Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.

During the morphogenesis of normal tissues, the balance between stem cell self-renewal and differentiation is regulated by symmetric and asymmetric cell divisions [1]. Certain features of these ontogenetic processes are hijacked in cancer by CSC, which are conceptualized as the cells that initiate a tumor, thus fuelling intra-tumoral clonal diversity and seeding metastasis [2]. Similar to their normal stem cell counterparts they appear to be endowed with a self-renewal capacity. Their quiescence, render CSC comparatively insensitive to classical anti-proliferative drugs [3]. Therefore, specific CSC targeting drugs were sought in recent years, which typically emerged from phenotypic screens [4,5]. However, most of these approaches delivered compounds with divergent targets. Often these targets were not obviously associated with stemness, unless inhibitors of stemness pathways such as Wnt and Hh were assessed [6]. One campaign stumbled across the fact that several experimental CSC drugs selectively affect K-Ras, but not H-Ras [7]. This was in line with data by the McCormick group showing that mutant K-Ras, but not H-Ras has exquisite potential to instruct stemness traits in cancer cells [8]. Earlier, the Settleman group made similar observations in the F9 stem cell model, showing that oncogenic K-Ras promotes proliferative expansion of the stem cells, and N-Ras adopts a neutral role, while H-Ras induces differentiation [9] (Figure 1). This Ras-isoform dependent propensity to promote stemness strikingly correlates with the mutation frequency of RAS genes, with KRAS, NRAS and HRAS being mutated in 75%, 17% and 7% of RAS-mutant human cancers [10]. In this review, we will examine the evidence for Ras proteins being involved with the emergence of stemness traits in cancer cells.

The canonical Ras proteins appear to have isoform specific potential to drive stemness.

Figure 1.
The canonical Ras proteins appear to have isoform specific potential to drive stemness.

In the few direct comparisons that have been studied, K-Ras has the highest potential to induce stemness traits. N-Ras appears to be neutral or have a bimodal activity. At the other end of the spectrum, H-Ras may rather drive differentiation, while it is in some context also able to support stemness.

Figure 1.
The canonical Ras proteins appear to have isoform specific potential to drive stemness.

In the few direct comparisons that have been studied, K-Ras has the highest potential to induce stemness traits. N-Ras appears to be neutral or have a bimodal activity. At the other end of the spectrum, H-Ras may rather drive differentiation, while it is in some context also able to support stemness.

Close modal

HRAS is the most frequently mutated (5.1%) RAS gene in head and neck squamous cell carcinomas [10]. Recently, the farnesyltransferase inhibitor tipifarnib has been reintroduced for treatment of HRAS mutant cancers [11]. While tipifarnib can affect several farnesylated proteins, it is interesting to note that it down-regulated CSC marker CD44 [11]. Expression of markers like CD44, CD133/prominin-1 or of classical pluripotency markers such as OCT4, SOX2 and NANOG are used to characterize stemness in cancer cells [12–15]. Functionally, stemness is frequently assessed in clonogenic 3D spheroid assays under serum-free conditions to analyze the self-renewal potential [16]. Consistently, serum depletion induces CSC-like properties in HRAS-G12V transformed mouse embryonic fibroblasts, which then displayed prominin-1 and elevated levels of OCT4 [17].

Some drug treatments may trigger intrinsic feedback loops, which turn into stemness promoting resistance mechanisms. Rapamycin increases the expression of galectin-1, a nanocluster scaffold of GTP-H-Ras [18,19]. Active Ras nanocluster are signaling platforms of Ras, Raf-effectors and other modulators of Ras signaling [20]. In addition to increasing Ras-MAPK-signaling, galectin-1 promoted the expression of the CSC marker CD44 and increased sphere formation in a HRAS- but not in a KRAS-mutant breast cancer cell line [19]. A related study established that stimulation of mTORC1 with amino acids increases oncogenic H-Ras- but decreases K-Ras-nanoclustering via a phosphatidic acid-dependent mechanism downstream of SREBP1, with attendant consequences for spheroid growth of HRAS and KRAS mutant cancer cells [21]. Similar to its intermediate activity in stem cells, oncogenic N-Ras appears to drive cancer cell stemness in a bi-modal fashion, increasing the self-renewal capacity in one subset of hematopoietic stem cells, while increasing cell division in another subset [22].

Activating KRAS mutations are most frequently observed in pancreatic cancer (88%) [10]. Several pancreatic cancer cell lines (e.g. PANC1, SW1990 and Patu8988) express prominin-1, OCT4, SOX2, NANOG and show increased sphere-forming capacity in a K-Ras dependent manner [23]. Activating mutations in KRAS furthermore correlated with a higher proportion of DLD1 colon cancer cells staining positively for CD44 and prominin-1, as well as for typical pluripotency markers, while xenografting of these cells demonstrated increased tumor propagation capacity [24]. Similarly, tumorospheres of KRAS-mutant lung adenocarcinoma cell lines, A549, H358, H23, up-regulated prominin-1, OCT4 and NANOG and showed enhanced self-renewal capacity [25].

It will be interesting to examine the CSC-specific effect of potent K-Ras inhibition, using recent G12C-specific covalent inhibitors as tools, given that these compounds reduce 3D spheroid growth more KRAS-selectively than 2D growth [26].

Oncogenic K-Ras can increase classical stemness signaling pathways, such as Hh-signaling in pancreatic ductal cells, which normally lack sonic hedgehog [27]. Likewise, K-Ras can up-regulate components of the Wnt/β-catenin-pathway [28]. Both the Wnt/β-catenin- and the Hh-pathways operate at the primary cilium (PC), an important sensory organelle with critical roles in stem cell self-renewal [29–32]. MAPK-signaling was found to be initiated from within the PC in NIH-3T3 fibroblasts [33] and treatment with MAPK inhibitor reduced PC length in MDCK cells [34]. Intriguingly, subcellular trafficking pathways of K-Ras imply its association with the PC [35,36].

The K-Ras stemness mechanism by Wang et al. suggested that the ability of K-Ras, but not H-Ras, to bind and sequester calmodulin (CaM), suppresses non-canonical Wnt-signaling. A K-RasG12V-dependent decrease in Ca2+/calmodulin-dependent kinase II (CaMKII) activity, then downmodulates the expression of the Wnt-ligand Fzd8 [8]. Importantly, the interaction between K-Ras and CaM is suppressed by phosphorylation of Ser181 in the C-terminal membrane anchoring region of K-Ras, while conversely binding of CaM prevents phosphorylation [37,38]. AMPK signaling, which exhibits a complex interplay with MAPK signaling [39], promotes Ser181 phosphorylation through PGK2 and could thus disrupt the K-Ras/CaM interaction [40]. Furthermore, drugs that have the potential to increase Ser181-phosphorylation, such as the atypical PKC agonist prostratin, as well as CaM inhibitors have been shown to reduce CSC properties [7,8].

