238; RGS, PS50132). In general, GAPs bound to their small G proteins contribute catalytic site residues to stimulate GTP hydrolysis. For example, GAPs for Ras and Rho GTPases contribute an essential arginine, called arginine-finger, whereas RabGAPs use an arginine/glutamine dual-finger, and GAPs for Rap and Ral use an asparagine, called asparagine-thumb [12,22,23]. RGS domains do not appear to contribute catalytic site residues but stabilize a pre-transition state of Gα [24,25]. Although minimal sequences exhibiting GAP activity have been defined, in some cases other regions or domains outside of the core GAP domain contribute supporting or inhibitory functions. For example, autoinhibition is a common feature of RhoGAPs [26] which has been confirmed for the platelet GAPs RhoGAP6 [27] and RASA3 [28]. The pleckstrin homology (PH) domain of the ArfGAP ASAP1 supports Arf binding whereas its predicted N-terminal Bin/amphiphysin/Rvs (BAR) domain inhibits GAP activity (Figure 2A) [29]. In contrast, nonmuscle myosin 2A (NM2A), a BAR domain binding partner, stimulates ASAP1 activity, possibly by relieving the autoinhibition [30]. Other examples for regulatory components within GAPs include the RhoA regulator RhoGAP35 which exhibits a protrusion localization sequence, including two pseudo GTPase regions (Figure 2D), involved in localization to lamellipodia in cancer cells that inhibits GAP activity [31].

Domain structures of platelet GAPs

Figure 2
Domain structures of platelet GAPs

Shown are GAPs of Arf (A), Rab (B), Ras/Rap (C), Rho (D), and alpha subunits of heterotrimeric (E) G proteins found in human platelets. Domains, domain boundaries, and protein lenghts are given according to UniProt, and proteins are sorted according to their expression levels (Table 2). Domain names and abbreviations are given.

Figure 2
Domain structures of platelet GAPs

Shown are GAPs of Arf (A), Rab (B), Ras/Rap (C), Rho (D), and alpha subunits of heterotrimeric (E) G proteins found in human platelets. Domains, domain boundaries, and protein lenghts are given according to UniProt, and proteins are sorted according to their expression levels (Table 2). Domain names and abbreviations are given.

Close modal

GAPs are typically large proteins including multiple domains (Figure 2). Only few GAPs appear to consist of a catalytic GAP domain alone. These catalytic domain only GAPs include the most highly expressed platelet RabGAP TBC1D13 as well as RGSs 10, 18, and 19 (Figure 2B, 2E). All other RabGAPs and RGSs as well as ArfGAPs, Ras/RapGAPs, and RhoGAPs (Figure 2A, 2C, 2D) contain a diverse set of additional domains. A prominent feature found in most GAPs are domains that can mediate lipid and membrane binding, as for example, PH (most ArfGAPs), C2 (Ras/RapGAPs) and BAR domains (RhoGAP). Membrane binding might be required for the interaction with G proteins as most G proteins are attached to membranes via lipid anchors [11]. Furthermore, a variety of protein/protein interaction domains are present in these GAPs including ankyrin repeats (ArfGAPs), Src homology 2 (SH2), Src homology 3 (SH3), WW, and post synaptic density protein, Drosophila disc large tumor suppressor, and zonula occludens-1 protein (PDZ) domains (Figure 2). Protein interaction domains might localise GAPs to specific G proteins, to other GAPs and GEFs, or to adapter proteins and thereby contribute to the formation of G protein networks required for the coordination of multiple platelet functions [21,32]. Another characteristic seen in platelet GAPs is their ability to regulate other cellular processes independent of their GAP activity. For example sequences outside the catalytic GAP domain enable interactions of Rap1GAP2 with Slp1 to modulate dense granule release (see below for details, Figure 3B) [33]. RhoGAP6 enhances protein transport through the secretory pathway and its RhoGAP activity actually inhibits this effect (Figure 3C) [27].

Most GAPs contain sites for possible post-translational modifications. For example, all platelets GAPs are predicted to contain 10 phosphorylation sites per protein on average (Table 2), estimate based on a conservative approach with a minimum of 5 references according to PhosphoSite) pointing towards complex regulation by multi-site phosphorylation [34]. GAP phosphorylation has been linked to changes in GAP activity during platelet activation and inhibition. Many G proteins are turned into their active GTP-bound versions during platelet activation. Maintenance of GTP-bound G proteins requires reduced GAP activities whereas classical platelet inhibitors tend to stimulate GAPs. This has been observed for RASA3, Rap1GAP2, RhoGAP17, Myo9B, RGS10 and RGS18 (see below for details). These activity changes have been linked to phosphorylation and dephosphorylation of regulatory sites involving binding of 14-3-3 adapter proteins. The adapter protein 14-3-3 is common phosphorylation dependent interaction partner of many GAPs including Rap1GAP2, RhoGAP6, RGS10 and RGS18 (Figure 3) and 14-3-3s play an established role in regulating platelet functions [35].

