Atlas of Genetics and Cytogenetics in Oncology and Haematology
RAPGEF1 (Rap guanine nucleotide exchange factor (GEF) 1)
| Identity |
| Other names | C3G |
| DKFZp781P1719 | |
| GRF2 | |
| HGNC (Hugo) | RAPGEF1 |
| LocusID (NCBI) | 2889 |
| Location | 9q34.13 |
| Location_base_pair | Starts at 134452157 and ends at 134612925 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| Local_order | c-Abl non-receptor tyrosine kinase, RapGEF1, sarcosine dehydrogenase, bromodomain containing 3, ADP-ribosylation factor 4 pseudogene. |
 | |
| Human chromosome 9 map showing the position of C3G (RapGEF1). | |
| DNA/RNA |
 | |
| Schematic showing the genome organization of C3G gene. | |
| Description | The human RAPGEF1/C3G gene is comprised of 24 exons, spanning 163 kb on chromosome 9q34.13. |
| Transcription | 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. |
| Pseudogene | None. |
| Protein |
 | |
| 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. | |
| Description | 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 | 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. |
| Localisation | Cytosolic. 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. |
 | |
| 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. | |
| Function | - 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: |
| Homology | C3G shares homology only in catalytic domain with other Ras family GTPases. It lacks multiple modular protein interaction domains seen in other family members. |
| Mutations |
| Note | Not known. |
| Implicated in |
| Entity | Various diseases |
| Note | 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. |
| External links |
| Bibliography |
| Four 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, Feller SM, Hanafusa H. |
| J Biol Chem. 1994 Dec 30;269(52):32781-7. |
| PMID 7806500 |
| C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. |
| Tanaka S, Morishita T, Hashimoto Y, Hattori S, Nakamura S, Shibuya M, Matuoka K, Takenawa T, Kurata T, Nagashima K, et al. |
| Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3443-7. |
| PMID 7512734 |
| Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. |
| Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, Kaibuchi K, Matsui H, Hatase O, Takahashi H, et al. |
| Mol Cell Biol. 1995 Dec;15(12):6746-53. |
| PMID 8524240 |
| Activation of R-Ras by Ras-guanine nucleotide-releasing factor. |
| Gotoh T, Niino Y, Tokuda M, Hatase O, Nakamura S, Matsuda M, Hattori S. |
| J Biol Chem. 1997 Jul 25;272(30):18602-7. |
| PMID 9228027 |
| Transformation suppressor activity of C3G is independent of its CDC25-homology domain. |
| Guerrero C, Fernandez-Medarde A, Rojas JM, Font de Mora J, Esteban LM, Santos E. |
| Oncogene. 1998 Feb 5;16(5):613-24. |
| PMID 9482107 |
| Direct binding of p130(Cas) to the guanine nucleotide exchange factor C3G. |
| Kirsch KH, Georgescu MM, Hanafusa H. |
| J Biol Chem. 1998 Oct 2;273(40):25673-9. |
| PMID 9748234 |
| CrkL activates integrin-mediated hematopoietic cell adhesion through the guanine nucleotide exchange factor C3G. |
| Arai A, Nosaka Y, Kohsaka H, Miyasaka N, Miura O. |
| Blood. 1999 Jun 1;93(11):3713-22. |
| PMID 10339478 |
| Activation of C3G guanine nucleotide exchange factor for Rap1 by phosphorylation of tyrosine 504. |
| Ichiba T, Hashimoto Y, Nakaya M, Kuraishi Y, Tanaka S, Kurata T, Mochizuki N, Matsuda M. |
| J Biol Chem. 1999 May 14;274(20):14376-81. |
| PMID 10318861 |