Ca2+/CaM is a trafficking chaperone of K-Ras, which can bind up to two K-Ras proteins via their C-terminal farnesyl-moiety [41–43]. Another trafficking chaperone of K-Ras is PDE6D (also known as PDEδ), which also sequesters the C-terminal farnesyl, and ultimately facilitates plasma membrane trafficking of K-Ras [35]. It essentially enhances the diffusion rate of K-Ras between cellular membranes and to the recycling endosome, from where K-Ras is actively transported back to the plasma membrane [44]. Plasma membrane anchorage is necessary for K-Ras to engage its canonical effectors, hence its disruption effectively reduces its oncogenic activity, such as demonstrated by various PDE6D inhibitors [45–47]. Consistently, inhibition of CaM could have similar effects on K-Ras trafficking, justifying renewed interest in screening for CaM inhibitors [48] (Figure 2A).

Pathways and interactions regulating K-Ras driven stemness.

Figure 2.
Pathways and interactions regulating K-Ras driven stemness.

(A) CaM enhances K-Ras driven stemness through inhibition of non-canonical Wnt-signaling. CaM inhibitors (CaMi) and several kinases facilitate Ser-181 phosphorylation, thus promoting apoptosis. Conversely, CaM prevents phosphorylation of K-Ras at Ser-181 and enables K-Ras translocation. (B) Given the dynamic localization of CaM to several mitotic structures and the plasma membrane during mitosis, K-Ras could access these structures while chaperoned by CaM. Similarly, PDE6D/ PDEδ solubilizes K-Ras from membranes and unloads it at the recycling endosome for transport. Both PDE6D and CaM could therefore position K-Ras on the basal body of the primary cilium, which harbors several components of stemness signaling, such as those of the canonical Wnt- and Hh-pathways. (C) In the plasma membrane, K-Ras is organized into nanoclusters, signaling centres that enhance MAPK-signaling. Nanoclustering can be stabilized by NPM1, which is known to control centrosome duplication. (D) The (mother) centrosome derived from the mother centriole of the basal body of the PC is typically retained by the stem cell during asymmetric division. CaM and PDE6D facilitate the distribution of K-Ras during the cell cycle. Moreover, unloading of mitotic cargoes at the centrosome by the recycling endosome may imply that in particular K-Ras can impact on these stemness processes.

Figure 2.
Pathways and interactions regulating K-Ras driven stemness.

(A) CaM enhances K-Ras driven stemness through inhibition of non-canonical Wnt-signaling. CaM inhibitors (CaMi) and several kinases facilitate Ser-181 phosphorylation, thus promoting apoptosis. Conversely, CaM prevents phosphorylation of K-Ras at Ser-181 and enables K-Ras translocation. (B) Given the dynamic localization of CaM to several mitotic structures and the plasma membrane during mitosis, K-Ras could access these structures while chaperoned by CaM. Similarly, PDE6D/ PDEδ solubilizes K-Ras from membranes and unloads it at the recycling endosome for transport. Both PDE6D and CaM could therefore position K-Ras on the basal body of the primary cilium, which harbors several components of stemness signaling, such as those of the canonical Wnt- and Hh-pathways. (C) In the plasma membrane, K-Ras is organized into nanoclusters, signaling centres that enhance MAPK-signaling. Nanoclustering can be stabilized by NPM1, which is known to control centrosome duplication. (D) The (mother) centrosome derived from the mother centriole of the basal body of the PC is typically retained by the stem cell during asymmetric division. CaM and PDE6D facilitate the distribution of K-Ras during the cell cycle. Moreover, unloading of mitotic cargoes at the centrosome by the recycling endosome may imply that in particular K-Ras can impact on these stemness processes.

Close modal

Of note, Ser181 phosphorylation changes also the specific lateral organization of K-Ras from a preferred co-distribution with phosphatidylserine (PS) to phosphatidyl-inositol-4,5-bisphosphate (PIP2) [49]. This could alter its selectivity for certain effectors that employ these lipids for co-incidence detection and/or change nanoclustering of K-Ras. Therefore, the precise distribution of acidic lipids across polarized cells, could significantly impact on K-Ras-signaling output.

While we are mostly concerned with cancer when discussing CSC, we may learn about the particular roles of Ras proteins from its normal function in stem cells and during development. Knockout studies support a requirement of KRAS for embryonal survival as compared with the other two RAS genes, which can be deleted without compromising viability [50]. This indicates some redundancy in the roles of the four cancer-associated Ras isoforms (splice isoforms K-Ras4A and K-Ras4B, N-Ras and H-Ras), which is further complicated by the fact that all Ras are capable of engaging the same set of effectors, notably of the MAPK- and PI3K/mTORC1-pathways [51]. It is currently not fully understood, how this promiscuous setting can give rise to biological specificity that would instruct distinct stemness potentials. However, fundamental differences in the membrane organization of Ras isoforms and the precise utilization of certain effector paralogs, plus additional specific modulatory protein interactions are emerging as key in this context [20,52–54].

A fundamental role of Ras-MAPK-signaling in stem cells is suggested by the fact that embryonic stem cells undergo a Ras-MAPK dependent transformation from the naïve to the primed pluripotent state, followed by their proliferation and differentiation during embryogenesis [55]. In line with this, isogenic iPSC derived from patients with KRAS–G13C mutations retained a higher level of stemness markers in G13C/wt cells and had a larger OCT4+ population than the wt/wt cells [56]. While similar observations for iPSC were made with N-Ras [57], again only KRAS–G12D, but not the other two Ras isoforms, was able to increase the neural stem cell pool when expressed in the mouse ventricular zone [58]. In this context, it may be interesting to understand, whether distinct oncogenic RAS alleles have a specific CSC promoting potential, given that they have different tumorigenicity [59]. A significant involvement of MAPK-signaling is furthermore supported by the fact that also BRAF-V600E promotes stemness traits [60], while MEK inhibitors broadly block stemness [9,24,56].

The diverse Ras-pathways that are relevant for stemness may be gleaned from E-Ras, which is specifically expressed in embryonic stem cells (ESC) and few adult cells, such as the hepatic stellate cells (HSC), a liver resident stem cell population [61]. Expression of E-Ras can enhance mouse iPSC induction via the mTORC2-pathway and repression of FOXO1 [62,63]. This Ras isoform is naturally GAP-insensitive, i.e. it is constitutively active and hence transcriptionally regulated [64]. In quiescent HSC of a healthy liver, E-Ras is expressed and stimulates e.g. the mTORC2-Akt- and RASSF5-HIPPO-pathways, thus repressing FOXO1 and YAP, respectively. Upon liver injury HSC become activated, which is accompanied by E-Ras down-regulation and a signaling shift to the MAPK-pathway by up-regulation of other Ras isoforms (M-Ras, R-Ras, RalA, Rap2A) [64,65]. Altogether, these data suggest that certain signaling pathways downstream of specific Ras isoforms, such as K-Ras and E-Ras, are important for the induction of cellular stemness states.

