RAPGEF1 (Rap guanine nucleotide exchange factor (GEF) 1)

2010-07-01   Aninda Mitra , Vegesna Radha 

Centre for Cellular, Molecular Biology, Uppal Road, Hyderabad - 500 007, India


Atlas Image
Human chromosome 9 map showing the position of C3G (RapGEF1).


Atlas Image
Schematic showing the genome organization of C3G gene.


The human RAPGEF1/C3G gene is comprised of 24 exons, spanning 163 kb on chromosome 9q34.13.


Expression is ubiquitous, with some tissues like the heart, uterus and skeletal muscle showing higher expression.
Alternative spliced forms: Human RAPGEF1/C3G has two isoforms - isoform a and b which differ in the N-terminal (3 aa of Isoform a replaced by 21 aa in isoform b). Isoform-a has 6085 bps of transcript length whereas isoform-b has 6256 bps of transcript length.
An alternate isoform in rat has a 153bp insertion which is expressed only in testis and brain.
A truncated isoform is expressed in CML cells (K562) named p87C3G which has 4.5 kb of transcript length.




Atlas Image
Schematic showing the domain organization of RAPGEF1/C3G protein. The C-terminal catalytic domain of C3G is homologous to CDC25 and is responsible for target G protein activation. The N-terminal region has a domain which interacts with E-cadherin. The central protein interaction domain (also known as Crk binding region, CBR) contains multiple proline-rich sequences that bind SH3 domains of Crk, Cas, c-Abl and Hck. The non-catalytic sequences negatively regulate catalytic activity of C3G.


This 140 kDa protein is a guanine nucleotide exchange factor for some members of Ras family GTPases.
Size: isoform a: 1077 amino acids; isoform b: 1095 amino acids.
Domains: C-terminal catalytic domain: homologous to CDC25, exchange factor activity.
Central protein interaction domain: contains poly-proline tracts, with the ability to bind to SH3 domains of various proteins.
N-terminal non-catalytic domain contains an E-cadherin binding domain.
Catalytic activity: Activates downstream GTPases like Ras family members Rap1, Rap2, R-Ras, TC21 and Rho family member TC-10.


Expression is ubiquitous. Higher levels of RAPGEF1/C3G are seen in differentiated human neuroblastoma cells compared to undifferentiated cells.
Interacting partners: p130Cas, Crk, Crk-L, Grb2, Hck, PDGF, Cas-L, Shc, Rap1, c-Abl, PP2A and E-cadherin.
Tyrosine phosphorylation: phosphorylated predominantly at Y504; phosphoryaltion also at other tyrosine residues. Kinases known to phosphorylate RAPGEF1/C3G are Hck, Src, c-Abl and Fyn. Rat and mouse isoforms show changes in sequence surrounding Y504.
Membrane anchoring: Constitutive association with Crk enables the complex to interact with phospho-tyrosine motifs upon stimulation of growth factor receptors in the cell membrane.
Actin cytoskeleton binding: Binds to actin cytoskeleton; phosphorylation at Y504 enhances F-actin binding.
Downstream effectors: Ras family members Rap1, Rap2, R-Ras, TC21, Rho family member TC-10.


Upon stimulation of growth factor receptors can be recruited to plasma membrane.
Upon phosphorylation by Src family kinases localizes to Golgi and sub-cortical cytoskeleton.
Also localizes to tips of filopodia and membranous ruffles.
Atlas Image
Cellular functions involving C3G mediated signalling. C3G is involved in signalling pathways triggered by upstream activators like integrin binding, B cell receptor, T cell receptor, insulin, EGF, NGF, TXT: interferon-gamma, Hepatocyte growth factor, growth hormone, Reelin, mechanical force, Nectin, cadherin engagement, Erythropoietin and interleukin-3. Through its catalytic function it activates downstream G proteins by switching them from an inactive GDP bound state to an active GTP bound form. It targets the Ras family members Rap1, Rap2, R-Ras, and Rho family member TC-10, leading to activation of MAP kinases that play a role in cell proliferation and integrin-mediated signaling. C3G also has functions which are independent of its catalytic domain, where it behaves like an adaptor protein. Such functions include apoptosis and suppression of transformation.


