An array of signalling molecules are located at the Golgi apparatus, including phosphoinositides, small GTPases, kinases, and phosphatases, which are linked to multiple signalling pathways. Initially considered to be associated predominantly with membrane trafficking, signalling pathways at the Golgi are now recognised to regulate a diverse range of higher-order functions. Many of these signalling pathways are influenced by the architecture of the Golgi. In vertebrate cells, the Golgi consists of individual stacks fused together into a compact ribbon structure and the function of this ribbon structure has been enigmatic. Notably, recent advances have identified a role for the Golgi ribbon in regulation of cellular processes. Fragmentation of the Golgi ribbon results in modulation of many signalling pathways. Various diseases and disorders, including cancer and neurodegeneration, are associated with the loss of the Golgi ribbon and the appearance of a dispersed fragmented Golgi. Here, we review the emerging theme of the Golgi as a cell sensor and highlight the relationship between the morphological status of the Golgi in vertebrate cells and the modulation of signalling networks.

Introduction

The evolution of higher organisms is associated with increased regulation of cellular networks, particularly networks regulating signalling, stress responses, and gene expression. Intracellular compartmentalisation provides an important mechanism for the recruitment and activation of complexes within a defined location. Moreover, the ER, mitochondria, and lysosomes are known to act as cell sensors to monitor stress and/or maintain cell homeostasis [14]. In contrast, the potential role of the Golgi apparatus as a cell sensor has been largely overlooked until relatively recently. Studies from many laboratories using a variety of approaches have uncovered evidence that the Golgi contributes to a range of higher-order functions such as cell polarisation [5], directed migration [6], stress [7], DNA repair [8], mitosis [9], metabolism [10], and autophagy [11,12]. Moreover, there is a strong relationship between the structural form, i.e. the architecture, of the Golgi and the cellular process triggered by this organelle [13,14], implying that the machinery responsible for promoting these cellular processes either regulate or is influenced by the morphological status of the Golgi.

The Golgi exists as a ribbon structure in almost all vertebrate cells during interphase and typically found in a juxtanuclear location in interphase cells [15]. Indeed, the Golgi ribbon represents one of the most characteristic features of vertebrate cells as revealed by electron microscopy. The few exceptions are highly differentiated cells, such as acid-producing gastric parietal cells [16] and uroepithelial cells of the urinary bladder [17], where the Golgi is found dispersed as mini-stacks scattered throughout the cytoplasm. Despite our knowledge of Golgi dynamics and the function of the individual Golgi stacks, the biological raison d'etre of the ‘ribbon’ structure of the Golgi has been poorly appreciated.

Structure of the Golgi

The individual stacks of the Golgi consist of 4–8 flattened, cisternal membranes. These stacks of cisternae are polarised; the two sides, designated cis and trans, are associated with networks of tubular structures — the cis-Golgi network and the trans-Golgi network (TGN), respectively, representing the cargo entry site from the ER and the cargo exit site to various destinations [18]. Each stack houses a large set of glycosyltransferases and processing glycosidases, arranged in the sequence of the biochemical pathway across the stack, and are responsible for the synthesis of the mature N- and O-glycans of glycoproteins and proteoglycans and also synthesises of glycolipids [19]. In single-cell organisms, higher and lower plants, and the invertebrates, Golgi stacks are independent from each other and are dispersed throughout the cytoplasm of the cell. In vertebrates, there are many Golgi membrane proteins which promote the lateral fusion of individual Golgi stacks into a twisted, ribbon structure, maintained around the centrosome by interactions with microtubules and dynein motors [20]. The Golgi ribbon structure is not static; rather it is very dynamic and can undergo profound and rapid remodelling events during many processes [21,22] either during interphase or mitosis. For example, a characteristic of vertebrate cells is the disassembly of the Golgi ribbon as an early event in G2/M transition and considered to play an important role in promoting mitotic entry [23]. Conceptually, the evolution of the Golgi ribbon in higher eukaryotes has provided an additional structural platform to enhance the regulation of complex cell systems compared with lower eukaryotic organisms. The relative importance of this platform is now being realised by recent discoveries.

Spatial regulation of signalling

Molecular events associated with individual intracellular organelles have been defined which regulate signalling, cell growth, survival, and homeostasis. For example, the endosomal system can promote selective signalling events [24], such as the independent Toll-like receptor 4 (TLR4) signalling pathway at the early endosomes which is distinct from the TLR4 signalling at cell surface [25,26], the ER can respond to intracellular and extracellular signals to increase secretion of soluble molecules [27], and the ER and mitochondria are major sensors of the cell to detect stress responses [1,2,28]. Given the central location of the Golgi apparatus in the cell, the importance of the Golgi in both the secretory and endocytic pathways [29,30], and the tenets of cellular networks [31,32], it is reasonable that the Golgi apparatus would also contribute to the co-ordination of signalling and higher-order processes.

Golgi and signalling

Many recent reviews have discussed in detail the relationship between signalling networks and the Golgi [6,7,13,27,33,34]. An important advance in the 1990s and early 2000s was the realisation that signalling pathways at the Golgi regulate membrane transport of protein and lipid cargoes along the secretory pathway. Initially, the view that anterograde transport, i.e. transport of cargo along the secretory pathway to the plasma membrane, was exclusively a constitutive process was challenged by the observation that a receptor-mediated kinase activity promoted ADP-ribosylation factor (ARF) recruitment to the Golgi to regulate membrane transport [35]. Subsequently, a Golgi located signalling network was identified, involving the KDEL receptor as a signalling receptor and Src family kinases, as necessary for membrane trafficking through the Golgi [36,37]. Other studies also revealed that there are signalling molecules on the Golgi, such as ERK (extracellular signal-related kinase)/MAP (mitogen-activated protein) kinases which regulate cell polarisation and migration [38], and ERK/MEK1 which mediates Golgi fragmentation and is essential for mitotic progression and thereby acting as a mitotic checkpoint [39]. During the 1990s and 2000s, an expanding list of signalling molecules were identified on Golgi membranes including phosphoinositides, small GTPases, kinases, phosphatases, and trimeric G proteins [27,33,34], implying the presence of a diverse range of signalling networks.

A landmark study in 2012 used a genome-wide kinome and phosphatome screen to identify phenotypes with altered Golgi morphology in HeLa cells [40]. The authors used a quantitative imaging approach to identify perturbations in Golgi morphology and 159 signalling genes were identified from this screen which affected the morphology of the Golgi. The changes in Golgi morphology included either fragmentation of the Golgi (loss of Golgi ribbon) or the formation of a very compact and condensed Golgi in the perinuclear location. The compact Golgi may represent an enhanced ribbon structure, although the ultrastructural status of this compact structure was not characterised in this particular study. Many kinases, for example ROCK1 and PAK1, were identified which regulate actin dynamics and modulate Golgi structure. Some of the signalling genes, which perturbed Golgi morphology, also affected cargo secretion and/or glycan biosynthesis, indicating that both processes are under control from the same networks [40]. The very abundant collection of kinases and phosphatases identified (20% of the total in the genome) also raised the possibility that the Golgi can receive and transmit a wide variety of signals that could influence a broad range of cellular processes.