RASopathies are caused by germline mutations in Ras-MAPK-pathway genes, thus introducing developmental imbalances at the earliest stages. Affected individuals broadly display skeletal malformations, cardiac defects, various degrees of mental retardation and an increased risk for certain types of cancer [66]. The most frequent RASopathy, neurofibromatosis type I (occurrence 1: 3000), is caused by mutations of the NF1 tumor suppressor gene, which in mice was also linked to neural stem cell hyperproliferation [67]. NF1 encodes neurofibromin, a Ras specific GTPase activating protein (GAP), which inactivates Ras-signaling [51]. Neurofibromin is targeted to the plasma membrane by SPRED proteins, while SPRED1 piggybacks on activated B-Raf, which delivers the complex to K-Ras membrane domains [68-70]. Intriguingly, in this mechanistic complex, three highly mutated cancer genes are involved, which may point to a particularly critical relevance of this process. Recently, the major mitosis driving kinase, CDK1, was shown to phosphorylate Ser105 on SPRED1 thus blocking its interaction with neurofibromin, suggesting an important cell cycle-dependent modulation of this interaction [71]. Together with the fact that up-regulation of SPRED proteins is associated with differentiation, this mechanism may point to a central, cell cycle and differentiation-associated function of K-Ras [72,73]. Hence, GAP-desensitizing hot spot mutations in Ras do not only promote cell cycle entry to stimulate proliferation, but in addition withdraw Ras from its inactivation during cell-cycle associated differentiation processes, such as mediated by neurofibromin-SPRED-complexes. Thus cell cycle re-entry requires concerted processes that involve not only canonical phosphorylation events by CDK1 of a wide range of targets that regulate centrosome maturation, nuclear envelope breakdown and spindle assembly during mitosis, but also CDK1-mediated licensing of K-Ras-signaling [74]. This connection is particularly interesting, considering that other CDKs, such as CDK4, cooperate with K-Ras in tumorigenesis [75,76]. With the above-mentioned regulation of the SPRED1/NF1 interaction by CDK1 during the cell cycle in mind, a continuous inhibition of CDKs may work for short bouts of cancer therapy, but not long-term for the treatment of typically younger RASopathy patients.

The dynamics of the subcellular distribution of Ras in the cellular life cycle are likely to provide selective access of Ras to subcellular compartments that are associated with the cellular machinery that decides between symmetric or asymmetric divisions [44,77,78]. The decision which of the two daughter cells inherits the stemness traits during asymmetric division depends on cell polarizing cues in the niche [1]. These cues can originate for instance from apical growth factor signal input or the basal extracellular matrix, and instruct the distribution of polarity proteins, which then effect the orientation of the spindle apparatus and the ensuing apportioning of cellular organelles during cytokinesis [79].

The PC emerges from the older centrosome after cell division, and it is this older centrosome that is typically inherited by the stemness-retaining cell during asymmetric division [80,81]. One reason for the stemness retention may be that the cell with the older centrosome gives rise earlier to the PC, and thus becomes sooner sensitive to Wnt- and Hh- stemness signaling [29].

Both the PC and centrosome are visited by the recycling endosome, which is significant for spindle organization and orientation [82–84]. K-Ras is trafficking via recycling endosomes [44], while CaM dynamically localizes to the centrosome and also PC [85–87]. It is not established, whether K-Ras indeed co-localizes with these centriolar structures, however its trafficking chaperone PDE6D does [36,88]. High affinity PDE6D clients like INPP5E localize deep inside of the cilium by the concerted activity of PDE6D, its release factor Arl3 and the Arl-GEF Arl13B [36]. However, the affinity of K-Ras to PDE6D is relatively low, which may preclude transport deep into the cilium, but could place it at the base of an organelle that is central to stemness pathways and cell fate decisions [89]. Thus, the K-Ras/ CaM-stemness axis is positioned at decisive points of the cellular machinery that executes cell fate decisions. It is therefore plausible to assume that certain inhibitors (e.g. against PDE6D or CaM) exert their somewhat selective anti-stemness activity on K-Ras not just at the plasma membrane, but more so during cell division, by fundamentally affecting the inheritance of centrosome-associated stemness traits (Figure 2B).

The most prominent stem cell marker CD133/prominin-1 is a penta-span cholesterol-binding protein enriched in curved membranes, including the tip of the PC [90]. Recently, it was shown that it actively promotes stem cell self-renewal and proliferation by controlling the recruitment of PC components [31]. Moreover, prominin-1 is important for autophagy inhibition, a process that is relevant for asymmetrically inherited midbody remnants, which are prominin-1 enriched in the stemness-retaining cell [91]. Under low serum conditions, prominin-1 is in complex with HDAC6 and traffics to the pericentrosomal region, where it inhibits the autophagy initiator GABARAP. From there, prominin-1 is returning to the plasma membrane via the recycling endosome [92]. Interestingly, the promotor of prominin-1 contains binding sites for Ets, downstream of the Ras-MAPK-pathway and its expression can be increased by oncogenic Ras [93]. Considering that autophagy inhibitors have been shown to attenuate tumorigenicity in K-Ras driven pancreatic cancer and are being evaluated in clinical trials [94], it could be important to understand, whether these compounds act by affecting fundamental stemness processes, such as midbody retention.

Ras impacts on cell cycle processes from multiple angles, such as for example by signaling for centrosome amplification [95]. The classical focus on Ras-signaling originates from its role to mediate mitogenic stimuli, thus driving cell cycle progression and proliferation. This focus is in line with standard 2D cancer cell proliferation assays. However, cancer is as much a disease of aberrant differentiation [96], and within the CSC-concept a disease of erroneous cell fate decisions that take place during the cell cycle.

Nucleophosmin 1 (NPM1) together with nucleolin increases K-Ras membrane binding, and NPM1 in addition nanoclustering by an as yet not fully defined mechanism [97] (Figure 2C). Like CaM, it binds less to K-RasG12V-S181D, the phosphomimetic mutant that has less stemness promoting activity [8,38,97]. Indeed, knockdown of NPM1 was shown to inhibit self-renewal in neural stem cells [98]. NPM1 localizes to the centrosome to control its duplication and has been shown previously to regulate mitotic spindle assembly [99–101]. Therefore, ciliary localization of K-Ras could position NPM1 to control centrosome duplication at the basal body. This would require access of nuclear NPM1 to K-Ras, which would also allow for the transient stabilization of K-Ras nanocluster. In line with this, we found that several nuclear export inhibitors of the leptomycin B family selectively block K-Ras nanoclustering and stemness traits [7].