| Activation of the Drosophila C3G leads to cell fate changes and overproliferation during development, mediated by the RAS-MAPK pathway and RAP1. |
| Ishimaru S, Williams R, Clark E, Hanafusa H, Gaul U. |
| EMBO J. 1999 Jan 4;18(1):145-55. |
| PMID 9878058 |
| CrkL 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, Arai A, Miyasaka N, Miura O. |
| J Biol Chem. 1999 Oct 15;274(42):30154-62. |
| PMID 10514505 |
| Identification of a novel splice variant of C3G which shows tissue-specific expression. |
| Shivakrupa, Singh R, Swarup G. |
| DNA Cell Biol. 1999 Sep;18(9):701-8. |
| PMID 10492401 |
| The adapter protein Crkl links Cbl to C3G after integrin ligation and enhances cell migration. |
| Uemura N, Griffin JD. |
| J Biol Chem. 1999 Dec 31;274(53):37525-32. |
| PMID 10608804 |
| The association of CRKII with C3G can be regulated by integrins and defines a novel means to regulate the mitogen-activated protein kinases. |
| Buensuceso CS, O'Toole TE. |
| J Biol Chem. 2000 Apr 28;275(17):13118-25. |
| PMID 10777617 |
| Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. |
| Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M. |
| J Biol Chem. 2000 Jun 30;275(26):20020-6. |
| PMID 10777492 |
| Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. |
| Chiang SH, Baumann CA, Kanzaki M, Thurmond DC, Watson RT, Neudauer CL, Macara IG, Pessin JE, Saltiel AR. |
| Nature. 2001 Apr 19;410(6831):944-8. |
| PMID 11309621 |
| Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. |
| Ohba Y, Ikuta K, Ogura A, Matsuda J, Mochizuki N, Nagashima K, Kurokawa K, Mayer BJ, Maki K, Miyazaki J, Matsuda M. |
| EMBO J. 2001 Jul 2;20(13):3333-41. |
| PMID 11432821 |
| Physical 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, Radha V, Sudhakar Ch, Swarup G. |
| J Biol Chem. 2003 Dec 26;278(52):52188-94. Epub 2003 Oct 9. |
| PMID 14551197 |
| The guanine nucleotide exchange factor C3G is necessary for the formation of focal adhesions and vascular maturation. |
| Voss AK, Gruss P, Thomas T. |
| Development. 2003 Jan;130(2):355-67. |
| PMID 12466202 |
| Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers. |
| Hirata T, Nagai H, Koizumi K, Okino K, Harada A, Onda M, Nagahata T, Mikami I, Hirai K, Haraguchi S, Jin E, Kawanami O, Shimizu K, Emi M. |
| J Hum Genet. 2004;49(6):290-5. Epub 2004 May 8. |
| PMID 15138850 |
| Rap1 regulates the formation of E-cadherin-based cell-cell contacts. |
| Hogan C, Serpente N, Cogram P, Hosking CR, Bialucha CU, Feller SM, Braga VM, Birchmeier W, Fujita Y. |
| Mol Cell Biol. 2004 Aug;24(15):6690-700. |
| PMID 15254236 |
| Phosphorylated guanine nucleotide exchange factor C3G, induced by pervanadate and Src family kinases localizes to the Golgi and subcortical actin cytoskeleton. |
| Radha V, Rajanna A, Swarup G. |
| BMC Cell Biol. 2004 Aug 20;5:31. |
| PMID 15320955 |
| Activation of a signaling cascade by cytoskeleton stretch. |
| Tamada M, Sheetz MP, Sawada Y. |
| Dev Cell. 2004 Nov;7(5):709-18. |
| PMID 15525532 |
| Interaction of Bcr/Abl with C3G, an exchange factor for the small GTPase Rap1, through the adapter protein Crkl. |
| Cho YJ, Hemmeryckx B, Groffen J, Heisterkamp N. |
| Biochem Biophys Res Commun. 2005 Aug 12;333(4):1276-83. |
| PMID 15982636 |
| Characterization of p87C3G, a novel, truncated C3G isoform that is overexpressed in chronic myeloid leukemia and interacts with Bcr-Abl. |
| Gutierrez-Berzal J, Castellano E, Martin-Encabo S, Gutierrez-Cianca N, Hernandez JM, Santos E, Guerrero C. |