In an independent genome-wide kinome and phosphatome screen, 122 kinases/phosphatases were identified which influenced trafficking in the ER and Golgi [41]. Of the 122 hits identified, 38 affected the morphology of the Golgi, and again changes in the morphology of the Golgi included a fragmented Golgi or a more compact Golgi. Many of the Golgi fragmented phenotypes affected cell migration [6,42], which lead to the identification of the phospholipase Cγ1 as a regulator of both Golgi structure and cell migration [42]. Strikingly, network analysis of the 122 hits identified potential links between Golgi structure and signalling pathways which regulate apoptosis, proliferation, cell size, and infection [41].

An emerging theme from these two genomic screens is the link between Golgi morphology and signalling networks. An explanation for this link is that the signalling components and/or their membrane scaffolds modulate the cytoskeleton, particularly actin dynamics. The relevance of this connection is yet to be understood but suggests that at least some of signalling networks regulate, and can be regulated, by cytoskeletal re-modelling of the Golgi morphology. The connection between Golgi morphology and signalling also has important ramifications on understanding diseases where alterations in Golgi morphology, particularly associated with fragmentation of the Golgi ribbon, are a characteristic feature of the cellular phenotype.

Form and function of the Golgi

The Golgi architecture is centred around the integrity of the compact ribbon structure. Some signalling pathways are dampened by the loss of the Golgi ribbon, and other pathways are activated following Golgi fragmentation. In addition, some signalling pathways involve scaffold components which are known to interact with the cytoskeleton and are required for maintenance of Golgi structure [13]. Defining the molecular pathways linking the morphology of the Golgi and signalling is in its infancy and the molecular basis for this intimate relationship is yet to be fully understood. An interesting possibility is that the balance between the Golgi ribbon and Golgi mini-stacks may define the qualitative and quantitative range of signalling responses.

Molecular scaffolds linking cytoskeleton and function

Membrane and peripheral Golgi proteins, the latter orientated on the cytoplasmic side of the Golgi membrane, interact with the microtubule and actin networks and regulate Golgi morphology. In addition, microtubule motors, both kinesin and dynein, and actinomyosin motors are also located on the Golgi and allow movement of Golgi membranes along cytoskeletal tracks [20,4346].

The role of microtubules and the microtubular array in the formation of the Golgi ribbon and its location adjacent to the MTOC (microtubule organizing centre) is well defined [47,48]. In contrast, the role of the actin-based cytoskeletal system in regulating the structure of the Golgi ribbon has only been recognised more recently. Many Golgi-localised molecular scaffolds (∼10) have been identified which interact with the actin cytoskeleton and affect Golgi morphology (see review, [13]). These include the coiled-coil golgins [30,49], such as giantin, GM130 (cis-Golgi matrix protein), golgin245, GCC88 [13] and optineurin [50], the stacking proteins GRASP55/65 (Golgi Reassembly Stacking Protein 55/65) [21], the membrane tether Golgi phosphoprotein 3 (GOLPH3) [51] and the formin FHDC1 [52]. In addition to the regulation of Golgi architecture, there are examples where actin dynamics can influence signalling pathways. For example, the Golgi structural protein, GOLPH3, has been reported to drive an extension of the Golgi ribbon and also to modulate mTOR (mechanistic target of rapamycin) signalling and cell proliferation [53]. Also, the TGN golgin, GCC88, modulates the ribbon structure and influences mTOR signalling [50].

Genetic manipulation of golgins in whole organisms has revealed functions across a diverse range of physiological processes [54]. The findings from in vivo analyses were not predicted from experiments using cultured cells and indicates the existence of golgin-specific binding partners which regulate different cellular pathways [54]. A more detailed analysis of the underlying molecular pathways leading to these in vivo defects will be very informative.

Systems for manipulating the Golgi ribbon and Golgi homeostasis

Previously, many different approaches have been used to disassemble and disperse the Golgi ribbon to study its function. A common approach has been the use of pharmacological agents, such as brefeldin A [55], which perturbs membrane transport and nocodazole [23], which depolymerises microtubules. The functional consequence of the loss of the ribbon structure has been difficult to interpret as these pharmacological agents used are not Golgi-specific. More recently, many strategies have been developed which are more selective. Firstly, genetic manipulations involving the knock-out of key Golgi structural proteins provide a specific mechanism for ablating the Golgi ribbon. GM130 is a key structural golgin which regulates both the Golgi ribbon and also ER to Golgi traffic. Conditional GM130 knockout mice have been generated and the impact of disruption of the Golgi ribbon could be analysed in specific tissues [56]. In the central nervous system, GM130 deficiency causes Golgi fragmentation, atrophy of dendrites and neuronal degeneration in mice. Another approach has been to manipulate the balance between the Golgi ribbon and Golgi mini-stacks by modulating the level of the TGN golgin, GCC88 [57]. This strategy allowed the generation and analysis of stable cell lines that lack a Golgi ribbon. Optical microscopic analyses and EM tomography quantified the morphology of the Golgi in this system. Modest overexpression of GCC88 resulted in loss of the compact ribbon with mini-stacks dispersed throughout the cytoplasm, some of which maintained very long tubular connections with neighbouring stacks. The combined use of optical and EM microscopy demonstrated the importance of using EM techniques to analyse the Golgi ultrastructure and raises questions whether different pathways may exist to dismantle the Golgi ribbon.

A third approach, published very recently, developed a system to analyse the relationship between Golgi structure and stress. The strategy used a chemical biological approach to induce misfolded proteins selectively in the Golgi [58]. The authors compared this approach with the more commonly used, and less specific, inducers of Golgi stress, nigericin, and xyloside. RNAseq analysis identified the upregulation of a set of Golgi-specific stress genes, which included both novel and well-characterised genes important in maintaining Golgi structure [58]. This development of this organelle-specific approach will be particularly useful to determine the Golgi-specific networks associated with stress and homeostasis.

Relationship between Golgi morphology and signalling

There are many examples where signalling influences or is influenced by the morphology of the Golgi, for example processes associated with cell migration, apoptosis, mitosis, DNA repair, Golgi stress response, metabolism, cell proliferation, and autophagy and are summarised in Table 1. Here, examples involving autophagy and metabolism will be discussed in more detail to clearly illustrate the nexus between the Golgi ribbon and signalling networks. For further discussion on the other cell processes regulated by the Golgi, see the following reviews [6,7,13,27,34].

