Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

C3G

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101544

Synonyms

Historical Background

Small GTPases belonging to Ras super family transmit extracellular signals to regulate multiple cellular functions. These proteins are inactive when they are bound to GDP and are active when bound to GTP, thereby acting as molecular switches. Conversion of GTPases from inactive GDP bound form to active GTP bound form is performed by GTP exchange factors (GEFs). GEFs are important hubs in pathways that integrate upstream signals to activate small GTPases, eventually translating the signals into required cellular functions.

C3G is a GEF having CDC25 homology domain characteristic to GEFs for Ras family GTPases. C3G was discovered as a Crk interacting protein that binds to SH3 domain of Crk and GRB2 in 1994 (Tanaka et al. 1994). Another study published in the same year also identified C3G as a Crk binding protein and characterized the proline-rich sequences, present in central region of C3G, required for binding to Crk (Knudsen et al. 1994). Upon cloning and sequencing the novel Crk interacting protein, it was found to have a C-terminal domain with sequence similarity to CDC25 and SOS and was therefore predicted to have GEF activity. It showed activity towards Rap1, a small GTPase of the Ras family (Gotoh et al. 1995). C3G was the first Rap GEF to be identified. It lacks various defined domains common in GEFs for Ras family GTPases. Generally, GEFs are specific for a single family of small GTPases, but C3G acts as a GEF for Ras family GTPases Rap1, Rap2, R-Ras, and TC21 (R-Ras2), as well as Rho family GTPase, TC10.

C3G Gene and Protein

Human C3G gene is present on chromosome 9 (9q34.3). It is about 160 kbp long and transcribes alternatively spliced variants. The variants differ only in the first exon coding for three protein isoforms (a, b and c). First three amino acids of isoform a are replaced by 21 and 20 amino acids in isoform b and c, respectively. A shorter isoform of C3G lacking N-terminal 305 amino acids including first two proline-rich sequences (p87) is expressed in chronic myeloid leukemia patient samples and cell lines (Fig. 1). Human C3G protein (isoform a) is 1077 amino acids long with Ras GEF (CDC25 homology) domain and Ras Exchanger Motif (REM) at the C-terminal and an N-terminal E-cadherin binding domain (Fig. 1). Ras GEF domain is the catalytic domain having GTP exchange activity. REM domain is indispensable for catalysis as it forms a hydrophobic pocket that helps in correct placement and stabilization of the helical HI hairpin structure of Ras GEF domain. Central Crk binding region of C3G encompasses five proline-rich sequences (Knudsen et al. 1994), which are conserved across species (Radha et al. 2011). It is through this region that C3G binds the SH3 domains of Crk and CrkL. Noncatalytic domain of C3G functions to inhibit its activity, as a deletion construct lacking N-terminal 579 amino acids is constitutively active.
C3G, Fig. 1

C3G protein and gene structure. (A) Schematic shows various domains in full length (FL) C3G (1077 amino acids, isoform a) and p87 C3G (lacking first 305 residues). N-terminal E-Cadherin binding domain, Crk binding region (CBR), catalytic region containing Ras exchanger motif (REM), and Ras Guanine nucleotide exchange factor (Ras GEF) domain are indicated. In the CBR domain, phosphorylation site at Tyrosine 504, and poly-proline sequences (P) are indicated. (B) Schematic shows structure of human C3G gene and alternate spliced variants located at chromosome 9 (location 9q34.3). Exons are denoted as vertical red lines. Number of amino acids (aa) in protein product of each transcript variant is indicated

Signaling Events Regulating C3G

A variety of upstream signals including growth factors, cytokines, extracellular matrix, trophic factors and mechanical force engage C3G to induce downstream events (Fig. 2). Various mechanisms involved in context specific regulation and engagement of C3G are described below.
  1. (a)

    Phosphorylation: Membrane targeting of the Crk-C3G complex causes phosphorylation at Y504 of human C3G, resulting in its activation. C3G is phosphorylated by Src, HCK, and c-Abl at tyrosine 504 (Ichiba et al. 1999; Radha et al. 2011). Mechanical stress and NGF cause phosphorylation of C3G leading to Rap1 activation. Integrin-mediated cell adhesion causes phosphorylation of C3G dependent on intact actin cytoskeleton. C3G was found to be phosphorylated during reelin stimulation of neurons in a study which also indicated that CrkL-C3G-Rap1 is involved in reelin-induced regulation of neuronal migration (Ballif et al. 2004). CDK5, a serine/threonine kinase, phosphorylates and increases C3G-mediated Rap1 activation (Utreras et al. 2013).