Arf proteins

G proteins of the Arf family are generally known has signalling molecules controlling diverse cellular functions including vesicle formation and membrane trafficking as well as remodelling of the actin cytoskeleton and cell adhesion [36]. Arf1, 3, 4, and 5 are expressed in high amounts in platelets [18] (Table 1) and are thought to have overlapping roles in vesicle formation and transport to and from the Golgi and in recycling endosomes [37–39]. For example, Arf1 initiates vesicle formation by recruiting coat protein complex I (COPI) and clathrin adapter proteins (AP-1, AP-3, and AP-4) to membranes. Coat proteins then complete vesicle formation and select protein and lipid cargo for vesicular transport [37]. Of all 27 Arf proteins found in platelets only Arf6 has been studied is some detail. Arf6 has a role in controlling signalling in the cell periphery. In platelets, Arf6 is involved in endocytosis of membrane receptors including the fibrinogen receptor integrin αIIbβ3, the P2Y12 ADP receptor [40] and Toll-like receptors 7 and 9 [41]. Reduced Arf6 expression in mouse platelets resulted in impaired fibrinogen endocytosis and uptake into alpha granules which correlated with increased platelet spreading and clot retraction [42]. In contrast with many other small G proteins Arf6 is typically found in its GTP-bound form in resting platelets. Arf6 transitions to the inactive GDP-bound form during platelet activation by collagen and thrombin [43], although one study has also described the opposite effect [44]. The ArfGAP regulating Arf6 in platelets is unknown. In vitro studies using purified proteins have provided evidence for specificity of GIT1, ACAP1, and ACAP2 towards Arf6 [45,46], and these three GAPs are present in platelets (Figure 2A). High Arf6-GTP levels might be maintained by cytohesin-2 which has been identified as GEF for Arf6 in platelets [47].

ArfGAPs

Interestingly, the most highly expressed ArfGAPs in platelets, ASAP1, ASAP2, and GIT1 (Figure 2A) have been described as integrin and receptor regulators [36,48]. Integrin regulation is thought to be mediated by effects on membrane trafficking and endocytosis possibly via Arf6 or other Arfs, or through Rac1 signalling. ASAP1 localizes to platelet focal adhesions through binding of the adapter protein CrkL [49]. GIT1 currently is the most extensively studied ArfGAP in platelets. Platelet activation has been shown to induce tyrosine phosphorylation of GIT1 probably through integrin αIIbβ3 induced outside-in signalling mediated by Src kinase [50]. Tyrosine phosphorylation correlates with translocation of GIT from a membrane to a cytoskeletal fraction together with integrin β3. As GIT1 is known to bind constitutively to the Rac1 regulators RhoGEF6 [51] and RhoGEF7 [50] in platelets cytoskeletal recruitment could contribute to Rac1 and possibly Arf6 mediated actin rearrangements during platelet activation. ARAP1, another highly expressed platelet ArfGAP (Figure 2A), contains a RhoGAP domain as well as a Ras-association region and might support the coordination of the function of multiple G proteins including Rap1, Rac1, RhoA, Cdc42, and Arf proteins [52]. Similar to other ArfGAPs ARAP1 contains PH domains (Figure 2A) which might facilitate close association to membrane surfaces required for effective Arf interaction [53].

In summary, platelet Arfs are only marginally described apart from Arf6 which has a role in receptor endocytosis and in the regulation of the actin cytoskeleton. As ArfGAPs appear to be recruiting additional G protein regulators future studies should consider analysing Arfs in combination with their GAPs (and GEFs) to improve understanding of the specific roles of Arf proteins in platelet signalling [36].

Rab proteins

Similar to Arfs Rab proteins are involved in controlling intracellular membrane and vesicle traffic. Rabs tend to associate with specific vesicles thus conferring membrane identity and enabling directed transport between donor and acceptor compartments, both in secretion as well as in endocytosis and recycling pathways [54,55]. For example, active Rab27-GTP localised at the cytosolic surface of platelet dense granules can bind to the effector protein Munc13-4 supporting tethering of the granule to the plasma membrane [56]. Tethering is followed by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) mediated membrane fusion and secretion of granule content [57]. Prominent vesicle/granule associated SNAREs in platelets are VAMP-8 and VAMP-7 which interact with target membrane SNAREs like syntaxin-11 and SNAP-23 as well as Munc18 proteins. The Ras family G protein Ral might be another component of the secretory complex through interactions with SNARE binding exocyst factors. However, mouse knockout studies suggest only minor roles for RalA and RalB in granule release, but a possible role for Ral in P-selectin translocation to the plasma membrane has been proposed [58]. Rab27B is the most highly expressed Rab in platelets [18] (Table 1) and its role in dense granule release has been confirmed [59]. Similar to Arf6 Rab27 is present predominantly in the GTP-bound form in unstimulated platelets, whereas granule release leads to a decrease of Rab27-GTP levels [60]. A possible GAP that could mediate Rab27 inactivation is TBC1D10B which has been shown to have activity towards Rab27B in other cells [61]. Rab8 might also support tethering of dense granules to the plasma membrane by interacting with synaptotagmin-like protein 4 [62]. Regarding the role of Rab proteins in the biogenesis of dense granules data have been obtained from Hermansky–Pudlak syndrome (HPS) patients and mouse models. Combined deficiency of Rab32 and Rab38 in mice leads to defective dense granule formation and impaired platelet function similar to defects seen in HPS patients [63]. Alpha granules were not affected by Rab32/38 deficiency and platelet counts were not changed indicating that dense granule deficiency does not necessarily impact on platelet biogenesis. These data support earlier findings obtained using the megakaryocytic cell line MEG-01 suggesting that Rab32 and Rab38 enable the transport of dense granule components from early endosomes via AP-3 and Rab7 labelled vesicles towards dense granule precursors [64]. Little data are available regarding biogenesis, tethering and release of alpha granules. Rab1B is down-regulated in patients with alpha granule defects due to deficiency of the transcription factor RUNX1 and Rab1B was shown to be involved in ER-Golgi transport of alpha granule content in megakaryocytic cells; however, changes in alpha granule release were not reported [65]. Endocytosis of extracellular proteins contributes to alpha granule content [40]. Rab31 appears to play an important role in this process as endosomal trafficking is impaired and alpha granule proteins like VWF accumulate in early endosomes of megakaryocytes lacking Rab31 [66]. Furthermore, endocytosed fibrinogen was detected in Rab5 positive granules equivalent to early endosomes, followed by Rab7 positive late endosomes, and finally P-selectin positive alpha granules of megakaryocytes [67]. Rab5 has also been shown to regulate endocytosis and trafficking of the GPIb receptor in megakaryocytes which was linked to proplatelet formation [68]. Alpha granule release might involve Rab4 based on studies using permeabilized platelets [69]. Further characterization of the localization and function of Rab proteins and their GEFs and GAPs might help in clarifying open questions regarding alpha granule subtypes with different release kinetics [70].