Table 1
Signalling pathways that are promoted upon fragmentation of the Golgi ribbon or that are associated with changes in the structure of the Golgi1
Golgi components which influence signalling pathways Alterations in the Golgi architecture Processes/pathways References 
p115 (fragments) Caspases 3 and 8 mediated cleavage of p115 leads to Golgi fragmentation Apoptosis [82,83
Golgin-160 (fragments) Caspases 2, 3, and 7 cleavage of golgin-160 leads to Golgi fragmentation Apoptosis [84
CREB3/ARF4 BFA-induced Golgi stress promotes proteolytic cleavage of CREB3 transcription factor which leads to up-regulation of AFR4 and Golgi fragmentation Golgi stress response/apoptosis [85
PI(4)P/GOLPH3 Golgi fragmentation and increased mTORC1 activity associated with GOLPH3 overexpression Cell proliferation/mTOR signalling [53
Bif-1/Atg9 Golgi localised Bif-1 regulates the fragmentation of Golgi membranes and biogenesis of autophagosomes during starvation Autophagy [70
GCC88 Overexpression of GCC88 fragments the Golgi ribbon and leads to the loss of mTORC1 recruitment and activation at the Golgi mTOR signalling/autophagy [57
ERK/MAP kinases ERK phosphorylation of GRASP65 promotes remodelling of Golgi architecture Cell polarisation/MAPK signalling [38
JNKs JNK2, JNK3, and p38α MAPK silencing inhibit cell migration through the disruption of the Golgi ribbon Cell migration/MAPK [41
p190RasGAP Cells lacking p190RasGAP exhibit higher levels of active ERK resulting in Golgi fragmentation, which perturbs directional cell migration Cell migration/ERK signalling [86
Protein kinase A (PKA)/cAMP Depletion or inhibition of PKA induces fragmentation of the Golgi; cAMP stimulation promotes the formation of a more compact Golgi ribbon Golgi-to-ER retrograde transport [8789
Hck (Src kinase family member) HIV Nef-mediated activation of Hck at the Golgi promotes cisternal unstacking through the phosphorylation of GRASP65 N-glycosylation/trafficking [90
PTEN/GOLGA2 (GM130) PTEN depletion leads to GOLGA2 exon skipping. The splice variant of GOLGA2 (GM130) promotes elongation of the Golgi and contributes to PTEN loss-of-function-induced secretion and tumorigenesis Secretion/tumorigenesis [72
ERK/MEK1 ERK1c is a Golgi-localised isoform of ERK1 that mediates Golgi fragmentation and is required for mitotic progression Mitosis [39
CG-NAP/AKAP450 PKN, PP2A, or PP1 are recruited to the cis-Golgi through an interaction with CG-NAP/AKAP450 where they may influence various signalling pathways
CG-NAP/AKAP450 is also essential for Golgi-microtubule nucleation 
Cell polarisation/centrosome–Golgi axis [91,92
DNA-PK/GOLPH3 DNA-PK phosphorylates GOLPH3 which induces the dispersal of the Golgi ribbon DNA damage [8
Golgi components which influence signalling pathways Alterations in the Golgi architecture Processes/pathways References 
p115 (fragments) Caspases 3 and 8 mediated cleavage of p115 leads to Golgi fragmentation Apoptosis [82,83
Golgin-160 (fragments) Caspases 2, 3, and 7 cleavage of golgin-160 leads to Golgi fragmentation Apoptosis [84
CREB3/ARF4 BFA-induced Golgi stress promotes proteolytic cleavage of CREB3 transcription factor which leads to up-regulation of AFR4 and Golgi fragmentation Golgi stress response/apoptosis [85
PI(4)P/GOLPH3 Golgi fragmentation and increased mTORC1 activity associated with GOLPH3 overexpression Cell proliferation/mTOR signalling [53
Bif-1/Atg9 Golgi localised Bif-1 regulates the fragmentation of Golgi membranes and biogenesis of autophagosomes during starvation Autophagy [70
GCC88 Overexpression of GCC88 fragments the Golgi ribbon and leads to the loss of mTORC1 recruitment and activation at the Golgi mTOR signalling/autophagy [57
ERK/MAP kinases ERK phosphorylation of GRASP65 promotes remodelling of Golgi architecture Cell polarisation/MAPK signalling [38
JNKs JNK2, JNK3, and p38α MAPK silencing inhibit cell migration through the disruption of the Golgi ribbon Cell migration/MAPK [41
p190RasGAP Cells lacking p190RasGAP exhibit higher levels of active ERK resulting in Golgi fragmentation, which perturbs directional cell migration Cell migration/ERK signalling [86
Protein kinase A (PKA)/cAMP Depletion or inhibition of PKA induces fragmentation of the Golgi; cAMP stimulation promotes the formation of a more compact Golgi ribbon Golgi-to-ER retrograde transport [8789
Hck (Src kinase family member) HIV Nef-mediated activation of Hck at the Golgi promotes cisternal unstacking through the phosphorylation of GRASP65 N-glycosylation/trafficking [90
PTEN/GOLGA2 (GM130) PTEN depletion leads to GOLGA2 exon skipping. The splice variant of GOLGA2 (GM130) promotes elongation of the Golgi and contributes to PTEN loss-of-function-induced secretion and tumorigenesis Secretion/tumorigenesis [72
ERK/MEK1 ERK1c is a Golgi-localised isoform of ERK1 that mediates Golgi fragmentation and is required for mitotic progression Mitosis [39
CG-NAP/AKAP450 PKN, PP2A, or PP1 are recruited to the cis-Golgi through an interaction with CG-NAP/AKAP450 where they may influence various signalling pathways
CG-NAP/AKAP450 is also essential for Golgi-microtubule nucleation 
Cell polarisation/centrosome–Golgi axis [91,92
DNA-PK/GOLPH3 DNA-PK phosphorylates GOLPH3 which induces the dispersal of the Golgi ribbon DNA damage [8

Abbreviations: mTOR, mechanistic target of rapamycin; Bif-1, bar-interacting factor 1; Atg9, autophagy-related protein 9; ERK, extracellular signal-related kinase; MAP, mitogen-activated protein; JNK, c-JUN N-terminal kinase; GAP, GTPase-activating protein; Hck, haematopoietic cell kinase; DUSP, dual specificity phosphatases; MEK1, MAP/ERK; CG-NAP, centrosome and Golgi-localised PKN-associated protein; AKAP450, A-kinase-anchoring protein 450; PKN, serine/threonine-protein kinase N1; PP2A, protein phosphatase 2A; PP2A, protein phosphatase 2; DNA-PK, DNA damage protein kinase; PTEN, phosphatase and tensin homologue.