     
  2. (b)

    Subcellular localization: Cellular C3G is present in the cytoplasm. Membrane targeting of C3G is important for its activation. Translocation of the C3G-Crk complex to plasma membrane results in positive regulation of C3G activity by tyrosine phosphorylation. Farnesylated C3G localizes to membrane and is constitutively active. C3G phosphorylated at Y504 by Src family kinases localizes to Golgi and cell junctions. Phosphorylated C3G is present at the Golgi in forskolin or NGF-treated neuroblastoma cells. c-Abl mediated phosphorylation at Y504 of C3G and Rap1 activation is regulated by localization of C3G to actin-rich retracting lamellipodia in apoptotic cells (Mitra and Radha 2010). C3G localizes to focal adhesions in differentiated myotubes. During insulin stimulation of adipocytes, C3G-CrkII is recruited to lipid rafts at the cell membrane by Cbl where C3G activates the Rho family GTPase, TC10. Activation of TC10 is essential for GLUT4-mediated glucose uptake in response to insulin (Chiang et al. 2001). In response to NGF, C3G containing multimolecular complex is seen in endosomes, where Rap1 is activated (Wu et al. 2001).

     
  3. (c)

    Protein interactions: C3G binds to SH3 domain of adapter proteins like Crk or CrkL through its proline-rich sequences. These adapter proteins, which have additional protein interaction domains, in turn bind to other proteins leading to changes in subcellular localization and activation of C3G. Erythropoietin or interleukin-3-mediated activation of Raf/Erk2 has been indicated to be regulated by C3G-CrkL-mediated activation of Ras (Nosaka et al. 1999). Activation of eosinophils by interleukin-5 results in C3G-mediated Rap1 activation dependent on CrkL. In human NB-4 cells, interferon-γ-induced c-Cbl-CrkL-C3G complex formation results in activation of Rap1 (Radha et al. 2011). C3G also binds to proteins that do not have an SH3 domain. It interacts with E-cadherin through its N-terminal domain and to β-catenin and TC48 through its central Crk binding region (CBR) (Mitra et al. 2011; Dayma et al. 2012).

     
  4. (d)
    Transcriptional regulation: Deregulation of β-catenin by GSK3β inhibition or mutated APC results in reduced transcript levels of C3G (Dayma et al. 2012). Hypomethylation of C3G gene has been detected in colon cancers, cervical squamous cell carcinomas, and ovarian cancers (Samuelsson et al. 2011). Transcript levels of C3G increase during myocyte differentiation (Sasi Kumar et al. 2015).
    C3G, Fig. 2

    C3G is regulated by multiple stimuli to perform downstream effector functions. Multiple stimuli like epidermal growth factor (EGF), nerve growth factor (NGF), hepatocyte growth factor (HGF), insulin, interferon-γ, interleukin-3, erythropoietin, activation of T-cell receptor, nectin, reelin, integrin, and mechanical force activate C3G by modulating its phosphorylation, subcellular localization, protein interactions, and gene expression. C3G relays upstream signals through its catalytic or noncatalytic domains to regulate cell proliferation, survival, differentiation, transformation, and cytoskeletal remodeling

     

Signaling Events Engaging C3G to Induce Cell Fate Changes

C3G acts as a hub for multiple signaling pathways that regulate cell fate. Transformation of cells by v-Crk-induced activation of Jun kinase is mediated by C3G in a manner dependent on its catalytic activity (Tanaka et al. 1997). Expression of farnesylated C3G, which anchors to the plasma membrane and shows constitutive activity, in hematopoietic progenitor cells resulted in marked expansion in population of blastic thymocytes in irradiated mice indicating transformation promoting role of C3G (Wang et al. 2008). In other circumstances, C3G played a negative role by suppressing oncogene-induced transformation independent of its catalytic activity. C3G overexpression inhibits ras-, cis-, and v-raf-induced transformation as shown by reduced foci formation. Farnesylated C3G reverted the transformed phenotype in v-Ki-ras transformed NIH3T3 cells dependent on Rap1 activation (Radha et al. 2011). By activating Rap1, C3G could inhibit Ras-mediated signaling in certain contexts. Stimulation of HEK 293 cells by hepatocyte growth factor (HGF) resulted in CrkL-C3G-mediated Rap1 activation (Sakkab et al. 2000). In PC12 cells, EGF or NGF treatment leads to transient or prolonged MAPK activation, dependent on the nature of multimolecular complex formed by C3G-Crk (Kao et al. 2001).