Rab regulated endocytotic pathways contribute to the recycling of plasma membrane proteins. Fibrinogen labelled integrin αIIbβ3, passes through a Rab4-positive early endosome compartment followed by colocalization with Rab11-positive structures which are considered recycling endosomes [42]. Similarly, the P2Y12 ADP receptor was shown to be recycled via a Rab5/Rab11 pathway in transfected cells [71]. Recycling pathways have also been shown to play a role in virus entry into platelets. HIV virions sequentially pass through Rab4 and Rab7 compartments in platelets finally accumulating in microtubule-associated protein 1A/1B-light chain 3 (LC3) positive compartments similar to those found in phagocytes [41]. Related pathways may be used for the internalization of influenza and/or SARS-COV-2 viruses leading to platelet activation [72,73]. Rab11A and B are actually among the most highly expressed Rabs in platelets (Table 1) pointing towards a prominent role for recycling pathways in platelet function. Furthermore, Rab11 might be cooperating closely with Arf6 in controlling integrin traffic as has been shown for neurons [74].

RabGAPs

A PubMed search using the terms ‘RabGAP’ and ‘platelets’ did not detect any platelet or megakaryocyte studies at this time. However, one might speculate about potential functions of the top three RabGAPs expressed in platelets based on data from other cells (Figure 2B). TBC1D13, the most highly expressed RabGAP, has been shown to interact with Rab10, to have GAP activity towards Rab35, and to regulate trafficking of membrane proteins towards the plasma membrane [75]. Both, Rab10 and Rab35, are also expressed in platelets (Table 1). TBC1D15, the second highest RabGAP, serves as GAP for Rab7 and regulates mitochondrial fission and regeneration of lysosomes [76,77]. And RabGAP1, the third most highly expressed RabGAP, is involved in recycling of integrins to the plasma membrane [78] pointing to potential cross-talk between RabGAP1 and some of the ArfGAPs like ASAP1 and GIT1 mentioned above.

Taken together, Rabs have been assigned specific roles in the biogenesis and release of dense granules as well as in endocytosis. Further analysis of the localization and function of Rab proteins and their GAPs is required to better understand alpha granules and their possible heterogeneity, as well as membrane recycling pathways, and might help in deciphering the exact roles of the multiple membrane bound compartments found in platelets including the canalicular systems.

Ras/Rap proteins

The Ras family proteins Rap1A and Rap1B are the most highly expressed small G proteins in platelets. With estimated copy numbers of 120,000 and 150,000 each per platelet [18], they outnumber other G-proteins by about 10-fold (Table 1). The key role of Rap1 proteins appears to be regulation of integrin αIIbβ3 activation and platelet aggregation [79]. Rap1-GTP interacts with talin at the plasma membrane triggering a major conformational change in integrin αIIbβ3 enabling fibrinogen binding and cross-linking of platelets. Platelet activation correlates with increased levels of Rap1-GTP whereas cyclic nucleotide mediated platelet inhibition reduces Rap1-GTP [80,81]. Reduced Rap1 activation for example due to mutation of the gene for CalDAG-GEFI, a Rap1 GEF, causes bleeding in humans and mice [82–86] which has been confirmed in Rap1A and Rap1B knockout mouse models [87–89]. Additional roles for the Rap1A isoform beyond integrin regulation include cross-activation of the Rho family G protein Rac1 as well as a regulation of alpha granule release in response to GPVI activation through unknown mechanisms [88]. Other Ras/Rap1 proteins expressed at higher levels in platelets include Rap2A, B, and C, RalA and B (mentioned above), and the prototypic Ras proteins KRas and NRas. The functions of these G proteins in platelets are not clear. However, RRas2 (TC21), a Ras family member detected in platelets, regulates Rap1B and integrin αIIbβ3 downstream of the GPVI receptor [90].

Ras/RapGAPs

RASA3 (GAP1-IP4BP) has been confirmed as GAP of Rap1 in megakaryocytes and platelets (Figures 2C and 3A). Complete deletion of RASA3 in megakaryocytes is embryonically lethal due to bleeding and defects in the development of the lymphatic system [91]. Megakaryocytes expressing catalytically inactive or reduced levels of RASA3 exhibit altered adhesive properties, reduced motility and structural alterations [92–94]. As expected, integrin αIIbβ3 was found to be constitutively activated in these cells which correlated with increased Rap1-GTP levels [94]. Basal and ADP stimulated levels of Rap1GTP and active αIIbβ3 were also found to be elevated in mature mouse platelets expressing reduced levels of H794L mutant RASA3 [91]. In particular, RASA3 inhibition was suggested to play a specific role in platelet activation downstream of the P2Y12 Gi coupled ADP receptor as P2Y12 and PI3K inhibitors lost their in efficiency in RASA3 mutant platelets. Interestingly, RASA3 was also detected in a proteomics approach aimed at identifying phosphatidylinositol 3,4,5-tris-phosphate (PI(3,4,5)P3)-binding proteins in platelets [95]. ADP binding to the P2Y12 receptor increased the association of RASA3 with the plasma membrane resulting in reduced GAP activity. These studies led to the proposal that the P2Y12 receptor might regulate RASA3 through Gi mediated activation of PI3K leading to the production of PI(3,4,5)P3 followed by recruitment and inactivation of RASA3 at the plasma membrane (Figure 3A). In this way, RASA3 mediated turnover of Rap1-GTP could be prevented during ADP-induced platelet activation [95]. RASA3 has been described as dual specificity GAP that is able to regulate both, Rap1 and Ras [96] and PI(3,4,5)P3 binding could potentially affect the specificity of RASA3 towards Rap1 or Ras. The N-terminal C2 and C-terminal PH domains of RASA3 involved in membrane binding are required for GAP activity towards Rap1, whereas the isolated GAP domain might be sufficient for activity towards Ras [28,97]. Thus, one might speculate that membrane recruitment could shift the activity of RASA3 away from Rap1 towards Ras. However, RASA3 has also been shown to bind to both, PI(4,5)P2 as well as PI(3,4,5)P3 via its PH domain [98]. In this study, constitutive association of transfected RASA3 with the plasma membrane was observed and PI3K inhibitors had no effect on plasma membrane binding.