Furthermore, K-Ras distribution may in this context be regulated by CaM, which highly dynamically distributes to the cell cortex and centrosome [85]. Alternatively, given that CaM is a bivalent binder, it could effectively act as a scaffold to up-concentrate proteins like K-Ras, while ‘holding on’ to another location, such as the centrosome [102]. Oncogenic activation of K-Ras could perturb NPM1 localization to the centrosomes, which are kept free from NPM1 after its phosphorylation by CDK1/ cyclin E between G1 and mitosis [103] (Figure 2D). This could inadvertently promote centrosome maturation, which in consequence would sabotage asymmetric cell division, as there would now effectively be two ‘mother centrosomes’ present. While this is a hypothetical scenario, mis-localization of oncogenic Ras-signaling complexes would effectively randomize their activities across the cell. Ultimately, this could lead to a fatal disruption of fundamental polarized signaling and asymmetric apportioning processes during stem cell division.

  • Tumor seeding during clonal evolution or metastasis is ascribed to CSC, which should position CSC in the focus of cancer therapy. However, the emergence of stemness traits in cancer cells is poorly understood.

  • KRAS mutations are associated with aggressive tumors and K-Ras is an established drug target with emerging direct inhibitors for K-Ras-G12C. The classical focus is on Ras-MAPK-signaling driving cell proliferation. However, reports from recent years support a significant role in particular of K-Ras in driving stemness processes.

  • Beyond its canonical functions, K-Ras may impact on the core cellular machinery that operates during cell fate decision-making. We know little about its activities and localization during the cell cycle and on organelles, such as the centrosome that can transmit stemness traits.

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

This work was supported by a grant from the Luxembourg National Research Fund (FNR) grant C19/BM/13673303-PolaRAS2 to DA.

D.A. selected and organized content and wrote major text sections. R.C. wrote the first draft and prepared the figure. Both authors reviewed the literature and critically revised the manuscript.