1

This is a modification and extension of a table published in ref. [13].

mTOR pathway

mTOR is one of the major signalling pathways of eukaryotic cells and known to be a negative regulator of autophagy [59]. Late endosomes/lysosomes are well recognised as a major site for mTORC1 activation [60] and evidence has also emerged over the past few years for a role of the secretory pathway, particularly the Golgi, in mTOR regulation. This evidence includes the following: (i) immunofluorescence microscopy has demonstrated that mTOR is partially localised at the Golgi [57,6164], (ii) the Golgi amino acid transporter, PAT4, influences the activation of mTOR [62], (iii) Rab1A, a small GTPase known to regulate ER to Golgi trafficking, was identified in an RNAi screen as a regulator of mTORC1[64], and (iv) mTOR signalling has also been shown to be modulated by membrane and cytoskeletal interactions mediated by the Golgi membrane tether GOLPH3 [53]. Recently, our laboratory showed that the organisation of the Golgi in a compact ribbon is essential for regulating the mTOR pathway and autophagy; this study used a stable HeLa cell system to modulate the Golgi ribbon by a modest increase in expression of the golgin GCC88 [57]. Loss of the Golgi ribbon in the stable HeLa clones resulted in reduced mTOR activity and an associated increase in autophagosome biogenesis. Our study also showed substantial co-localization of mTOR with a marker of the trans-Golgi network (TGN) in parental HeLa cells. Significantly, there was reduction of both mTOR and activated p-mTOR on the scattered Golgi mini-stacks of HeLa clones lacking a ribbon structure. Assays to monitor the recruitment of mTOR to lysosomes and the Golgi indicated that the two organelles represent distinct sites for mTOR recruitment and activation [57].

Based on the above studies, there is now substantial evidence for a major functional pool of mTOR at the Golgi and that the architecture of the Golgi influences mTOR activation. We propose that mTORC1 is recruited to the Golgi ribbon and then activated by Golgi localised Rheb [57] (Figure 1A,B). Fragmentation of the Golgi ribbon into Golgi mini-stacks abolishes Golgi recruitment of mTORC1, whereas mTORC1 levels on lysosomes remain unchanged. Furthermore, our study suggests that Golgi mTOR contributes to the total active mTOR pool which inhibits autophagy and, moreover, the loss of Golgi mTOR results in the induction of autophagy in cells with a fragmented Golgi ribbon.

Models for Golgi ribbon structure in the regulation of mTOR.

Figure 1.
Models for Golgi ribbon structure in the regulation of mTOR.

(A and B) In the presence of an intact Golgi ribbon, mTORC1 is localised to the Golgi and activated by Golgi localised Rheb. Fragmentation of the Golgi ribbon into Golgi mini-stacks results in reduced levels of activated mTORC1 and conversion of the Golgi ribbon into Golgi mini-stacks, which then leads to induction of autophagy (see the text). (C) Golgi–lysosome membrane contact sites may allow the transfer of mTOR and activated mTOR between lysosome membranes and Golgi membranes.

Figure 1.
Models for Golgi ribbon structure in the regulation of mTOR.

(A and B) In the presence of an intact Golgi ribbon, mTORC1 is localised to the Golgi and activated by Golgi localised Rheb. Fragmentation of the Golgi ribbon into Golgi mini-stacks results in reduced levels of activated mTORC1 and conversion of the Golgi ribbon into Golgi mini-stacks, which then leads to induction of autophagy (see the text). (C) Golgi–lysosome membrane contact sites may allow the transfer of mTOR and activated mTOR between lysosome membranes and Golgi membranes.

Interestingly, there is also another recent report, indicating that the majority of the small GTPase Rheb, an essential activator of mTORC1, is localised to the Golgi and may co-ordinate mTOR activation of lysosomal mTOR via membrane contact sites between the Golgi and lysosomes [65,66] (Figure 1C). An important question pertinent to mTOR activation is how the morphology of the Golgi might influence these membrane Golgi–lysosome contact sites.

Metabolism and proliferation

There is a strong connection between Golgi architecture and cellular processes associated with metabolic control. The connection may be mediated by multiple pathways, such as the mTOR pathway discussed above. Also from a series of studies over the past 10–15 years, there is compelling evidence that the Golgi regulates metabolism by changes in glycosylation which in turn influence signalling events at the cell surface [67,68]. Highly branched glycans on membrane glycoproteins promote galectin–glycoprotein clustering at the PM that subsequently modulates receptor responses and cell growth. Changes associated with galectin-mediated responses have been reported for tumour cells with fragmented Golgi ribbons [69]. Also of potential relevance is that cell starvation promotes fragmentation of the Golgi ribbon [70]. The loss of the Golgi ribbon appears to impact on a sub-set of glycosylation events: disruption of the continuous Golgi ribbon, by depletion of the cis-Golgi matrix protein GM130, has been shown to result in a perturbation in the distribution of glycosyltransferases involved in O-glycosylation and alterations in glycosylation of glycoproteins expressed at the cell surface [69,71]. Conversely, a splice variant of GM130 has recently been described, which is induced following phosphatase and tensin homologue (PTEN) knockdown, which elongates the Golgi and enhances secretion and proliferation [72]. Hence, the events associated with the formation of the Golgi ribbon may be integrated to the metabolic status of the cell.

Proliferation and apoptosis are also linked to changes associated with Golgi morphology. Prostate tumour cells which are resistant to androgens often have a fragmented Golgi, whereas normal prostate cells have a typical compact Golgi morphology. Golgi fragmentation is associated with altered O-glycan synthesis in these tumour cells and considered a likely explanation for defects in galectin-1-induced apoptosis [69]. This proposal was supported by the finding that treatment of the tumour cells with drugs to inhibit actin polymerisation restored of a ‘ribbon-like’ Golgi in the androgen-refractory prostate tumour cells and also restored increased susceptibility to galectin-1-mediated apoptosis [69]. These findings indicate that the organisation of the Golgi as a ribbon structure is critical for regulating the glycan–galectin signalling pathways which influence proliferation and apoptosis [67].

Perturbations in Golgi morphology associated with disorders and disease

Various diseases and disorders are associated with the loss of the Golgi ribbon [73,74] and the appearance of a dispersed fragmented Golgi. These include responses to stress from intracellular damage or from infection, neurodegeneration, and cancer. In most cases, the precise nature of these Golgi fragments has not been characterised ultra-structurally and could be Golgi ‘mini-stacks’.

A large number of diseases have been identified with inherited mutations associated with Golgi machinery (reviewed in [75,76]). Golgi fragmentation is also associated with a number of these genetically inherited diseases, for example, mutations in genes encoding Golgi components involved with membrane trafficking and/or glycosylation, such as defects in the conserved oligomeric Golgi complex (COG) in congenital disorders of glycosylation [77]. The pathological phenotype of these inherited diseases is likely to arise from not only the deficiencies in glycosylation and secretion, as documented in the literature [78], but also alterations in signalling networks associated with the loss of the Golgi ribbon, such as Golgi stress responses.