Examples of regulation and function of platelet GAPs

Figure 3
Examples of regulation and function of platelet GAPs

(A) RASA3 is a Rap1GAP which is inhibited by binding to phosphatidylinositol 3,4,5-tris-phosphate (PIP3) at the plasma membrane. PIP3 is generated by phosphatidylinositol 3-kinase (PI3K) downstream of the P2Y12 receptor for ADP. In this way ADP could lead to inhibition of RASA3 leading to elevated Rap1-GTP levels stimulating integrin activation and aggregation. (B) Rap1GAP2 is inhibited by binding of the adapter protein 14-3-3 to phosphorylated serine 9 of Rap1GAP2. cAMP- and cGMP-dependent protein kinase (PKA, PKG) mediated phosphorylation of serine 7 of Rap1GAP2 inhibits 14-3-3 binding resulting in increased GAP activity, formation of inactive Rap1-GDP and inhibition of aggregation. Rap1GAP2 also interacts with synaptotagmin-like protein 1 (Slp1) through a TKxT motif in the C-terminal part of Rap1GAP2 (T524-K525-X-T527). Slp1 inhibits dense granule release whereas binding of Rap1GAP2 to Slp1 reverses this inhibition. (C) The Rho-specific GAP RhoGAP6 interacts with δ-COP, a core component of the COPI vesicle coat, through a triple tryptophane motif ((W-W)3). Through this interaction GAP6 is able to regulate intracellular protein transport along the secretory pathway. The exact role of COPI in platelets is not known. At the same time RhoGAP6 is regulated by 14-3-3 binding to serine 37 which has a negative impact on the δ-COP interaction. (D) The Rac1-specific GAP RhoGAP17 is regulated by PKA and PKG mediated phosphorylation of serine 702 which interferes with binding to the actin-regulating Cdc42-interacting protein 4 (CIP4). CIP4 is also an effector of Rac1-GTP. Serine 702 phosphorylation stimulates the GAP function of RhoGAP17 presumably by interfering with an inhibitory function of CIP4. In addition, Src family kinases (SFK) can phosphorylate RhoGAP17 on tyrosines 124 and 314 leading to GAP activation. (E) RGS18 has GAP activity towards Gαq and Gαi. RGS18 is negatively regulated by 14-3-3 and spinophilin. During platelet inhibition PKA and PKG mediated phosphorylation of serine 216 on RGS18 triggers the dephosphorylation of the 14-3-3 binding phospho-serine 218 on RGS18 resulting in detachment of 14-3-3 and activation of RGS18 function. PKA mediated phosphorylation of serine 94 on spinophilin contributes to dissolution of the RGS18/14-3-3/spinophilin complex. Spinophilin also interacts with the serine/threonine phosphatase PP1 and the tyrosine phosphatase SHP-1. PP1 binding to spinophilin is negatively regulated by the SHP-1. During platelet activation SHP-1 detaches from spinophilin enabling PP1 recruitment, de-phosphorylation of PKA/PKG-dependent regulatory sites, enhanced 14-3-3 and spinophilin binding and reduced RGS activity. P refers to protein phosphorylations detected in platelets. Double arrowhead lines refer to protein/protein interactions.