     
  • AMPK

    AMP-activated protein kinase

  •  
  • aPKC

    atypical protein kinase C

  •  
  • Arl13B

    ADP-ribosylation factor-like protein 13B

  •  
  • CaM

    calmodulin

  •  
  • CaMKII

    Ca2+/calmodulin-dependent kinase II

  •  
  • CDK1

    cyclin dependent kinase 1

  •  
  • CSC

    cancer stem cell

  •  
  • ESC

    embryonic stem cells

  •  
  • Fzd8

    frizzled 8

  •  
  • GAP

    GTPase activating protein

  •  
  • GEF

    guanine nucleotide exchange factor

  •  
  • HDAC6

    histone deacetylase 6

  •  
  • Hh

    hedgehog

  •  
  • HSC

    hepatic stellate cells

  •  
  • INPP5E

    phosphatidylinositol polyphosphate 5-phosphatase type IV

  •  
  • iPSC

    induced pluripotent stem cell

  •  
  • MAPK

    mitogen activated protein kinase

  •  
  • MEK

    mitogen activated protein kinase kinase

  •  
  • mTORC1

    mammalian target of rapamycin complex 1

  •  
  • NF1

    neurofibromin 1

  •  
  • NPM1

    nucleophosmin-1

  •  
  • PC

    primary cilium

  •  
  • PDE6D

    phosphodiesterase 6 δ subunit

  •  
  • PGK2

    GMP-dependent protein kinase 2

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PIP2

    phosphatidyl-inositol-4,5-bisphosphate

  •  
  • PS

    phosphatidylserine

  •  
  • Shh

    sonic hedgehog

  •  
  • SPRED1

    sprouty related EVH1-domain containing protein 1

  •  
  • SREBP1

    sterol regulatory element-binding protein 1

  •  
  • YAP

    yes associated protein

1
Santoro
,
A.
,
Vlachou
,
T.
,
Carminati
,
M.
,
Pelicci
,
P.G.
and
Mapelli
,
M.
(
2016
)
Molecular mechanisms of asymmetric divisions in mammary stem cells
.
EMBO Rep.
17
,
1700
1720
2
Batlle
,
E.
and
Clevers
,
H.
(
2017
)
Cancer stem cells revisited
.
Nat. Med.
23
,
1124
1134
3
Dean
,
M.
,
Fojo
,
T.
and
Bates
,
S.
(
2005
)
Tumour stem cells and drug resistance
.
Nat. Rev. Cancer
5
,
275
284
4
Gupta
,
P.B.
,
Onder
,
T.T.
,
Jiang
,
G.
,
Tao
,
K.
,
Kuperwasser
,
C.
,
Weinberg
,
R.A.
et al (
2009
)
Identification of selective inhibitors of cancer stem cells by high-throughput screening
.
Cell
138
,
645
659
5
Sachlos
,
E.
,
Risueno
,
R.M.
,
Laronde
,
S.
,
Shapovalova
,
Z.
,
Lee
,
J.H.
,
Russell
,
J.
et al (
2012
)
Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells
.
Cell
149
,
1284
1297
6
Lv
,
J.
and
Shim
,
J.S.
(
2015
)
Existing drugs and their application in drug discovery targeting cancer stem cells
.
Arch. Pharm. Res.
38
,
1617
1626
7
Najumudeen
,
A.K.
,
Jaiswal
,
A.
,
Lectez
,
B.
,
Oetken-Lindholm
,
C.
,
Guzman
,
C.
,
Siljamaki
,
E.
et al (
2016
)
Cancer stem cell drugs target K-ras signaling in a stemness context
.
Oncogene
35
,
5248
5262
8
Wang
,
M.T.
,
Holderfield
,
M.
,
Galeas
,
J.
,
Delrosario
,
R.
,
To
,
M.D.
,
Balmain
,
A.
et al (
2015
)
K-Ras promotes tumorigenicity through suppression of non-canonical Wnt signaling
.
Cell
163
,
1237
1251
9
Quinlan
,
M.P.
,
Quatela
,
S.E.
,
Philips
,
M.R.
and
Settleman
,
J.
(
2008
)
Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion
.
Mol Cell Biol.
28
,
2659
2674
10
Prior
,
I.A.
,
Hood
,
F.E.
and
Hartley
,
J.L.
(
2020
)
The frequency of Ras mutations in cancer
.
Cancer Res.
80
,
2969
2974
11
Gilardi
,
M.
,
Wang
,
Z.
,
Proietto
,
M.
,
Chillà
,
A.
,
Calleja-Valera
,
J.L.
,
Goto
,
Y.
et al (
2020
)
Tipifarnib as a precision therapy for HRAS-Mutant head and neck squamous cell carcinomas
.
Mol. Cancer Ther.
19
,
1784
1796
12
Wang
,
L.
,
Zuo
,
X.
,
Xie
,
K.
and
Wei
,
D.
(
2018
)
The role of CD44 and cancer stem cells
.
Methods Mol. Biol.
1692
,
31
42
13
Liou
,
G.Y.
(
2019
)
CD133 as a regulator of cancer metastasis through the cancer stem cells
.
Int. J. Biochem. Cell Biol.
106
,
1
7
14
Müller
,
M.
,
Hermann
,
P.C.
,
Liebau
,
S.
,
Weidgang
,
C.
,
Seufferlein
,
T.
,
Kleger
,
A.
et al (
2016
)
The role of pluripotency factors to drive stemness in gastrointestinal cancer
.
Stem Cell Res.
16
,
349
357
15
Vaddi
,
P.K.
,
Stamnes
,
M.A.
,
Cao
,
H.
and
Chen
,
S.
(
2019
)
Elimination of SOX2/OCT4-Associated prostate cancer stem cells blocks tumor development and enhances therapeutic response
.
Cancers (Basel)
11
,
1331
16
Mehta
,
P.
,
Novak
,
C.
,
Raghavan
,
S.
,
Ward
,
M.
and
Mehta
,
G.
(
2018
)
Self-Renewal and CSCs In vitro enrichment: growth as floating spheres
.
Methods Mol. Biol.
1692
,
61
75
17
Monji
,
K.
,
Uchiumi
,
T.
,
Hoshizawa
,
S.
,
Yagi
,
M.
,
Matsumoto
,
T.
,
Setoyama
,
D.
et al (
2016
)
Serum depletion induced cancer stem cell-like phenotype due to nitric oxide synthesis in oncogenic HRas transformed cells
.
Oncotarget
7
,
75221
75234
18
Blazevits
,
O.
,
Mideksa
,
Y.G.
,
Solman
,
M.
,
Ligabue
,
A.
,
Ariotti
,
N.
,
Nakhaeizadeh
,
H.
et al (
2016
)
Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering
.
Sci. Rep.
6
,
24165
19
Posada
,
I.M.D.
,
Lectez
,
B.
,
Sharma
,
M.
,
Oetken-Lindholm
,
C.
,
Yetukuri
,
L.
,
Zhou
,
Y.
et al (
2017
)
Rapalogs can promote cancer cell stemness in vitro in a galectin-1 and H-ras-dependent manner
.
Oncotarget
8
,
44550
44566
20
Abankwa
,
D.
and
Gorfe
,
A.A.
(
2020
)
Mechanisms of Ras membrane organization and signaling: Ras rocks again
.
Biomolecules
10
,
1522
21
Posada
,
I.M.D.
,
Lectez
,
B.
,
Siddiqui
,
F.A.
,
Oetken-Lindholm
,
C.
,
Sharma
,
M.
and
Abankwa
,
D.
(
2017
)
Opposite feedback from mTORC1 to H-ras and K-ras4B downstream of SREBP1
.
Sci. Rep.
7
,
8944
22
Li
,