Co-expression of HCK and C3G in HeLa, MCF-7, and J774 cells resulted in apoptosis dependent on catalytic activity of HCK but independent of Y504 phosphorylation or catalytic domain of C3G. C3G phosphorylation and catalytic activity was important for c-Abl-mediated apoptosis (Radha et al. 2011). But in K562 cells treated with STI-571 (imatinib mesylate), C3G-Rap1-mediated p38α activation was involved in reducing apoptosis. In neuroblastoma cells, knockdown of C3G increases serum starvation-induced cell death. In mouse embryonic fibroblasts (MEFs), C3G promotes apoptosis during oxidative stress and cell survival during serum starvation by inhibiting p38α which assumes opposing roles of a pro-apoptotic or antiapoptotic molecule under different conditions. Upon NGF treatment of PC12 cells, C3G-induced Rap1 activation mediates increased activation of MAPK. Loss of C3G leads to cell death during differentiation of neuroblastoma cells and myocytes, suggesting that C3G is required for survival. C3G is required for activation of Akt, an important mediator of survival signaling (Sasi Kumar et al. 2015).

Signaling Mediated by C3G to Induce Cytoskeletal Remodeling and Cell Adhesion

C3G is required for c-Abl-induced formation of filopodia in a CDC42 independent and N-Wasp dependent manner (Radha et al. 2011). In highly metastatic breast cancer cells, C3G overexpression induces the formation of neurite-like extensions (NLE) dependent on the activity of Rac and CDC42 (Dayma and Radha 2011). Expression of CrkL increases integrin-mediated cell adhesion in hematopoietic cells dependent on catalytic activity of C3G. Chat (Cas/HEF1-associated signal transducer) activation leads to Cas-Crk-C3G-dependent Rap1 activation resulting in increased cell adhesion (Sakakibara et al. 2002). C3G associates with E-cadherin at newly formed adherence junctions. Inhibition of C3G-mediated Rap1 activation by SPA1, a Rap GAP, resulted in reduced cell adhesion and spreading in HeLa cells (Tsukamoto et al. 1999). Fibroblasts devoid of C3G show reduced Rap1 activation and cell adhesion (Ohba et al. 2001).

Nectin-induced recruitment and activation of Src at newly forming cell-cell junctions results in activation of Rap1 by C3G. C3G overexpression rescues PLCγ1 knockdown-induced abrogation of cell adhesion in human prostate carcinoma cells, PC3LN3 (Peak et al. 2008). Mouse embryonic fibroblasts lacking C3G show increased cell motility, suggesting that C3G negatively regulates cell motility. Mouse embryos lacking C3G show defective brain development with reduced migration of cortical neurons (Voss et al. 2008). In human microvascular endothelial cells, tissue inhibitor of metalloproteinases-2 induces C3G-mediated Rap1 activation (Oh et al. 2004). Overexpressed C3G inhibited the motility of invasive breast cancer cell line MDA-MB-231 (Dayma and Radha 2011). CrkL-C3G activates Rap1 upon reelin stimulation in embryonic cortical neurons. Studies carried out in C3G knockout mouse embryos also indicate that C3G functions downstream of reelin to regulate migration of cortical neurons (Yip et al. 2012).

C3G Mediated Inside-Out Signaling

C3G also mediates relay of signals that modulate integrins for response of the cell towards its microenvironment, that is, inside-out signaling (Fig. 3). C3G is required for hematopoietic cell adhesion and migration. Upon T-cell receptor activation, WASP family verprolin-homologous protein-2, WAVE2 activates CrkL-C3G complex to activate Rap1 and increase the affinity of integrin towards extracellular matrix thereby modulating migration of these cells (Nolz et al. 2008). In developing brain, reelin stimulation activates C3G-CrkL through Dab1 leading to activation of Rap1 that modulates the adhesion of integrin α5β1 to extracellular matrix (Sekine et al. 2012). C3G signaling is involved in the regulation of initial events in the formation of E-cadherin-based adherence junctions (Fukuyama et al. 2005).
C3G, Fig. 3