Figure 3
Examples of regulation and function of platelet GAPs

(A) RASA3 is a Rap1GAP which is inhibited by binding to phosphatidylinositol 3,4,5-tris-phosphate (PIP3) at the plasma membrane. PIP3 is generated by phosphatidylinositol 3-kinase (PI3K) downstream of the P2Y12 receptor for ADP. In this way ADP could lead to inhibition of RASA3 leading to elevated Rap1-GTP levels stimulating integrin activation and aggregation. (B) Rap1GAP2 is inhibited by binding of the adapter protein 14-3-3 to phosphorylated serine 9 of Rap1GAP2. cAMP- and cGMP-dependent protein kinase (PKA, PKG) mediated phosphorylation of serine 7 of Rap1GAP2 inhibits 14-3-3 binding resulting in increased GAP activity, formation of inactive Rap1-GDP and inhibition of aggregation. Rap1GAP2 also interacts with synaptotagmin-like protein 1 (Slp1) through a TKxT motif in the C-terminal part of Rap1GAP2 (T524-K525-X-T527). Slp1 inhibits dense granule release whereas binding of Rap1GAP2 to Slp1 reverses this inhibition. (C) The Rho-specific GAP RhoGAP6 interacts with δ-COP, a core component of the COPI vesicle coat, through a triple tryptophane motif ((W-W)3). Through this interaction GAP6 is able to regulate intracellular protein transport along the secretory pathway. The exact role of COPI in platelets is not known. At the same time RhoGAP6 is regulated by 14-3-3 binding to serine 37 which has a negative impact on the δ-COP interaction. (D) The Rac1-specific GAP RhoGAP17 is regulated by PKA and PKG mediated phosphorylation of serine 702 which interferes with binding to the actin-regulating Cdc42-interacting protein 4 (CIP4). CIP4 is also an effector of Rac1-GTP. Serine 702 phosphorylation stimulates the GAP function of RhoGAP17 presumably by interfering with an inhibitory function of CIP4. In addition, Src family kinases (SFK) can phosphorylate RhoGAP17 on tyrosines 124 and 314 leading to GAP activation. (E) RGS18 has GAP activity towards Gαq and Gαi. RGS18 is negatively regulated by 14-3-3 and spinophilin. During platelet inhibition PKA and PKG mediated phosphorylation of serine 216 on RGS18 triggers the dephosphorylation of the 14-3-3 binding phospho-serine 218 on RGS18 resulting in detachment of 14-3-3 and activation of RGS18 function. PKA mediated phosphorylation of serine 94 on spinophilin contributes to dissolution of the RGS18/14-3-3/spinophilin complex. Spinophilin also interacts with the serine/threonine phosphatase PP1 and the tyrosine phosphatase SHP-1. PP1 binding to spinophilin is negatively regulated by the SHP-1. During platelet activation SHP-1 detaches from spinophilin enabling PP1 recruitment, de-phosphorylation of PKA/PKG-dependent regulatory sites, enhanced 14-3-3 and spinophilin binding and reduced RGS activity. P refers to protein phosphorylations detected in platelets. Double arrowhead lines refer to protein/protein interactions.

Close modal

Recently, a PI3K independent pathway of Rap1 regulation downstream of P2Y12 has been proposed [99], which could potentially involve Rap1GAP2, another highly expressed GAP of Rap1 in human platelets (Figure 2C) [100]. Mouse platelets contain only low levels of Rap1GAP2, whereas humans express Rap1GAP2 at the highest level in platelets compared with other tissues [101] (Table 2). Rap1GAP2 is regulated by activating and inhibitory signalling pathways (Figure 3B). During platelet activation Rap1GAP2 is phosphorylated on serine 9 leading to binding of the adapter protein 14-3-3. 14-3-3 binding correlates with reduced Rap1GAP2 function [102], however, the kinase mediating serine 9 phosphorylation has not yet been identified. In contrast, inhibitory cyclic nucleotide pathways phosphorylate Rap1GAP2 on serine 7 leading to detachment of 14-3-3 (Figure 3B). Thus platelet activators appear to reduce Rap1GAP2 activity to retain high Rap1-GTP levels required for aggregation, whereas platelet inhibitors like the endothelium-dependent cyclic nucleotide pathways reverse this effect. In addition, a TKxT motif in the C-terminal part of Rap1GAP2 (amino acids 524-527) was shown to mediate binding of Rap1GAP2 to synaptotagmin-like protein 1 (Slp1), a protein regulating dense granule release (Figure 3B) [33]. Thus, Rap1GAP2 might link two important platelet responses, aggregation via Rap1 regulation as well as dense granule release via Slp1 binding.

The RasGAP domain of IQGAPs is lacking GAP activity (Figure 2C). Instead, IQGAPs are acting primarily as scaffolds linking receptors to intracellular signalling networks [103]. IQGAPs bind to Rho family G proteins like Racs, RhoG and Cdc42 stabilizing their active GTP-bound forms as well as to Arf6, Rap1 and GDP-bound Rab27a [104,105]. Studies of IQGAP1 deficient platelets indicate that IQGAP1 inhibits intracellular calcium elevation in response to thrombin exposure. IQGAP1 also inhibits alpha granule release and attenuates the development of a procoagulant plasma membrane [106]. IQGAP2, a particularly highly expressed protein in platelets, interacts with the actin-binding protein Arp3 in thrombin treated platelets [107].

In summary, Rap1 has attracted a lot of attention as highly expressed G protein and integrin αIIbβ3 regulator leading to the discovery of RASA3 and Rap1GAP2 as major RapGAPs. However, many open questions remain regarding the regulation of these GAPs and further studies are required to identify the specific roles of the other Ras proteins like Ral, Rap2 or NRas.

Rho proteins

Rac1, Rac2, Cdc42, RhoA, RhoC, and RhoG are the most highly expressed Rho family proteins in platelets, and RhoF is strikingly platelet specific [18] (Table 1). These G proteins appear to have multiple roles in controlling platelet signalling, cytoskeletal reorganization, granule release, aggregation, and clot retraction [13]. Rac1 is essential for signalling downstream of GPVI and CLEC2 receptors activation [108], and both, Rac1 and Rac2, control lamellipodia formation and platelet spreading and are required for the stabilization of platelet aggregates [109]. Cytoplasmic FMR1 Interacting Protein 1 (CYFIP1) has been identified as Rac1 effector mediating lamellipodia formation in platelets [110]. Cdc42 has inhibitory roles in alpha and dense granule release correlating with increased aggregation of knockout platelets [111] although opposing data have been obtained in a different Cdc42 knockout model [112]. RhoA plays a role in shape change, alpha and dense granule release, and clot retraction downstream of Gα13-coupled thrombin and TXA2 receptors of mature platelets [113]. Target proteins mediating the effects of RhoA-GTP include the Rho-associated protein kinases 1 and 2 (ROCK1/2); however, deletion of these proteins only partly copied the RhoA knockout phenotype [114,115]. For example, loss of ROCK2 lead to reduced Thr853 phosphorylation of myosin phosphatase target 1 and to reduced platelet adhesion [115]. Deletion of other RhoA effectors like Protein diaphanous homolog 1 (mDia1) and FH1/FH2 domain-containing protein 1 (Fhod1) did not result in platelet defects suggesting multiple compensatory Rho effector pathways [116]. A normal phenotype was also described for RhoF mouse knockout platelets again indicating compensatory mechanisms [117]; however, RhoF is expressed only at very low levels in mouse compared to human platelets [101]. On the other hand, RhoG is present at high levels in mouse platelets and RhoG knockout leads to defect in alpha and dense granule release specifically in response to GPVI activation [118,119]. Platelet activation is often associated with the formation of the GTP-bound versions of Rho family proteins, whereas endothelial platelet inhibitors tend to keep these proteins inactive [10].