- Suppression of transformation: In cells expressing various oncogenes C3G shows transformation-suppression activity independent of its catalytic domain. This function is mediated by inhibition of ERK phosphorylation and cyclin A expression.
- Cell survival and apoptosis: C3G expression protects against serum starvation induced cell death in neuroblastoma cells through induction of p21. Co-expression of Hck with C3G induced high level of apoptosis in many cell lines. C3G is phosphorylated at Y504 in cells undergoing apoptosis as a consequence of c-Abl expression. C3G is required for c-Abl induced apoptosis.
Upon serum deprivation, C3G induces survival in MEFs through inhibition of p38alpha MAPK activity, which mediates apoptosis. In response to oxidative stress, C3G behaves as a pro-apoptotic molecule, as its knockdown or knockout enhances survival through up-regulation of p38alpha activity, which plays an anti-apoptotic role under these conditions.
- Cell cycle arrest: C3G expression induced the cell cycle inhibitor p21 in human neuroblastoma cells.
- Filopodia formation: C3G is required for c-Abl-induced filopodia during cell spreading on fibronectin. C3G expression induces actin cytoskeletal reorganization and promotes filopodia formation independent of its catalytic activity.
- Neuronal differentiation: C3G is induced during neuronal differentiation and is required for differentiation of human neuroblastoma cells.
- Cell Proliferation: Expression of membrane targeted C3G in Drosophila leads to cell fate changes and overproliferation during development, mediated by the RAS-MAPK pathway and RAP1.
- Muscle integrity: C3G is an accessory component of the Drosophila musculature, essential for the proper localization of integrins at muscle-muscle and muscle-epidermis attachment sites and important for maintaining muscle integrity during larval stages.

Knockout phenotype:
- Knockout mice show embryonic lethality with C3G-/- homozygous animals dying before embryonic day 7.5. Fibroblasts from knockout animals show impaired cell adhesion, delayed cell spreading and accelerated cell migration.
- Animals expressing hypomorphic allele of C3G show overproliferation of the cortical neuroepithelium, cortical neuron migration defects, and defects in blood vessel maturation.


C3G shares homology only in catalytic domain with other Ras family GTPases. It lacks multiple modular protein interaction domains seen in other family members.



Not known.

Implicated in

Entity name
Various diseases
p87 isoform of C3G lacking N-terminal 305 residues expressed in CML cell lines and Ph+ patients has been suggested to play a role in pathogenesis of CML. Decreased C3G expression due to hypermethylation was seen in cervical squamous cell carcinomas.
Amplification of C3G is associated with primary non-small cell lung carcinomas, which also show higher levels of protein expression in cancerous cells.
SNPs in the C3G gene have shown association with Type 2 diabetes in Korean and Finnish populations.