Q.
,
Bohin
,
N.
,
Wen
,
T.
,
Ng
,
V.
,
Magee
,
J.
,
Chen
,
S.C.
et al (
2013
)
Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness
.
Nature
504
,
143
147
23
Zhao
,
H.
,
Wu
,
S.
,
Li
,
H.
,
Duan
,
Q.
,
Zhang
,
Z.
,
Shen
,
Q.
et al (
2019
)
ROS/KRAS/AMPK signaling contributes to gemcitabine-induced stem-like cell properties in pancreatic cancer
.
Mol. Ther. Oncolytics
14
,
299
312
24
Moon
,
B.S.
,
Jeong
,
W.J.
,
Park
,
J.
,
Kim
,
T.I.
,
Min do
,
S.
and
Choi
,
K.Y.
(
2014
)
Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/β-Catenin signaling
.
J. Natl Cancer Inst.
106
,
djt373
25
Ali
,
S.A.
,
Justilien
,
V.
,
Jamieson
,
L.
,
Murray
,
N.R.
and
Fields
,
A.P.
(
2016
)
Protein kinase Cι drives a NOTCH3-dependent stem-like phenotype in mutant KRAS lung adenocarcinoma
.
Cancer Cell
29
,
367
378
26
Moore
,
A.R.
,
Rosenberg
,
S.C.
,
McCormick
,
F.
and
Malek
,
S.
(
2020
)
RAS-targeted therapies: is the undruggable drugged?
Nat. Rev. Drug Discov.
19
,
533
552
27
Gu
,
D.
,
Schlotman
,
K.E.
and
Xie
,
J.
(
2016
)
Deciphering the role of hedgehog signaling in pancreatic cancer
.
J. Biomed. Res.
30
,
353
360
28
Hwang
,
J.
,
Yoon
,
J.
,
Cho
,
Y.
,
Cha
,
P.
,
Park
,
J.
and
Choi
,
K.
(
2020
)
A mutant KRAS-induced factor REG4 promotes cancer stem cell properties via Wnt/β-catenin signaling
.
Int. J. Cancer
146
,
2877
2890
29
Gerdes
,
J.M.
,
Davis
,
E.E.
and
Katsanis
,
N.
(
2009
)
The vertebrate primary cilium in development, homeostasis, and disease
.
Cell
137
,
32
45
30
Guen
,
V.J.
,
Chavarria
,
T.E.
,
Kroger
,
C.
,
Ye
,
X.
,
Weinberg
,
R.A.
and
Lees
,
J.A.
(
2017
)
EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and hedgehog signaling
.
Proc. Natl Acad. Sci. U.S.A.
114
,
E10532
E9
31
Singer
,
D.
,
Thamm
,
K.
,
Zhuang
,
H.
,
Karbanova
,
J.
,
Gao
,
Y.
,
Walker
,
J.V.
et al (
2019
)
Prominin-1 controls stem cell activation by orchestrating ciliary dynamics
.
EMBO J.
38
,
1023
32
Venugopal
,
N.
and
Dhawan
,
J.
(
2015
)
Primary cilia in myoblasts: a role in quiescence
.
Cilia
4
,
P79
33
Schneider
,
L.
,
Clement
,
C.A.
,
Teilmann
,
S.C.
,
Pazour
,
G.J.
,
Hoffmann
,
E.K.
,
Satir
,
P.
et al (
2005
)
PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts
.
Curr. Biol.
15
,
1861
1866
34
Kim
,
J.I.
,
Kim
,
J.
,
Jang
,
H.S.
,
Noh
,
M.R.
,
Lipschutz
,
J.H.
and
Park
,
K.M.
(
2013
)
Reduction of oxidative stress during recovery accelerates normalization of primary cilia length that is altered after ischemic injury in murine kidneys
.
Am. J. Physiol. Renal. Physiol.
304
,
F1283
F1294
35
Chandra
,
A.
,
Grecco
,
H.E.
,
Pisupati
,
V.
,
Perera
,
D.
,
Cassidy
,
L.
,
Skoulidis
,
F.
et al (
2011
)
The GDI-like solubilizing factor PDEdelta sustains the spatial organization and signalling of Ras family proteins
.
Nat. Cell Biol.
14
,
148
158
36
Fansa
,
E.K.
,
Kosling
,
S.K.
,
Zent
,
E.
,
Wittinghofer
,
A.
and
Ismail
,
S.
(
2016
)
PDE6delta-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity
.
Nat. Commun.
7
,
11366
37
Alvarez-Moya
,
B.
,
Lopez-Alcala
,
C.
,
Drosten
,
M.
,
Bachs
,
O.
and
Agell
,
N.
(
2010
)
K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function
.
Oncogene
29
,
5911
5922
38
Lopez-Alcala
,
C.
,
Alvarez-Moya
,
B.
,
Villalonga
,
P.
,
Calvo
,
M.
,
Bachs
,
O.
and
Agell
,
N.
(
2008
)
Identification of essential interacting elements in K-Ras/calmodulin binding and its role in K-Ras localization
.
J. Biol. Chem.
283
,
10621
10631
39
Yuan
,
J.
,
Dong
,
X.
,
Yap
,
J.
and
Hu
,
J.
(
2020
)
The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy
.
J. Hematol. Oncol.
13
,
113
40
Cho
,
K.J.
,
Casteel
,
D.E.
,
Prakash
,
P.
,
Tan
,
L.
,
van der Hoeven
,
D.
,
Salim
,
A.A.
et al (
2016
)
AMPK and endothelial nitric oxide synthase signaling regulates K-Ras plasma membrane interactions via cyclic GMP-dependent protein kinase 2
.
Mol. Cell. Biol.
36
,
3086
3099
41
Agamasu
,
C.
,
Ghirlando
,
R.
,
Taylor
,
T.
,
Messing
,
S.
,
Tran
,
T.H.
,
Bindu
,
L.
et al (
2019
)
KRAS prenylation is required for bivalent binding with calmodulin in a nucleotide-independent manner
.
Biophys. J.
116
,
1049
1063
42
Grant
,
B.M.M.
,
Enomoto
,
M.
,
Back
,
S.I.
,
Lee
,
K.Y.
,
Gebregiworgis
,
T.
,
Ishiyama
,
N.
et al (
2020
)
Calmodulin disrupts plasma membrane localization of farnesylated KRAS4b by sequestering its lipid moiety
.
Sci. Signal.
13
,
eaaz0344
43
Wu
,
L.J.
,
Xu
,
L.R.
,
Liao
,
J.M.
,
Chen
,
J.
and
Liang
,
Y.
(
2011
)
Both the C-terminal polylysine region and the farnesylation of K-RasB are important for its specific interaction with calmodulin
.
PLoS ONE
6
,
e21929
44
Schmick
,
M.
,
Vartak
,
N.
,
Papke
,
B.
,
Kovacevic
,
M.
,
Truxius
,
D.C.
,
Rossmannek
,
L.
et al (
2014
)
KRas localizes to the plasma membrane by spatial cycles of solubilization, trapping and vesicular transport
.
Cell
157
,
459
471
45
Martín-Gago
,
P.
,
Fansa
,
E.K.
,
Klein
,
C.H.
,
Murarka
,
S.
,
Janning
,
P.
,
Schürmann
,
M.
et al (
2017
)
A PDE6δ-KRas inhibitor chemotype with up to seven H-bonds and picomolar affinity that prevents efficient inhibitor release by Arl2
.
Angew. Chem. Int. Ed. Engl.
56
,
2423
2428
46
Siddiqui
,
F.A.
,
Alam
,
C.
,
Rosenqvist
,
P.
,
Ora
,
M.
,
Sabt
,
A.
,
Manoharan
,
G.B.
et al (
2020
)
PDE6D inhibitors with a New design principle selectively block K-Ras activity
.
ACS Omega
5
,
832
842
47
Zimmermann
,
G.
,
Papke
,
B.
,
Ismail
,
S.
,
Vartak
,
N.
,
Chandra
,
A.
,