C3G mediated outside-in and inside-out signaling. Activation of very low density lipoprotein receptor (VLDLR) by reelin or T cell receptor leads to functional activation of CrkL-C3G complex mediated by Dab1 and WASP family verprolin-homologous protein-2 (WAVE2), respectively. C3G catalyses exchange of GDP to GTP on Rap1 and activated Rap1 leads to modulation of integrin adhesion to extracellular matrix

Role of C3G in Differentiation

C3G positively regulates differentiation and its expression is enhanced during differentiation of myocytes, adipocytes, neuroblasts, and hematopoietic cells (Radha et al. 2011). C3G associates with c-Crk upon induction of adipocyte differentiation in preadipocytes. In mouse pheochromocytoma cells, PC12, the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) activates C3G-mediated Rap1 activation, which is involved in the induction of neurite outgrowth (Schonherr et al. 2010). Induction of neurite outgrowth by serum starvation, NGF, or forskolin treatment results in increased C3G protein levels in human neuroblastoma cells, IMR32. Overexpression of C3G in these cells increased neurite outgrowth dependent on Rap1 activity. C3G expression increases levels of CDK inhibitor which enables proliferation arrest. Overexpression of C3G augments myotube formation and its downregulation impaired myosin heavy chain expression and myocyte differentiation (Sasi Kumar et al. 2015).

Role of C3G in Embryonic Development

C3G has an indispensable role in vertebrate as well as invertebrate embryonic development. In drosophila, C3G knockout induces semilethality at larval stage and flies that survive till adulthood have shorter life span and reduced general fitness. The larvae of these flies show defects in muscle architecture and improper localization of integrin at muscle attachment sites. Overexpression of constitutively active C3G in drosophila lead to morphological defects and defective actin organization in somatic muscles. Transgenic flies overexpressing DC3G (Drosophila C3G) or membrane targeted (myristylated) C3G in eye and wing show developmental defects similar to that observed in case of activation of Ras pathway. These phenotypes were reverted by reducing the gene dosage of Ras and MAPK pathway components. Similarly, phenotype of overexpression of dominant negative C3G, lacking the catalytic domain, was rescued upon expression of the components of Ras signaling pathway. These results suggest that C3G plays an important role in Drosophila embryonic development by activating the Ras-MAPK pathway (Shirinian et al. 2010).

C3G is expressed in all cell types during mouse embryonic development, and C3G knock out is embryonic lethal. Mouse embryos lacking C3G die around 5 dpc. MEFs lacking C3G showed increased cell motility which was antagonized by the activation of C3G substrates Rap1, Rap2, and R-Ras. Human C3G was able to complement mouse C3G deficiency in MEFs (Ohba et al. 2001). Embryos from mice expressing C3G hypomorphic allele C3Ggt/gt, which produces 5% of total C3G protein, survived up to embryonic day 14.5 and showed blood vessel maturation defects. The endothelial cells had normal morphology and arboration of blood vessels, but the vascular supporting cells did not associate tightly around blood vessels (Voss et al. 2003). Overproliferation of cells of the cerebral cortical neuroepithelium and defective neuronal migration was observed in C3Ggt/gt embryos. This was due to the fact that neuroepithelium cells in C3G-deficient embryos were taking longer time to exit cell cycle. C3G deficiency inhibited Rap1 activation during differentiation conditions and mitogen stimulation. Hence, it is possible that C3G is involved in regulating size of cortical neuron precursor population through a Rap1-mediated pathway (Voss et al. 2006). C3G deficiency also causes defective migration of sympathetic preganglionic neurons (Yip et al. 2012). C3G-mediated Rap1 activation is involved in reelin-induced neuronal layering in the neocortex of developing brain (Sekine et al. 2012). Conditional knockout of C3G in developing mouse brain revealed that C3G regulates multi-to-bipolar transition of neurons and is required in cortical lamination, axon formation, and migration of neurons (Shah et al. 2016).