Pubmed IDLast YearTitleAuthors
103394781999CrkL activates integrin-mediated hematopoietic cell adhesion through the guanine nucleotide exchange factor C3G.Arai A et al
107776172000The association of CRKII with C3G can be regulated by integrins and defines a novel means to regulate the mitogen-activated protein kinases.Buensuceso CS et al
113096212001Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10.Chiang SH et al
159826362005Interaction of Bcr/Abl with C3G, an exchange factor for the small GTPase Rap1, through the adapter protein Crkl.Cho YJ et al
186786182008Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes.Gaulton KJ et al
85242401995Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G.Gotoh T et al
92280271997Activation of R-Ras by Ras-guanine nucleotide-releasing factor.Gotoh T et al
94821071998Transformation suppressor activity of C3G is independent of its CDC25-homology domain.Guerrero C et al
164432202006Characterization of p87C3G, a novel, truncated C3G isoform that is overexpressed in chronic myeloid leukemia and interacts with Bcr-Abl.Gutiérrez-Berzal J et al
199258632010C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death.Gutiérrez-Uzquiza A et al
151388502004Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers.Hirata T et al
152542362004Rap1 regulates the formation of E-cadherin-based cell-cell contacts.Hogan C et al
192970532009RAPGEF1 gene variants associated with type 2 diabetes in the Korean population.Hong KW et al
103188611999Activation of C3G guanine nucleotide exchange factor for Rap1 by phosphorylation of tyrosine 504.Ichiba T et al
98780581999Activation of the Drosophila C3G leads to cell fate changes and overproliferation during development, mediated by the RAS-MAPK pathway and RAP1.Ishimaru S et al
97482341998Direct binding of p130(Cas) to the guanine nucleotide exchange factor C3G.Kirsch KH et al
78065001994Four proline-rich sequences of the guanine-nucleotide exchange factor C3G bind with unique specificity to the first Src homology 3 domain of Crk.Knudsen BS et al
205818642010F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death.Mitra A et al
188097282008The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1.Nolz JC et al
105145051999CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3.Nosaka Y et al
114328212001Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis.Ohba Y et al
107774922000Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3.Ohba Y et al
166817582006Inactivation of Crk SH3 domain-binding guanine nucleotide-releasing factor (C3G) in cervical squamous cell carcinoma.Okino K et al
189570522008The guanine nucleotide exchange factor, C3G regulates differentiation and survival of human neuroblastoma cells.Radha V et al
202091362010The Rap1 guanine nucleotide exchange factor C3G is required for preservation of larval muscle integrity in Drosophila melanogaster.Shirinian M et al
145511972003Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain.Shivakrupa R et al
104924011999Identification of a novel splice variant of C3G which shows tissue-specific expression.Shivakrupa et al
155255322004Activation of a signaling cascade by cytoskeleton stretch.Tamada M et al
75127341994C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins.Tanaka S et al
106088041999The adapter protein Crkl links Cbl to C3G after integrin ligation and enhances cell migration.Uemura N et al
185060282008C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment.Voss AK et al
124662022003The guanine nucleotide exchange factor C3G is necessary for the formation of focal adhesions and vascular maturation.Voss AK et al
168583992006C3G regulates the size of the cerebral cortex neural precursor population.Voss AK et al

Other Information

Locus ID:

NCBI: 2889
MIM: 600303
HGNC: 4568
Ensembl: ENSG00000107263


dbSNP: 2889
ClinVar: 2889
TCGA: ENSG00000107263


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Focal adhesionKEGGko04510
Insulin signaling pathwayKEGGko04910
Renal cell carcinomaKEGGko05211
Focal adhesionKEGGhsa04510
Insulin signaling pathwayKEGGhsa04910
Renal cell carcinomaKEGGhsa05211
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Regulation of signaling by CBLREACTOMER-HSA-912631
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by METREACTOMER-HSA-6806834
MET promotes cell motilityREACTOMER-HSA-8875878
MET activates RAP1 and RAC1REACTOMER-HSA-8875555

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
188097282008The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1.51
186604892008Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.26
204160772010Identification of type 2 diabetes-associated combination of SNPs using support vector machine.26
145511972003Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain.21
256178012015The C3G/Rap1 pathway promotes secretion of MMP-2 and MMP-9 and is involved in serous ovarian cancer metastasis.21
126977632003Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b.20
153209552004Phosphorylated guanine nucleotide exchange factor C3G, induced by pervanadate and Src family kinases localizes to the Golgi and subcortical actin cytoskeleton.18
201908162010Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells.17
216284232011The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL-C3G complex and activating Rap1 at the leading edge.15


Aninda Mitra ; Vegesna Radha

RAPGEF1 (Rap guanine nucleotide exchange factor (GEF) 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-07-01

Online version: http://atlasgeneticsoncology.org/gene/42045/rapgef1-(rap-guanine-nucleotide-exchange-factor-(gef)-1)