Fragmentation of the Golgi ribbon is a feature of many neurodegenerative diseases including Alzheimer's disease, Huntington disease, amyotrophic lateral sclerosis, and Parkinson's disease, from both animal models and human disease (for reviews, see [73,74,79]). A key question that was difficult to resolve is whether the fragmentation of the Golgi contributes directly to the cellular processes associated with neuronal death and neurodegeneration or whether the altered Golgi morphology is a secondary consequence of pathways leading to the cellular dysfunction and pathology. Given the recent discoveries of the relationship between Golgi morphology and signalling discussed in this review, it is very likely that the perturbations in the Golgi in these diseases results in substantial changes in signalling networks affecting multiple cellular processes. The analysis of GM130-deficient neurons, discussed earlier, clearly showed neuronal degeneration and neuronal loss [56]. Further support comes from the overexpression of the microtubule-binding protein, tau, widely used as a model of neurodegeneration [80]. Following expression of tau in the neuroblastoma cells, SK-N-SH, we demonstrated that fragmentation of the Golgi ribbon was an early event, followed by compromised mTOR activity and induction of autophagy [57]. These findings show that mTOR signalling is affected by different pathways leading to the Golgi fragmentation and also indicate that mTOR signalling may play an important role in the loss of the Golgi ribbon associated with these disorders. Perturbations in Golgi morphology have also been reported with many tumours [8,81], and there is evidence that changes in Golgi morphology can contribute to tumorigenesis by enhanced cell survival after DNA damage.

Advances are now likely to be rapid using a range of tools to uncover the molecular pathways that link the architectural status of the Golgi to various pathological conditions, information which could provide new targets for pharmacological intervention.

Summary

In addition to its classic functions of glycosylation and membrane trafficking, it is now clear that the Golgi apparatus regulates a diverse range of higher-order functions. Moreover, there is an intimate relationship between the Golgi architecture and signalling networks. Fragmentation of the Golgi ribbon structure is associated with changes in a diverse range of cellular processes. The challenge now is to map the full set of signalling networks at the Golgi and to determine how the changes in the dynamic ribbon morphology of the Golgi influence these networks. Given the identification of many Golgi scaffold molecules which regulate Golgi architecture, the genetic manipulation of these components allows ribbon morphology to be modulated in cell lines and in whole organisms to understand how this organelle regulates cell development, metabolism, and proliferation in a variety of different primary cells and why fragmentation of the ribbon architecture is associated with a variety of pathological conditions.

Abbreviations

     
  • ARF

    ADP-ribosylation factor

  •  
  • ERK

    extracellular signal-related kinase

  •  
  • GM130

    cis-Golgi matrix protein

  •  
  • GOLPH3

    Golgi phosphoprotein 3

  •  
  • GRASP

    Golgi reassembly stacking protein

  •  
  • MAP

    mitogen-activated protein

  •  
  • mTOR

    mechanistic target of rapamycin

  •  
  • PI(4)P

    phosphatidylinositol-4-phosphate

  •  
  • PTEN

    phosphatase and tensin homologue

  •  
  • TGN

    trans-Golgi network

  •  
  • TLR4

    Toll-like receptor 4

Funding

This work was supported by funding from Australian Research Council [DP160102394].