| Exp Cell Res. 2006 Apr 1;312(6):938-48. Epub 2006 Jan 27. |
| PMID 16443220 |
| Inactivation of Crk SH3 domain-binding guanine nucleotide-releasing factor (C3G) in cervical squamous cell carcinoma. |
| Okino K, Nagai H, Nakayama H, Doi D, Yoneyama K, Konishi H, Takeshita T. |
| Int J Gynecol Cancer. 2006 Mar-Apr;16(2):763-71. |
| PMID 16681758 |
| C3G regulates the size of the cerebral cortex neural precursor population. |
| Voss AK, Krebs DL, Thomas T. |
| EMBO J. 2006 Aug 9;25(15):3652-63. Epub 2006 Jul 20. |
| PMID 16858399 |
| C3G is required for c-Abl-induced filopodia and its overexpression promotes filopodia formation. |
| Radha V, Rajanna A, Mitra A, Rangaraj N, Swarup G. |
| Exp Cell Res. 2007 Jul 1;313(11):2476-92. Epub 2007 Mar 30. |
| PMID 17475248 |
| Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. |
| Gaulton KJ, Willer CJ, Li Y, Scott LJ, Conneely KN, Jackson AU, Duren WL, Chines PS, Narisu N, Bonnycastle LL, Luo J, Tong M, Sprau AG, Pugh EW, Doheny KF, Valle TT, Abecasis GR, Tuomilehto J, Bergman RN, Collins FS, Boehnke M, Mohlke KL. |
| Diabetes. 2008 Nov;57(11):3136-44. Epub 2008 Aug 4. |
| PMID 18678618 |
| The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1. |
| Nolz JC, Nacusi LP, Segovis CM, Medeiros RB, Mitchell JS, Shimizu Y, Billadeau DD. |
| J Cell Biol. 2008 Sep 22;182(6):1231-44. |
| PMID 18809728 |
| The guanine nucleotide exchange factor, C3G regulates differentiation and survival of human neuroblastoma cells. |
| Radha V, Rajanna A, Gupta RK, Dayma K, Raman T. |
| J Neurochem. 2008 Dec;107(5):1424-35. Epub 2008 Oct 24. |
| PMID 18957052 |
| C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment. |
| Voss AK, Britto JM, Dixon MP, Sheikh BN, Collin C, Tan SS, Thomas T. |
| Development. 2008 Jun;135(12):2139-49. |
| PMID 18506028 |
| RAPGEF1 gene variants associated with type 2 diabetes in the Korean population. |
| Hong KW, Jin HS, Lim JE, Ryu HJ, Go MJ, Lee JY, Woo JT, Park HK, Oh B. |
| Diabetes Res Clin Pract. 2009 May;84(2):117-22. Epub 2009 Mar 17. |
| PMID 19297053 |
| C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death. |
| Gutierrez-Uzquiza A, Arechederra M, Molina I, Banos R, Maia V, Benito M, Guerrero C, Porras A. |
| Cell Signal. 2010 Mar;22(3):533-42. |
| PMID 19925863 |
| F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death. |
| Mitra A, Radha V. |
| Oncogene. 2010 Aug 12;29(32):4528-42. Epub 2010 Jun 28. |
| PMID 20581864 |
| The Rap1 guanine nucleotide exchange factor C3G is required for preservation of larval muscle integrity in Drosophila melanogaster. |
| Shirinian M, Grabbe C, Popovic M, Varshney G, Hugosson F, Bos H, Rehmann H, Palmer RH. |
| PLoS One. 2010 Mar 3;5(3):e9403. |
| PMID 20209136 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 07-2010 | Aninda Mitra, Vegesna Radha |
| Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad - 500 007, India |
| Citation |
| This paper should be referenced as such : |
| Mitra A, Radha V . RAPGEF1 (Rap guanine nucleotide exchange factor (GEF) 1). Atlas Genet Cytogenet Oncol Haematol. July 2010 . URL : http://AtlasGeneticsOncology.org/Genes/RAPGEF1ID42045ch9q34.html |
This paper is referenced by INIST as such : |
| http://documents.irevues.inist.fr/bitstream/2042/44996/1/07-2010-RAPGEF1ID42045ch9q34.pdf [ Bibliographic record ] |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed May 1 13:02:56 CEST 2013 |
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