Association of C3G with Diseases

Several studies have shown the association of C3G with many human disorders (Table 1). A type 2 diabetes (T2D) associated single nucleotide polymorphism (SNP) has been found in the C3G gene in a Finnish population. This SNP, rs4740283, was present 4 kb downstream of C3G gene and showed a positive association with T2D (Gaulton et al. 2008). Another SNP located in intron 13 of C3G gene of a Korean population, rs11243444, showed protective effect on the development of T2D (Hong et al. 2009). SNPs in C3G gene have been associated with gastric cancer risk in a Korean population (Yang et al. 2011).
C3G, Table 1

Association of C3G with various diseases

Disease

Association

Reference

Type 2 diabetes

Single nucleotide polymorphisms with positive and negative effects

Gaulton et al. 2008, Hong et al. 2009

Gastric cancer

Single nucleotide polymorphism associated with high risk

Yang et al. 2011

Colon cancer

Hypomethylation of C3G gene

Samuelsson et al. 2011

Cervical squamous cell carcinomas

(a) Hypomethylation of C3G gene

(b) Reduced expression

(a) Samuelsson et al. 2011

(b) Okino et al. 2006

Ovarian cancer

(a) Hypomethylation of C3G gene

(b) Elevated levels

(a) Samuelsson et al. 2011

(b) Che et al. 2015

Non- small cell lung carcinoma

Upregulated

Hirata et al. 2004

Glomerulonephritis (experimental model)

Upregulated

Rufanova et al. 2009

Chronic myeloid leukemia (CML)

Truncated protein expressed

Gutierrez-Berzal et al. 2006

Chronic lymphocytic leukemia (CLL)

Downregulated

Fernandez et al. 2008

Lymphoproliferative disorder

Mutation, Y572C

Parker et al. 2016

Human prostate carcinoma

Regulates PLCγ1-mediated adhesion

Peak et al. 2008

Juvenile neuronal ceroid lipofuscinosis

Upregulated

Lebrun et al. 2011

Deregulated C3G expression, both high and low levels, is seen in human cancers. Hypomethylation of C3G gene in a relaxed criteria CpG island, present in the first exon of transcript variant 1, has been detected in 40% colon cancers, 47% of cervical squamous cell carcinomas, and 33% of ovarian cancers. Whether hypomethylation alters C3G expression is not known (Samuelsson et al. 2011). C3G is upregulated in several samples of non-small cell lung carcinoma. In cell line models of the same carcinoma, C3G was overexpressed in six of the seven cell lines tested (Hirata et al. 2004). In cervical squamous cell carcinomas, C3G expression was less compared to control. Downregulation of C3G by siRNA increased cell growth in human cervical cancer cell line SIHA, indicating a role for C3G as a tumor suppressing gene (Okino et al. 2006). In ovarian cancers, elevated levels of C3G were found. Knockdown of C3G in SKOV3 cells, which is a cell culture model for ovarian cancer, resulted in decreased secretion of MMP-2 and MMP-9 and decreased metastasis in xenograft experiments (Che et al. 2015).

In early stage chronic lymphocytic leukemia (CLL) patients, C3G expression was found downregulated (Fernandez et al. 2008). In a patient sample of B cell neoplasm, phenotypically resembling chronic lymphocytic leukemia (CLL), a mutation was found in C3G at Y572C (isoform b) (Parker et al. 2016). In chronic myeloid leukemia (CML) cell lines and Ph+ (Philadelphia chromosomal translocation t(9;22)(q34;q11) positive) patients, an alternately spliced form of C3G, p87 C3G, which lacks N-terminal 305 residues, is expressed and its expression has been suggested to play a role in pathogenesis of CML (Gutierrez-Berzal et al. 2006). C3G-R-Ras-mediated signaling has been implicated in an experimental model of glomerular nephritis (Rufanova et al. 2009). In juvenile neuronal ceroid lipofuscinosis patients, C3G was found to be upregulated (Lebrun et al. 2011).

Summary

C3G is ubiquitously expressed in all mammalian cells and is well conserved across a large number of vertebrate species examined. Loss of C3G causes early embryonic lethality in mice. In the two decades since C3G was identified, studies have shown it to play an important role in cellular response to a variety of signals. C3G seems to be able to engage several downstream effectors, which enable it to simultaneously signal to control proliferation, survival, and differentiation; suggestive of its playing an important role as a cell fate determinant. While its catalytic activity enables activation of small GTPases of Ras family, it also has cellular roles independent of its catalytic activity. The fact that other Rap1 GEFs do not compliment C3G during mammalian embryonic development suggests important noncatalytic functions, or its ability to activate other GTPases. Recent studies have shown that altered C3G levels are associated with human cancers and other disorders, suggesting its role in maintaining homeostasis in adult tissues.

See Also

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.CSIR-Centre for Cellular and Molecular BiologyHyderabadIndia