Competing Interests

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

References

References
1
Su
,
J.
,
Zhou
,
L.
,
Kong
,
X.
,
Yang
,
X.
,
Xiang
,
X.
,
Zhang
,
Y.
et al. 
(
2013
)
Endoplasmic reticulum is at the crossroads of autophagy, inflammation, and apoptosis signaling pathways and participates in the pathogenesis of diabetes mellitus
.
J. Diabetes Res.
2013
,
193461
2
Bohovych
,
I.
and
Khalimonchuk
,
O.
(
2016
)
Sending out an SOS: mitochondria as a signaling hub
.
Front. Cell Dev. Biol.
4
,
109
3
Perera
,
R.M.
and
Zoncu
,
R.
(
2016
)
The lysosome as a regulatory hub
.
Annu. Rev. Cell Dev. Biol.
32
,
223
253
4
Settembre
,
C.
,
Fraldi
,
A.
,
Medina
,
D.L.
and
Ballabio
,
A.
(
2013
)
Signals from the lysosome: a control centre for cellular clearance and energy metabolism
.
Nat. Rev. Mol. Cell Biol.
14
,
283
296
5
Kupfer
,
A.
,
Dennert
,
G.
and
Singer
,
S.J.
(
1983
)
Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets
.
Proc. Natl Acad. Sci. U.S.A.
80
,
7224
7228
6
Millarte
,
V.
and
Farhan
,
H.
(
2012
)
The Golgi in cell migration: regulation by signal transduction and its implications for cancer cell metastasis
.
ScientificWorldJournal.
2012
,
498278
7
Sasaki
,
K.
and
Yoshida
,
H.
(
2015
)
Organelle autoregulation-stress responses in the ER, Golgi, mitochondria and lysosome
.
J. Biochem.
157
,
185
195
8
Farber-Katz
,
S.E.
,
Dippold
,
H.C.
,
Buschman
,
M.D.
,
Peterman
,
M.C.
,
Xing
,
M.
,
Noakes
,
C.J.
et al. 
(
2014
)
DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3
.
Cell
156
,
413
427
9
Rabouille
,
C.
and
Kondylis
,
V.
(
2007
)
Golgi ribbon unlinking: an organelle-based G2/M checkpoint
.
Cell Cycle
6
,
2723
2729
10
Abdel Rahman
,
A.M.
,
Ryczko
,
M.
,
Nakano
,
M.
,
Pawling
,
J.
,
Rodrigues
,
T.
,
Johswich
,
A.
et al. 
(
2015
)
Golgi N-glycan branching N-acetylglucosaminyltransferases I, V and VI promote nutrient uptake and metabolism
.
Glycobiology
25
,
225
240
11
Yamamoto
,
H.
,
Kakuta
,
S.
,
Watanabe
,
T.M.
,
Kitamura
,
A.
,
Sekito
,
T.
,
Kondo-Kakuta
,
C.
et al. 
(
2012
)
Atg9 vesicles are an important membrane source during early steps of autophagosome formation
.
J. Cell Biol.
198
,
219
233
12
Lamb
,
C.A.
,
Yoshimori
,
T.
and
Tooze
,
S.A.
(
2013
)
The autophagosome: origins unknown, biogenesis complex
.
Nat. Rev. Mol. Cell Biol.
14
,
759
774
13
Gosavi
,
P.
and
Gleeson
,
P.A.
(
2017
)
The function of the Golgi ribbon structure—an enduring mystery unfolds!
BioEssays
39
,
1700063
.
14
Wei
,
J.H.
and
Seemann
,
J.
(
2017
)
Golgi ribbon disassembly during mitosis, differentiation and disease progression
.
Curr. Opin. Cell Biol.
47
,
43
51
15
De Matteis
,
M.A.
,
Mironov
,
A.A.
and
Beznoussenko
,
G.V
. (
2008
) The Golgi ribbon and the function of the golgins. In
The Golgi Apparatus
(
Mironov
,
A.
,
Pavelka
,
M.
, eds), pp.
223
246
,
Springer-Verlag/Wein
,
New York
16
Gunn
,
P.A.
,
Gliddon
,
B.L.
,
Londrigan
,
S.L.
,
Lew
,
A.M.
,
van Driel
,
I.R.
and
Gleeson
,
P.A.
(
2011
)
The Golgi apparatus in the endomembrane-rich gastric parietal cells exist as functional stable mini-stacks dispersed throughout the cytoplasm
.
Biol. Cell
103
,
559
572
17
Kreft
,
M.E.
,
Di Giandomenico
,
D.
,
Beznoussenko
,
G.V.
,
Resnik
,
N.
,
Mironov
,
A.A.
and
Jezernik
,
K.
(
2010
)
Golgi apparatus fragmentation as a mechanism responsible for uniform delivery of uroplakins to the apical plasma membrane of uroepithelial cells
.
Biol. Cell
102
,
593
607
18
Boncompain
,
G.
and
Perez
,
F.
(
2013
)
The many routes of Golgi-dependent trafficking
.
Histochem. Cell Biol.
140
,
251
260
19
Varki
,
A.
,
Cummings
,
R.D.
,
Esko
,
J.D.
,
Freeze
,
H.H.
,
Stanley
,
P.
and
Bertozzi
,
C.R.
(eds) (
2009
)
Essentials of Glycobiology
,
Cold Spring Harbor
,
New York
20
Rios
,
R.M.
and
Borens
,
M.
(
2003
)
The Golgi apparatus at the cell centre
.
Curr. Opin. Cell Biol.
15
,
60
66
21
Ramirez
,
I.B.
and
Lowe
,
M.
(
2009
)
Golgins and GRASPs: holding the Golgi together
.
Semin. Cell Dev. Biol.
20
,
770
779
22
Yadav
,
S.
,
Puri
,
S.
and
Linstedt
,
A.D.
(
2009
)
A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing
.
Mol. Biol. Cell
20
,
1728
1736
23
Wei
,
J.H.
and
Seemann
,
J.
(
2010
)
Unraveling the Golgi ribbon
.
Traffic
11
,
1391
1400
24
Murphy
,
J.E.
,
Padilla
,
B.E.
,
Hasdemir
,
B.
,
Cottrell
,
G.S.
and
Bunnett
,
N.W.
(
2009
)
Endosomes: a legitimate platform for the signaling train
.
Proc. Natl Acad. Sci. U.S.A.
106
,
17615
17622
25
Watts
,
C.
(
2008
)
Location, location, location: identifying the neighborhoods of LPS signaling
.
Nat. Immunol.
9
,
343
345
26
Kagan
,
J.C.
,
Su
,
T.
,
Horng
,
T.
,
Chow
,
A.
,
Akira
,
S.
and
Medzhitov
,
R.
(
2008
)
TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β
.
Nat. Immunol.
9
,
361
368
27
Farhan
,
H.
and
Rabouille
,
C.
(
2011
)
Signalling to and from the secretory pathway
.
J. Cell Sci.
124
(
Pt 2
),
171
180
28
Chen
,
Y.
and
Brandizzi
,
F.
(
2013
)
IRE1: ER stress sensor and cell fate executor
.
Trends Cell Biol.
23
,
547
555
29
Chia
,
P.Z.
and
Gleeson
,
P.A.
(
2011
)
The regulation of endosome-to-Golgi retrograde transport by tethers and scaffolds
.
Traffic
12
,
939
947
30
Goud
,
B.
and
Gleeson
,
P.A.
(
2010
)
TGN golgins, Rabs and cytoskeleton: regulating the Golgi trafficking highways
.
Trends Cell Biol.
20
,
329
336
31
Mitra
,
K.
,
Carvunis
,
A.R.
,
Ramesh
,
S.K.
and
Ideker
,
T.
(
2013
)
Integrative approaches for finding modular structure in biological networks
.
Nat. Rev. Genet.
14
,
719
732
32
Kitano
,
H.
(
2010
)
Grand challenges in systems physiology
.
Front. Physiol.
1
,
3
33
Luini
,
A.
and