RhoGAPs

Thirty-five RhoGAPs have been detected in platelets [18] (Table 2 and Figure 2D), and the G protein/GAP ratio appears to be particularly low for this group of proteins suggesting that Rho proteins might be regulated by more than one GAP per G protein. The specificities of all RhoGAPs towards RhoA, Rac1, and Cdc42 have recently been studied by Müller et al. using a cell-based assay and these data are included in Table 2 [26]. However, as only RhoA, Rac1, and Cdc42 were tested, activities towards other Rho family G proteins remain unknown. Using affinity purification of overexpressed GAPs and GEFs coupled to mass spectrometry Müller et al. also provided evidence for interactions among GAP family members as well as between GAPs and GEFs. In addition, information on spatial distribution was obtained, indicating that many RhoGAPs associate with the actin cytoskeleton, at least in transfected cells.

RhoGAP1 (ARHGAP1) and 18 (ARHGAP18) are the most highly expressed RhoGAPs in platelets (Table 2 and Figure 2D). RhoGAP1 contains a CRAL-TRIO domain (BNIP-2 and Cdc42GAP Homology domain (BCH) subclass) that can bind RhoA with its prenylation moiety resulting in GAP activation [120]. Interestingly, an amino acid change at the start of the catalytic GAP domain of RhoGAP1 (L263F) was identified as putative causal variant in a patient with a primary platelet secretion defect [121]. RhoGAP18 is known to contribute to localized RhoA regulation in distinct cellular compartments [122–124]; however, platelet functions of RhoGAP18 have not yet been described. RhoGAP6 (ARHGAP6), another highly expressed RhoGAP, has been shown to bind to δ-COP, a component of the COPI coat, in platelets (Figure 3C). COPI is usually thought to be involved in vesicle transport between the Golgi and the ER and COPI function requires Arf1 and ArfGAP1-3 [37,125]. But only ArfGAP2 appears to be expressed in platelets at detectable levels (Figure 2A). δ-COP binding involves three tryptophan motifs (LIG_deltaCOP1_diTrp_1 according to the ELM resource [126]) in the C-terminal part of RhoGAP6 (amino acids 947-958). This tryptophan motif has previously been characterized only in ArfGAP1 [27]. The δ-COP interaction is inhibited by 14-3-3 binding to phosphorylated serine 37, and RhoGAP6 stimulates vesicle transport and protein secretion in transfected cells which depends on COPI binding but not on GAP activity (Figure 3C). Taken together RhoGAP6 might link RhoA regulation with protein transport processes in platelets.

Other RhoGAPs that have been studied in platelets include oligophrenin 1 (OPHN1), RhoGAP21 (ARHGAP21), Oculocerebrorenal syndrome of Lowe 1 and Inositol 5-phosphatase (OCRL), RhoGAP17 (ARHGAP17), and Myo9B (Table 2). Oligophrenin 1 inhibits lamellipodia formation and adhesion, alpha and dense granule release and thrombus formation under low shear rates, whereas platelet aggregation does not appear to be regulated according to a mouse study [127]. In this study evidence was provided for GAP activity of oligophrenin towards RhoA, Rac1, as well as Cdc42; however, other Rho family proteins have not been tested. Similarly, investigation of RhoGAP21 in mouse platelets revealed a role for this GAP in attenuating alpha granule release, platelet aggregation, and thrombus formation which was linked to inactivation of RhoA and Cdc42 [128]. In the GAP domain of OCRL, the catalytic arginine is replaced by a glutamine and no GAP activity can be detected, nevertheless OCLR has been shown to bind to Rac1-GTP [129]. OCRL also contains a central inositol 5-phosphatase phosphatase domain processing PIP2 into phosphatidylinositol 4-phosphate (PI4P). Defects in OCRL cause a rare inherited disorder which is associated with a bleeding phenotype. A recent study of platelets from these patients showed reduced adhesion to collagen surfaces, enhanced filopodia and reduced lamellipodia formation on fibrinogen, which correlated with reduced Rac1-GTP and enhanced RhoA-GTP levels but reduced myosin light chain phosphorylation, clot retraction, and thrombus formation [130]. Similar findings were obtained by pharmacological inhibition of OCRL’s phosphatase activity including enhanced filopodia and actin nodule formation, reduced spreading and reduced myosin light chain phosphorylation [131]. Taken together, OCRL might regulate actin dynamics by Rac1 binding as well as by lowering PIP2 levels in the plasma membrane with follow-on effects on PIP2-binding proteins. RhoGAP17 is another GAP with activities towards Rac1 and RhoA found in platelets. RhoGAP17 has been identified as a target of various signalling pathways. PKA and PKG phosphorylate RhoGAP17 on serine 702 leading to detachment of the Cdc42-interacting protein 4 (CIP4) from RhoGAP17 [51]. CIP4 is an effector of Rac1-GTP and Cdc42-GTP involved in proplatelet formation [132,133]. Loss of CIP4 binding to RhoGAP17 correlates with enhanced inhibition of cell migration possibly through increased GAP activity leading to reduced Rac1-GTP levels [51]. Thus, PKA/G-mediated detachment of CIP4 might activate RhoGAP17 and terminate Rac1 signalling towards CIP4 (Figure 3D). Interestingly, RhoGAP17 can also be activated by tyrosine phosphorylation (Y124 and Y314) through Src family kinases during platelet activation [134] suggesting that both, platelet activation and inhibition pathways, might lead to RhoGAP17 activation. These phosphorylations could potentially have additive effects on GAP activity levels; however, cross-regulation of RhoGAP17 phosphorylation sites has not been investigated. PKA/G also phosphorylate the RhoGAP and myosin motor protein Myo9B which moves along actin filaments and has been implied in lamellipodia formation in various cells [135,136]. Phosphorylation of Myo9B on serine 1354 enhanced the GAP activity of Myo9B towards RhoA [137] possibly contributing to a modulation of local RhoA activity around actin filaments [138].