Hoffmann
,
M.
et al (
2013
)
Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling
.
Nature
497
,
638
642
48
Manoharan
,
G.B.
,
Kopra
,
K.
,
Eskonen
,
V.
,
Harma
,
H.
and
Abankwa
,
D.
(
2019
)
High-throughput amenable fluorescence-assays to screen for calmodulin-inhibitors
.
Anal. Biochem.
572
,
25
32
49
Zhou
,
Y.
,
Prakash
,
P.
,
Liang
,
H.
,
Cho
,
K.J.
,
Gorfe
,
A.A.
and
Hancock
,
J.F.
(
2017
)
Lipid-Sorting specificity encoded in K-Ras membrane anchor regulates signal output
.
Cell
168
,
239
51 e16
50
Malumbres
,
M.
and
Barbacid
,
M.
(
2003
)
Timeline: RAS oncogenes: the first 30 years
.
Nat. Rev. Cancer
3
,
459
465
51
Simanshu
,
D.K.
,
Nissley
,
D.V.
and
McCormick
,
F.
(
2017
)
RAS proteins and their regulators in human disease
.
Cell
170
,
17
33
52
Adhikari
,
H.
and
Counter
,
C.M.
(
2018
)
Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability
.
Nat. Commun.
9
,
3646
53
Kovalski
,
J.R.
,
Bhaduri
,
A.
,
Zehnder
,
A.M.
,
Neela
,
P.H.
,
Che
,
Y.
,
Wozniak
,
G.G.
et al (
2019
)
The functional proximal proteome of oncogenic Ras includes mTORC2
.
Mol. Cell
73
,
830
44 e12
54
Yuan
,
T.L.
,
Amzallag
,
A.
,
Bagni
,
R.
,
Yi
,
M.
,
Afghani
,
S.
,
Burgan
,
W.
et al (
2018
)
Differential effector engagement by oncogenic KRAS
.
Cell Rep.
22
,
1889
1902
55
Blair
,
K.
,
Wray
,
J.
and
Smith
,
A.
(
2011
)
The liberation of embryonic stem cells
.
PLoS Genet.
7
,
e1002019
56
Kubara
,
K.
,
Yamazaki
,
K.
,
Ishihara
,
Y.
,
Naruto
,
T.
,
Lin
,
H.T.
,
Nishimura
,
K.
et al (
2018
)
Status of KRAS in iPSCs impacts upon self-renewal and differentiation propensity
.
Stem Cell Rep.
11
,
380
394
57
Haghighi
,
F.
,
Dahlmann
,
J.
,
Nakhaei-Rad
,
S.
,
Lang
,
A.
,
Kutschka
,
I.
,
Zenker
,
M.
et al (
2018
)
bFGF-mediated pluripotency maintenance in human induced pluripotent stem cells is associated with NRAS-MAPK signaling
.
Cell Commun. Signal.
16
,
96
58
Bender
,
R.H.
,
Haigis
,
K.M.
and
Gutmann
,
D.H.
(
2015
)
Activated k-ras, but not h-ras or N-ras, regulates brain neural stem cell proliferation in a raf/rb-dependent manner
.
Stem Cells
33
,
1998
2010
59
Smith
,
G.
,
Bounds
,
R.
,
Wolf
,
H.
,
Steele
,
R.J.C.
,
Carey
,
F.A.
and
Wolf
,
C.R.
(
2010
)
Activating K-Ras mutations outwith hotspot codons in sporadic colorectal tumours-implications for personalised cancer medicine
.
Br. J Cancer.
102
,
693
703
60
Bozorg-Ghalati
,
F.
,
Hedayati
,
M.
,
Dianatpour
,
M.
,
Mosaffa
,
N.
and
Azizi
,
F.
(
2019
)
Targeting the BRAF signaling pathway in CD133pos cancer stem cells of anaplastic thyroid carcinoma
.
Asian Pac. J. Cancer Prev.
20
,
1353
1360
61
Kordes
,
C.
,
Sawitza
,
I.
,
Gotze
,
S.
and
Haussinger
,
D.
(
2013
)
Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells
.
Cell Physiol. Biochem.
31
,
290
304
62
Kwon
,
Y.W.
,
Jang
,
S.
,
Paek
,
J.S.
,
Lee
,
J.W.
,
Cho
,
H.J.
,
Yang
,
H.M.
et al (
2015
)
E-Ras improves the efficiency of reprogramming by facilitating cell cycle progression through JNK-Sp1 pathway
.
Stem Cell Res.
15
,
481
494
63
Yu
,
Y.
,
Liang
,
D.
,
Tian
,
Q.
,
Chen
,
X.
,
Jiang
,
B.
,
Chou
,
B.K.
et al (
2014
)
Stimulation of somatic cell reprogramming by ERas-Akt-FoxO1 signaling axis
.
Stem Cells
32
,
349
363
64
Nakhaei-Rad
,
S.
,
Nakhaeizadeh
,
H.
,
Gotze
,
S.
,
Kordes
,
C.
,
Sawitza
,
I.
,
Hoffmann
,
M.J.
et al (
2016
)
The role of embryonic stem cell-expressed RAS (ERAS) in the maintenance of quiescent hepatic stellate cells
.
J. Biol. Chem.
291
,
8399
8413
65
Hamilton
,
W.B.
,
Mosesson
,
Y.
,
Monteiro
,
R.S.
,
Emdal
,
K.B.
,
Knudsen
,
T.E.
,
Francavilla
,
C.
et al (
2019
)
Dynamic lineage priming is driven via direct enhancer regulation by ERK
.
Nature
575
,
355
360
66
Rauen
,
K.A.
(
2013
)
The RASopathies
.
Annu. Rev. Genom. Hum. Genet.
14
,
355
369
67
Lee
,
D.Y.
,
Gianino
,
S.M.
and
Gutmann
,
D.H.
(
2012
)
Innate neural stem cell heterogeneity determines the patterning of glioma formation in children
.
Cancer Cell
22
,
131
138
68
Dunzendorfer-Matt
,
T.
,
Mercado
,
E.L.
,
Maly
,
K.
,
McCormick
,
F.
and
Scheffzek
,
K.
(
2016
)
The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation
.
Proc. Natl Acad. Sci. U.S.A.
113
,
7497
7502
69
Siljamaki
,
E.
and
Abankwa
,
D.
(
2016
)
SPRED1 interferes with K-ras but Not H-ras membrane anchorage and signaling
.
Mol. Cell. Biol.
36
,
2612
2625
70
Stowe
,
I.B.
,
Mercado
,
E.L.
,
Stowe
,
T.R.
,
Bell
,
E.L.
,
Oses-Prieto
,
J.A.
,
Hernandez
,
H.
et al (
2012
)
A shared molecular mechanism underlies the human rasopathies legius syndrome and neurofibromatosis-1
.
Genes Dev.
26
,
1421
1426
71
Yan
,
W.
,
Markegard
,
E.
,
Dharmaiah
,
S.
,
Urisman
,
A.
,
Drew
,
M.
,
Esposito
,
D.
et al (
2020
)
Structural insights into the SPRED1-Neurofibromin-KRAS complex and disruption of SPRED1-Neurofibromin interaction by oncogenic EGFR
.
Cell Rep.
32
,
107909
72
Bundschu
,
K.
,
Walter
,
U.
and
Schuh
,
K.
(
2007
)
Getting a first clue about SPRED functions
.
Bioessays
29
,
897
907
73
Wakioka
,
T.
,
Sasaki
,
A.
,
Kato
,
R.
,
Shouda
,
T.
,
Matsumoto
,
A.
,
Miyoshi
,
K.
et al (
2001
)
Spred is a sprouty-related suppressor of Ras signalling
.
Nature
412
,
647
651
74
Gavet
,
O.
and
Pines
,
J.
(
2010
)
Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis
.
Dev. Cell
18
,
533
543
75
Lazarov
,
M.
,
Kubo
,
Y.
,
Cai
,
T.
,
Dajee
,
M.
,
Tarutani
,
M.
,
Lin
,
Q.
et al (
2002
)
CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis
.
Nat. Med.
8
,
1105
1114
76
Wang
,
Y.
,
Lin
,
R.
,
Ling
,
H.
,
Ke
,
Y.
,
Zeng
,
Y.
,
Xiong
,
Y.
et al (
2019
)
Dual inhibition of CDK4 and FYN leads to selective cell death in KRAS-mutant colorectal cancer
.
Signal. Transduct. Target Ther.
4
,
52
77
Rocks
,
O.
,
Peyker
,
A.
,
Kahms
,
M.
,
Verveer
,
P.J.
,
Koerner
,
C.
,
Lumbierres
,
M.
et al (
2005
)
An acylation cycle regulates localization and activity of palmitoylated Ras isoforms
.
Science
307
,
1746
1752
78
Rocks
,
O.
,
Gerauer
,
M.
,
Vartak
,
N.
,
Koch
,
S.
,
Huang
,
Z.P.
,
Pechlivanis
,
M.
et al (
2010
)
The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins
.
Cell
141
,
458
471
79
Martin-Belmonte
,
F.
and
Perez-Moreno
,
M.
(
2011
)
Epithelial cell polarity, stem cells and cancer
.
Nat. Rev. Cancer
12
,
23
38
80
Anderson
,
C.T.
and
Stearns
,
T.
(
2009
)
Centriole age underlies asynchronous primary cilium growth in mammalian cells
.
Curr. Biol.
19
,
1498
1502
81
Pelletier
,
L.
and
Yamashita
,
Y.M.
(
2012
)
Centrosome asymmetry and inheritance during animal development
.
Curr. Opin. Cell Biol.
24
,
541
546
82
Feng
,
S.
,
Knodler
,
A.
,
Ren
,
J.
,
Zhang
,
J.
,
Zhang
,
X.
,
Hong
,
Y.
et al (
2012
)
A Rab8 guanine nucleotide exchange factor-effector interaction network regulates primary ciliogenesis
.
J. Biol. Chem.
287
,
15602
9
83
Hehnly
,
H.
and
Doxsey
,
S.
(
2014
)
Rab11 endosomes contribute to mitotic spindle organization and orientation
.
Dev. Cell
28
,
497
507
84
Jongsma
,
M.L.
,
Berlin
,
I.
and
Neefjes
,
J.
(
2015
)
On the move: organelle dynamics during mitosis
.
Trends Cell Biol.
25
,
112
124
85
Li
,
C.J.
,
Heim
,
R.
,
Lu
,
P.
,
Pu
,
Y.
,
Tsien
,
R.Y.
and
Chang
,
D.C.
(
1999
)
Dynamic redistribution of calmodulin in heLa cells during cell division as revealed by a GFP-calmodulin fusion protein technique
.
J Cell Sci.
112
,
1567
1577
PMID:
[PubMed]
86
Plotnikova
,
O.V.
,
Nikonova
,
A.S.
,
Loskutov
,
Y.V.
,
Kozyulina
,
P.Y.
,
Pugacheva
,
E.N.
and
Golemis
,
E.A.
(
2012
)
Calmodulin activation of aurora-A kinase (AURKA) is required during ciliary disassembly and in mitosis
.
Mol. Biol. Cell
23
,
2658
2670
87
Yu
,
Y.Y.
,
Dai
,
G.
,
Pan
,
F.Y.
,
Chen
,
J.
and
Li
,
C.J.
(
2005
)
Calmodulin regulates the post-anaphase reposition of centrioles during cytokinesis
.
Cell Res.
15
,
548
552
88
Humbert
,
M.C.
,
Weihbrecht
,
K.
,
Searby
,
C.C.
,
Li
,
Y.
,
Pope
,
R.M.
,
Sheffield
,
V.C.
et al (
2012
)
ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting
.
Proc. Natl Acad. Sci. U.S.A.
109
,
19691
19696
89
Dharmaiah
,
S.
,
Bindu
,
L.
,
Tran
,
T.H.
,
Gillette
,
W.K.
,
Frank
,
P.H.
,
Ghirlando
,
R.
et al (
2016
)
Structural basis of recognition of farnesylated and methylated KRAS4b by PDEdelta
.
Proc. Natl Acad. Sci. U.S.A.
113
,
E6766
E6E75
90
Fargeas
,
C.A.
,
Fonseca
,
A.V.
,
Huttner
,
W.B.
and
Corbeil
,
D.
(
2006
)
Prominin-1 (CD133): from progenitor cells to human diseases
.
Future Lipidol.
1
,
213
225
91
Kuo
,
T.C.
,
Chen
,
C.T.
,
Baron
,
D.
,
Onder
,
T.T.
,
Loewer
,
S.
,
Almeida
,
S.
et al (
2011
)
Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity
.
Nat. Cell Biol.
13
,
1214
1223
92
Izumi
,
H.
,
Li
,
Y.
,
Shibaki
,
M.
,
Mori
,
D.
,
Yasunami
,
M.
,
Sato
,
S.
et al (
2019
)
Recycling endosomal CD133 functions as an inhibitor of autophagy at the pericentrosomal region
.
Sci. Rep.
9
,
2236
93
Tabu
,
K.
,
Kimura
,
T.
,
Sasai
,
K.
,
Wang
,
L.
,
Bizen
,
N.
,
Nishihara
,
H.
et al (
2010
)
Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks
.
Mol. Cancer
9
,
39
94
Piffoux
,
M.
,
Eriau
,
E.
and
Cassier
,
E.
(
2020
)
Autophagy as a therapeutic target in pancreatic cancer
.
Br. J. Cancer
124
,
333
344
95
Zeng
,
X.
,
Shaikh
,
F.Y.
,
Harrison
,
M.K.
,
Adon
,
A.M.
,
Trimboli
,
A.J.
,
Carroll
,
K.A.
et al (
2010
)
The Ras oncogene signals centrosome amplification in mammary epithelial cells through cyclin D1/Cdk4 and Nek2
.
Oncogene
29
,
5103
5112
96
Friedmann-Morvinski
,
D.
and
Verma
,
I.M.
(
2014
)
Dedifferentiation and reprogramming: origins of cancer stem cells
.
EMBO Rep.
15
,
244
253
97
Inder
,
K.L.
,
Lau
,
C.
,
Loo
,
D.
,
Chaudhary
,
N.
,
Goodall
,
A.
,
Martin
,
S.
et al (
2009
)
Nucleophosmin and nucleolin regulate K-Ras plasma membrane interactions and MAPK signal transduction
.
J. Biol. Chem.
284
,
28410
9
98
Qing
,
Y.
,
Yingmao
,
G.
,
Lujun
,
B.
and
Shaoling
,
L.
(
2008
)
Role of Npm1 in proliferation, apoptosis and differentiation of neural stem cells
.
J. Neurol. Sci.
266
,
131
137
99
Amin
,
M.A.
,
Matsunaga
,
S.
,
Uchiyama
,
S.
and
Fukui
,
K.
(
2008
)
Nucleophosmin is required for chromosome congression, proper mitotic spindle formation, and kinetochore-microtubule attachment in heLa cells
.
FEBS Lett.
582
,
3839
3844
100
Grisendi
,
S.
,
Mecucci
,
C.
,
Falini
,
B.
and
Pandolfi
,
P.P.
(
2006
)
Nucleophosmin and cancer
.
Nat. Rev. Cancer
6
,
493
505
101
Wang
,
W.
,
Budhu
,
A.
,
Forgues
,
M.
and
Wang
,
X.W.
(
2005
)
Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication
.
Nat. Cell Biol.
7
,
823
830
102
Villalobo
,
A.
,
Ishida
,
H.
,
Vogel
,
H.J.
and
Berchtold
,
M.W.
(
2018
)
Calmodulin as a protein linker and a regulator of adaptor/scaffold proteins
.
Bichim. Biophys. Acta Mol. Cell Res.
1865
,
507
521
103
Okuda
,
M.
(
2002
)
The role of nucleophosmin in centrosome duplication
.
Oncogene
21
,
6170
6174
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).