Parashuraman
,
S.
(
2016
)
Signaling at the Golgi: sensing and controlling the membrane fluxes
.
Curr. Opin. Cell Biol.
39
,
37
42
34
Mayinger
,
P.
(
2011
)
Signaling at the Golgi
.
Cold Spring Harb. Perspect. Biol.
3
,
a005314
35
De Matteis
,
M.A.
,
Santini
,
G.
,
Kahn
,
R.A.
,
Di Tullio
,
G.
and
Luini
,
A.
(
1993
)
Receptor and protein kinase C-mediated regulation of ARF binding to the Golgi complex
.
Nature
364
,
818
821
36
Pulvirenti
,
T.
,
Giannotta
,
M.
,
Capestrano
,
M.
,
Capitani
,
M.
,
Pisanu
,
A.
,
Polishchuk
,
R.S.
et al. 
(
2008
)
A traffic-activated Golgi-based signalling circuit coordinates the secretory pathway
.
Nat. Cell Biol.
10
,
912
922
37
Bard
,
F.
,
Mazelin
,
L.
,
Pechoux-Longin
,
C.
,
Malhotra
,
V.
and
Jurdic
,
P.
(
2003
)
Src regulates Golgi structure and KDEL receptor-dependent retrograde transport to the endoplasmic reticulum
.
J. Biol. Chem.
278
,
46601
6
38
Bisel
,
B.
,
Wang
,
Y.
,
Wei
,
J.H.
,
Xiang
,
Y.
,
Tang
,
D.
,
Miron-Mendoza
,
M.
et al. 
(
2008
)
ERK regulates Golgi and centrosome orientation towards the leading edge through GRASP65
.
J. Cell Biol.
182
,
837
843
39
Shaul
,
Y.D.
and
Seger
,
R.
(
2006
)
ERK1c regulates Golgi fragmentation during mitosis
.
J. Cell Biol.
172
,
885
897
40
Chia
,
J.
,
Goh
,
G.
,
Racine
,
V.
,
Ng
,
S.
,
Kumar
,
P.
and
Bard
,
F.
(
2012
)
RNAi screening reveals a large signaling network controlling the Golgi apparatus in human cells
.
Mol. Syst. Biol.
8
,
629
41
Farhan
,
H.
,
Wendeler
,
M.W.
,
Mitrovic
,
S.
,
Fava
,
E.
,
Silberberg
,
Y.
,
Sharan
,
R.
et al. 
(
2010
)
MAPK signaling to the early secretory pathway revealed by kinase/phosphatase functional screening
.
J. Cell Biol.
189
,
997
1011
42
Millarte
,
V.
,
Boncompain
,
G.
,
Tillmann
,
K.
,
Perez
,
F.
,
Sztul
,
E.
and
Farhan
,
H.
(
2015
)
Phospholipase C gamma1 regulates early secretory trafficking and cell migration via interaction with p115
.
Mol. Biol. Cell
26
,
2263
2278
43
Allan
,
V.J.
,
Thompson
,
H.M.
and
McNiven
,
M.A.
(
2002
)
Motoring around the Golgi
.
Nat. Cell Biol.
4
,
E236
E242
44
Egea
,
G.
,
Serra-Peinado
,
C.
,
Salcedo-Sicilia
,
L.
and
Gutiérrez-Martínez
,
E.
(
2013
)
Actin acting at the Golgi
.
Histochem. Cell Biol.
140
,
347
360
45
Rexach
,
M.F.
,
Latterich
,
M.
and
Schekman
,
R.W.
(
1994
)
Characteristics of endoplasmic reticulum-derived transport vesicles
.
J. Cell Biol.
126
,
1133
1148
46
Zhu
,
X.
and
Kaverina
,
I.
(
2013
)
Golgi as an MTOC: making microtubules for its own good
.
Histochem. Cell Biol.
140
,
361
367
47
Sanders
,
A.A.
and
Kaverina
,
I.
(
2015
)
Nucleation and dynamics of Golgi-derived microtubules
.
Front. Neurosci.
9
,
431
48
Sutterlin
,
C.
and
Colanzi
,
A.
(
2010
)
The Golgi and the centrosome: building a functional partnership
.
J. Cell Biol.
188
,
621
628
49
Munro
,
S.
(
2011
)
The golgin coiled-coil proteins of the Golgi apparatus
.
Cold Spring Harb. Perspect. Biol.
3
,
a005256
50
Sahlender
,
D.A.
,
Roberts
,
R.C.
,
Arden
,
S.D.
,
Spudich
,
G.
,
Taylor
,
M.J.
,
Luzio
,
J.P.
et al. 
(
2005
)
Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis
.
J. Cell Biol.
169
,
285
295
51
Buschman
,
M.D.
,
Xing
,
M.
and
Field
,
S.J.
(
2015
)
The GOLPH3 pathway regulates Golgi shape and function and is activated by DNA damage
.
Front. Neurosci.
9
,
362
52
Copeland
,
S.J.
,
Thurston
,
S.F.
and
Copeland
,
J.W.
(
2016
)
Actin- and microtubule-dependent regulation of Golgi morphology by FHDC1
.
Mol. Biol. Cell
27
,
260
276
53
Scott
,
K.L.
,
Kabbarah
,
O.
,
Liang
,
M.C.
,
Ivanova
,
E.
,
Anagnostou
,
V.
,
Wu
,
J.
et al. 
(
2009
)
GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer
.
Nature
459
,
1085
1090
54
Toh
,
W.H.
and
Gleeson
,
P.A.
(
2016
)
Emerging insights into the roles of membrane tethers from analysis of whole organisms: the tip of an iceberg?
Front. Cell Dev. Biol.
4
,
12
55
Ignashkova
,
T.I.
,
Gendarme
,
M.
,
Peschk
,
K.
,
Eggenweiler
,
H.M.
,
Lindemann
,
R.K.
and
Reiling
,
J.H.
(
2017
)
Cell survival and protein secretion associated with Golgi integrity in response to Golgi stress-inducing agents
.
Traffic
18
,
530
544
56
Liu
,
C.
,
Mei
,
M.
,
Li
,
Q.
,
Roboti
,
P.
,
Pang
,
Q.
,
Ying
,
Z.
et al. 
(
2017
)
Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice
.
Proc. Natl Acad. Sci. U.S.A.
114
,
346
351
57
Gosavi
,
P.
,
Houghton
,
F.J.
,
McMillan
,
P.J.
,
Hanssen
,
E.
and
Gleeson
,
P.A.
(
2018
)
The Golgi ribbon in mammalian cells negatively regulates autophagy by modulating mTOR activity
.
J. Cell Sci.
131
,
jcs211987
58
Serebrenik
,
Y.V.
,
Hellerschmied
,
D.
,
Toure
,
M.
,
López-Giráldez
,
F.
,
Brookner
,
D.
and
Crews
,
C.M.
(
2018
)
Targeted protein unfolding uncovers a Golgi-specific transcriptional stress response
.
Mol. Biol. Cell
29
,
1284
1298
59
Wullschleger
,
S.
,
Loewith
,
R.
and
Hall
,
M.N.
(
2006
)
TOR signaling in growth and metabolism
.
Cell
124
,
471
484
60
Sancak
,
Y.
,
Bar-Peled
,
L.
,
Zoncu
,
R.
,
Markhard
,
A.L.
,
Nada
,
S.
and
Sabatini
,
D.M.
(
2010
)
Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids
.
Cell
141
,
290
303
61
Drenan
,
R.M.
,
Liu
,
X.
,
Bertram
,
P.G.
and
Zheng
,
X.F.
(
2004
)
FKBP12-rapamycin-associated protein or mammalian target of rapamycin (FRAP/mTOR) localization in the endoplasmic reticulum and the Golgi apparatus
.
J. Biol. Chem.
279
,
772
778
62
Fan
,
S.J.
,
Snell
,
C.
,
Turley
,
H.
,
Li
,
J.L.
,
McCormick
,
R.
,
Perera
,
S.M.
et al. 
(
2016
)
PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer
.
Oncogene
35
,
3004
3015
63
Liu
,
X.
and
Zheng
,
X.F.
(
2007
)
Endoplasmic reticulum and Golgi localization sequences for mammalian target of rapamycin