In summary, Rho family G proteins are appearing to be regulated by a complex set of RhoGAPs integrating numerous additional domains and functions. Specific combinations of Rhos and GAPs/GEFs might be involved in controlling distinct cellular processes beyond the classical roles of RhoA, Cdc42, and Rac1 in stress fibre, filopodia and lamellipodia formation.

Heterotrimeric G proteins

Heterotrimeric (αβγ) G proteins transduce signals from ligand binding GPCRs to downstream targets at the plasma membrane [139]. Platelets express all 3 Gαi isoforms (Gαi1-3) and Gαq at highest levels [18] (Table 1). Gα13, Gαz (another Gi family member), and Gαs are less prominent. The most highly expressed corresponding beta and gamma subunits are β1, β4, β2, β5, and γ11, γ5, γ10 (in descending order of expression level). Activated GPCRs act as GEFs and GTP-bound α subunits dissociate from βγ subunits to interact with downstream effector targets. Activation of the P2Y12 receptor by ADP induces Gαi2- and Gαz-GTP formation which inhibits AC leading to reduced cAMP synthesis and facilitating platelet activation and aggregation [140–142]. Overexpression of a GAP resistant Gαi2 mutant led to reduced cAMP levels, and increased aggregation in response to GPCR agonists confirming the inhibitory role of Gαi in platelets [143]. The P2Y1 ADP receptor as well as thrombin and TXA2 receptors activate Gαq (Figure 1) [144,145] leading to stimulation of PLCβ followed by the release of Ca2+ ions from intracellular stores and platelet activation [146,147]. The PAR1 thrombin receptor and the TP receptor are also linked to Gα13 which activates RhoA [148] probably through direct interaction with a RhoGEF like RhoGEF1 (p115RhoGEF) [149]. Information on the role of Gs, linked to the prostacyclin receptor (IP receptor), has been obtained using Gs-deficient platelets from patients with pseudohypoparathyroidism types Ia [150,151]. In these platelets reduced Gs expression results in attenuated responses to IP receptor activation including reduced AC stimulation, followed by reduced cAMP/PKA activation and reduced inhibition of platelet aggregation. Gs overexpression has been associated with an increased bleeding risk [152]. Only few studies have addressed roles of Gβγ subunits of heterotrimeric G proteins in platelets. Gβ1 was shown to interact with the catalytic subunit of protein phosphatase 1 and with PLCβ3 [153], and a small molecule inhibitor of Gβγ inhibits platelet aggregation and granule release [154]. Gβγ subunits contribute to PI3K activation downstream of Gi-coupled receptors [155,156] and to AC activation downstream of Gs-coupled receptors [157]. Multiple combinations of α, β and γ subunits are expected to exist leading to many possible functions [158].

RGSs

GAP roles are provided by RGS proteins some of which have been studied in platelets (Table 2 and Figure 2E). Only 20 (RGS1-20) of the 35 proteins containing RGS or RGS-homology (RH) domains are considered canonical RGS proteins based on structural and functional (GAP activity) similarities [25,159]. RGS18 is the most highly expressed and platelet-specific RGS (Table 2) and exhibits selectivity towards Gαq and Gαi (Figure 3E) [159]. Knockout mouse studies revealed a role for RGS18 in megakaryocyte development and platelet production [160,161]. Mature platelets lacking RGS18 are hyperactive exhibiting increased basal as well as thrombin and TXA2 stimulated alpha and dense granule release, integrin activation and aggregation. RGS18 interacts with Gαq and Gαi in human platelets, as well as with the adapter proteins spinophilin (neurabin-2, PPP1R9B), and 14-3-3 [162–165]. A regulatory cycle was proposed for RGS18 leading to RGS inhibition during platelet activation (associated with 14-3-3 binding to phosphorylated serines 49 and 218 and loss of spinophilin binding) and activation during platelet inhibition (associated with cyclic nucleotide mediated loss of 14-3-3 due to S216 phosphorylation) (Figure 3E) [10] PKA-mediated phosphorylation of serine 94 on spinophilin contributes to dissolution of the RGS18/14-3-3/spinophilin complex [165]. Recruitment of the serine/threonine phosphatase PP1 to spinophilin is regulated by the tyrosine phosphatase SHP-1 [166] and might play a role in dephosphorylating the regulatory sites on RGS18 [163]. A recent study has revealed further complexity of heterotrimeric G protein regulation as Gαq was shown to interact with either RGS10 or RGS18 or with PLCβ [167]. RGS10 is another via Gαq/Gαi-specific abundantly expressed RGS in platelets which has been shown to negatively regulate release of calcium ions from intracellular stores, alpha granule release, aggregation, and thrombus formation downstream of thrombin, TXA2, and ADP receptors in mice and to be regulated by spinophilin and 14-3-3 binding similar to RGS18 [168–170]. RGS16 has been described as a platelet regulator [171]; however, proteomics have provided little evidence for RGS16 expression in platelets (Table 2).