.
Mol. Biol. Cell
18
,
1073
1082
64
Thomas
,
J.D.
,
Zhang
,
Y.J.
,
Wei
,
Y.H.
,
Cho
,
J.H.
,
Morris
,
L.E.
,
Wang
,
H.Y.
et al. 
(
2014
)
Rab1a is an mTORC1 activator and a colorectal oncogene
.
Cancer Cell
26
,
754
769
65
Hao
,
F.
,
Kondo
,
K.
,
Itoh
,
T.
,
Ikari
,
S.
,
Nada
,
S.
,
Okada
,
M.
et al. 
(
2018
)
Rheb localized on the Golgi membrane activates lysosome-localized mTORC1 at the Golgi-lysosome contact site
.
J. Cell Sci.
131
,
jcs208017
66
Starling
,
G.P.
,
Yip
,
Y.Y.
,
Sanger
,
A.
,
Morton
,
P.E.
,
Eden
,
E.R.
and
Dodding
,
M.P.
(
2016
)
Folliculin directs the formation of a Rab34-RILP complex to control the nutrient-dependent dynamic distribution of lysosomes
.
EMBO Rep.
17
,
823
841
67
Boscher
,
C.
,
Dennis
,
J.W.
and
Nabi
,
I.R.
(
2011
)
Glycosylation, galectins and cellular signaling
.
Curr. Opin. Cell Biol.
23
,
383
392
68
Ryczko
,
M.C.
,
Pawling
,
J.
,
Chen
,
R.
,
Abdel Rahman
,
A.M.
,
Yau
,
K.
,
Copeland
,
J.K.
et al. 
(
2016
)
Metabolic reprogramming by hexosamine biosynthetic and Golgi N-glycan branching pathways
.
Sci. Rep.
6
,
23043
69
Petrosyan
,
A.
,
Holzapfel
,
M.S.
,
Muirhead
,
D.E.
and
Cheng
,
P.W.
(
2014
)
Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis
.
Mol. Cancer Res.
12
,
1704
1716
70
Takahashi
,
Y.
,
Meyerkord
,
C.L.
,
Hori
,
T.
,
Runkle
,
K.
,
Fox
,
T.E.
,
Kester
,
M.
et al. 
(
2011
)
Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy
.
Autophagy
7
,
61
73
71
Puthenveedu
,
M.A.
,
Bachert
,
C.
,
Puri
,
S.
,
Lanni
,
F.
and
Linstedt
,
A.D.
(
2006
)
GM130 and GRASP65-dependent lateral cisternal fusion allows uniform Golgi-enzyme distribution
.
Nat. Cell Biol.
8
,
238
248
72
Shen
,
S.M.
,
Ji
,
Y.
,
Zhang
,
C.
,
Dong
,
S.S.
,
Yang
,
S.
,
Xiong
,
Z.
et al. 
(
2018
)
Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role
.
Nat. Commun.
9
,
2392
73
Rabouille
,
C.
and
Haase
,
G.
(
2015
)
Editorial: Golgi pathology in neurodegenerative diseases
.
Front. Neurosci.
9
,
489
74
Sundaramoorthy
,
V.
,
Sultana
,
J.M.
and
Atkin
,
J.D.
(
2015
)
Golgi fragmentation in amyotrophic lateral sclerosis, an overview of possible triggers and consequences
.
Front. Neurosci.
9
,
400
75
Bexiga
,
M.G.
and
Simpson
,
J.C.
(
2013
)
Human diseases associated with form and function of the Golgi complex
.
Int. J. Mol. Sci.
14
,
18670
18681
76
Zappa
,
F.
,
Failli
,
M.
and
De Matteis
,
M.A.
(
2018
)
The Golgi complex in disease and therapy
.
Curr. Opin. Cell Biol.
50
,
102
116
77
Miller
,
V.J.
and
Ungar
,
D.
(
2012
)
Re‘COG'nition at the Golgi
.
Traffic
13
,
891
897
78
Smith
,
R.D.
and
Lupashin
,
V.V.
(
2008
)
Role of the conserved oligomeric Golgi (COG) complex in protein glycosylation
.
Carbohydr. Res.
343
,
2024
2031
79
Gonatas
,
N.K.
,
Stieber
,
A.
and
Gonatas
,
J.O.
(
2006
)
Fragmentation of the Golgi apparatus in neurodegenerative diseases and cell death
.
J. Neurol. Sci.
246
,
21
30
80
Liazoghli
,
D.
,
Perreault
,
S.
,
Micheva
,
K.D.
,
Desjardins
,
M.
and
Leclerc
,
N.
(
2005
)
Fragmentation of the Golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons
.
Am. J. Pathol.
166
,
1499
1514
81
McKinnon
,
C.M.
and
Mellor
,
H.
(
2017
)
The tumor suppressor RhoBTB1 controls Golgi integrity and breast cancer cell invasion through METTL7B
.
BMC Cancer
17
,
145
82
Chiu
,
R.
,
Novikov
,
L.
,
Mukherjee
,
S.
and
Shields
,
D.
(
2002
)
A caspase cleavage fragment of p115 induces fragmentation of the Golgi apparatus and apoptosis
.
J. Cell Biol.
159
,
637
648
83
How
,
P.C.
and
Shields
,
D.
(
2011
)
Tethering function of the caspase cleavage fragment of Golgi protein p115 promotes apoptosis via a p53-dependent pathway
.
J. Biol. Chem.
286
,
8565
8576
84
Mancini
,
M.
,
Machamer
,
C.E.
,
Roy
,
S.
,
Nicholson
,
D.W.
,
Thornberry
,
N.A.
,
Casciola-Rosen
,
L.A.
et al. 
(
2000
)
Caspase-2 is localized at the Golgi complex and cleaves golgin-160 during apoptosis
.
J. Cell Biol.
149
,
603
612
85
Reiling
,
J.H.
,
Olive
,
A.J.
,
Sanyal
,
S.
,
Carette
,
J.E.
,
Brummelkamp
,
T.R.
,
Ploegh
,
H.L.
et al. 
(
2013
)
A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens
.
Nat. Cell Biol.
15
,
1473
1485
86
Kulkarni
,
S.V.
,
Gish
,
G.
,
van der Geer
,
P.
,
Henkemeyer
,
M.
and
Pawson
,
T.
(
2000
)
Role of p120 Ras-GAP in directed cell movement
.
J. Cell Biol.
149
,
457
470
87
Cabrera
,
M.
,
Muñiz
,
M.
,
Hidalgo
,
J.
,
Vega
,
L.
,
Martín
,
M.E.
and
Velasco
,
A.
(
2003
)
The retrieval function of the KDEL receptor requires PKA phosphorylation of its C-terminus
.
Mol. Biol. Cell
14
,
4114
4125
88
Bejarano
,
E.
,
Cabrera
,
M.
,
Vega
,
L.
,
Hidalgo
,
J.
and
Velasco
,
A.
(
2006
)
Golgi structural stability and biogenesis depend on associated PKA activity
.
J. Cell Sci.
119
(
Pt 18
),
3764
3775
89
Mavillard
,
F.
,
Hidalgo
,
J.
,
Megias
,
D.
,
Levitsky
,
K.L.
and
Velasco
,
A.
(
2010
)
PKA-mediated Golgi remodeling during cAMP signal transmission
.
Traffic
11
,
90
109
90
Hiyoshi
,
M.
,
Takahashi-Makise
,
N.
,
Yoshidomi
,
Y.
,
Chutiwitoonchai
,
N.
,
Chihara
,
T.
,
Okada
,
M.
et al. 
(
2012
)
HIV-1 Nef perturbs the function, structure, and signaling of the Golgi through the Src kinase Hck
.
J. Cell Physiol.
227
,
1090
1097
91
Takahashi
,
M.
,
Shibata
,
H.
,
Shimakawa
,
M.
,
Miyamoto
,
M.
,
Mukai
,
H.
and
Ono
,
Y.
(
1999
)
Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the Golgi apparatus
.
J. Biol. Chem.
274
,
17267
17274
92
Rivero
,
S.
,
Cardenas
,
J.
,
Bornens
,
M.
and
Rios
,
R.M.
(
2009
)
Microtubule nucleation at the cis-side of the Golgi apparatus requires AKAP450 and GM130
.
EMBO J.
28
,
1016
1028