In addition to the classical RGS proteins a few related proteins containing RH domains are expressed in platelets. The G protein–coupled receptor kinases (GRK) appear to have some GAP activity towards Gα, but many of these have numerous ways of regulating receptor functions [25]. GRK2 has been shown to specifically terminate P2Y12 and P2Y1 coupled Gq and possibly Gi signalling in platelets [172]. Of note, in this study, GRK2 was seen to bind to Gβq but not the Gαq or Gαi subunits. In contrast, GRK6 regulates PAR1 receptors. GRK6 has been shown to bind to the PAR1 receptor in thrombin treated platelets which was linked to increased receptor phosphorylation but GRK6 might also regulate PAR4, at least in mice [173]. GRK5 also regulates PAR1 and PAR4 mediated platelet activation in a mouse knockout model where lack of GRK5 led to increased thrombin-induced aggregation. The common intronic GRK5 variant rs1088643 linked to reduced transcript numbers is associated with increased thrombin-induced platelet reactivity in humans [174,175]. As GRK5 was shown to bind to the PAR1 receptor GRK5 might de-activate PAR signalling through phosphorylation and β-arrestin mediated receptor internalization.

Taken together, RGS proteins are emerging as essential regulators of GPCR function in platelets. RGS18 has been shown to regulate transmission of Gq and Gi mediated thrombin and TXA2 receptor signalling in many studies. Further analyses are required to clarify GPCR specificities and regulatory complexes forming around RGSs.

Platelets play a major role in arterial and venous thrombotic disease. However, current antiplatelet therapies are targeting only a restricted set of molecules like the P2Y12 ADP receptor, cyclooxygenase-1 required for TXA2 synthesis, or the cAMP degrading phosphodiesterase type 3 [176,177]. Furthermore, the major drawback of any anti-haemostatic approach, an increased bleeding risk, has not been overcome. G proteins and their regulators might represent a new class of targets for antiplatelet therapy.

The approval of sotorasib in 2021 as first G protein inhibitor targeting K-Ras in cancer patients indicates the feasibility of targeting these types of proteins [178]. Both, GTP- and GDP-bound states of K-Ras can be targeted by small molecules, and drugs are being developed that interfere with effector and/or GEF and GAP binding sites. Highly expressed and platelet specific G proteins like Rap1B or Rab27B could be promising targets for the development of similar drugs for antiplatelet therapy. In principal, it should also be possible to identify small molecules that stimulate GAP functions, for example, by interfering with negative regulatory regions. The platelet specific Rap1GAP RASA3 could potentially be activated by interference with the regulatory PH domain of RASA3 whereas blocking 14-3-3 interaction would activate Rap1GAP2 (Figure 3A,B). Similarly, impeding interactions between RGS18 and spinophilin or 14-3-3 would be expected to lead to platelet inhibition (Figure 3E) and the development of 14-3-3 interaction inhibitors is an area of active research [179]. As GAPs are regulated by complex phosphorylation patters targeting protein kinases might be another way of influencing platelet function. Kinase inhibitors have become a major area of drug development since the discovery and clinical implementation of imatinib as highly effective inhibitor of the tyrosine kinase BCR-ABL in cancer therapy. Around 20 kinase inhibitors are already in clinical use and 20% of the entire kinome of 560 kinases is being targeted in clinical trials [180]. Studies are also underway addressing the potential of PI3K and tyrosine kinase inhibitors for platelet inhibition [176]. Kinases appear to have a major role in regulating GAPs (Table 2), however, further studies are required to identify specific kinase/GAP interactions with therapeutic potential in platelets.

Platelets contain a unique set of G proteins and G protein regulators which are likely to be adapted to the specialised functions of this cell type. So far only few platelet GAPs have been studied in detail. The multi-domain structure of GAPs might contribute to local control of G proteins and facilitate complex connections between G proteins of different families required for the regulation of receptor function, membrane and vesicle traffic and the cytoskeleton. Platelets represent a unique cell model for signalling research as gene expression changes do not need to be considered. In addition to platelet focused omics studies careful validation of the specificities, control mechanisms, and localization of individual proteins will be essential to build a solid foundation for improved understanding of platelet function, meaningful modelling of signalling networks, and for the identification of new therapeutic targets in vascular disease.

The authors declare that there are no competing interests associated with the manuscript.

The authors would like to thank UCD School of Medicine and UCD Conway Institute for funding and continued support, and three anonymous reviewers for their helpful comments and suggestions.

Lorna O'Donoghue: Conceptualization, Formal analysis, Visualization, Writing—original draft, Writing—review & editing. Albert Smolenski: Conceptualization, Formal analysis, Visualization, Writing—original draft, Writing—review & editing.

AP

adapter protein

cGMP

cyclic guanosine monophosphate

CIP4

Cdc42-interacting protein 4

COPI

coat protein complex I

CYFIP1

cytoplasmic FMR1 interacting protein 1

DAG

1,2-diacylglycerol

FcRγ

Fc gamma receptor

Fhod1

FH1/FH2 domain-containing protein 1

GAP

GTPase-activating protein

GEF

guanine nucleotide exchange factor

HPS

Hermansky–Pudlak syndrome

IP3

inositol 1,4,5-triphosphate

OCRL

Oculocerebrorenal syndrome of Lowe 1 and Inositol 5-phosphatase

PKG

protein kinase G

ROCK1/2

Rho-associated protein kinases 1 and 2

Slp1

synaptotagmin-like protein 1

SNARE

soluble N-ethylmaleimide-sensitive factor attachment protein receptor

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