Encyclopedia of Signaling Molecules

Living Edition
| Editors: Sangdun Choi


Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-6438-9_101544-1


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...


Chronic Lymphocytic Leukemia Neuronal Ceroid Lipofuscinosis Cervical Squamous Cell Carcinoma Rap1 Activation Mouse Pheochromocytoma Cell 
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  1. Ballif BA, Arnaud L, Arthur WT, Guris D, Imamoto A, Cooper JA. Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons. Curr Biol. 2004;CB 14:606–10.CrossRefPubMedGoogle Scholar
  2. Che YL, Luo SJ, Li G, Cheng M, Gao YM, Li XM, et al. The C3G/Rap1 pathway promotes secretion of MMP-2 and MMP-9 and is involved in serous ovarian cancer metastasis. Cancer Lett. 2015;359:241–9.CrossRefPubMedGoogle Scholar
  3. Chiang SH, Baumann CA, Kanzaki M, Thurmond DC, Watson RT, Neudauer CL, et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature. 2001;410:944–8.CrossRefPubMedGoogle Scholar
  4. Dayma K, Radha V. Cytoskeletal remodeling by C3G to induce neurite-like extensions and inhibit motility in highly invasive breast carcinoma cells. Biochim Biophys Acta. 2011;1813:456–65.CrossRefPubMedGoogle Scholar
  5. Dayma K, Ramadhas A, Sasikumar K, Radha V. Reciprocal negative regulation between the guanine nucleotide exchange factor C3G and beta-catenin. Genes Cancer. 2012;3:564–77.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Fernandez V, Jares P, Salaverria I, Gine E, Bea S, Aymerich M, et al. Gene expression profile and genomic changes in disease progression of early-stage chronic lymphocytic leukemia. Haematologica. 2008;93:132–6.CrossRefPubMedGoogle Scholar
  7. Fukuyama T, Ogita H, Kawakatsu T, Fukuhara T, Yamada T, Sato T, et al. Involvement of the c-Src-Crk-C3G-Rap1 signaling in the nectin-induced activation of Cdc42 and formation of adherens junctions. J Biol Chem. 2005;280:815–25.CrossRefPubMedGoogle Scholar
  8. Gaulton KJ, Willer CJ, Li Y, Scott LJ, Conneely KN, Jackson AU, et al. Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. Diabetes. 2008;57:3136–44.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995;15:6746–53.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Gutierrez-Berzal J, Castellano E, Martin-Encabo S, Gutierrez-Cianca N, Hernandez JM, Santos E, et al. Characterization of p87C3G, a novel, truncated C3G isoform that is overexpressed in chronic myeloid leukemia and interacts with Bcr-Abl. Exp Cell Res. 2006;312:938–48.CrossRefPubMedGoogle Scholar
  11. Hirata T, Nagai H, Koizumi K, Okino K, Harada A, Onda M, et al. Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers. J Hum Genet. 2004;49:290–5.CrossRefPubMedGoogle Scholar
  12. Hong KW, Jin HS, Lim JE, Ryu HJ, Go MJ, Lee JY, et al. RAPGEF1 gene variants associated with type 2 diabetes in the Korean population. Diabetes Res Clin Pract. 2009;84:117–22.CrossRefPubMedGoogle Scholar
  13. Ichiba T, Hashimoto Y, Nakaya M, Kuraishi Y, Tanaka S, Kurata T, et al. Activation of C3G guanine nucleotide exchange factor for Rap1 by phosphorylation of tyrosine 504. J Biol Chem. 1999;274:14376–81.CrossRefPubMedGoogle Scholar
  14. Kao S, Jaiswal RK, Kolch W, Landreth GE. Identification of the mechanisms regulating the differential activation of the mapk cascade by epidermal growth factor and nerve growth factor in PC12 cells. J Biol Chem. 2001;276:18169–77.CrossRefPubMedGoogle Scholar
  15. Knudsen BS, Feller SM, Hanafusa H. Four proline-rich sequences of the guanine-nucleotide exchange factor C3G bind with unique specificity to the first Src homology 3 domain of Crk. J Biol Chem. 1994;269:32781–7.PubMedGoogle Scholar
  16. Lebrun AH, Moll-Khosrawi P, Pohl S, Makrypidi G, Storch S, Kilian D, et al. Analysis of potential biomarkers and modifier genes affecting the clinical course of CLN3 disease. Mol Med. 2011;17:1253–61.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Mitra A, Radha V. F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death. Oncogene. 2010;29:4528–42.CrossRefPubMedGoogle Scholar
  18. Mitra A, Kalayarasan S, Gupta V, Radha V. TC-PTP dephosphorylates the guanine nucleotide exchange factor C3G (RapGEF1) and negatively regulates differentiation of human neuroblastoma cells. PLoS One. 2011;6:e23681.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Nolz JC, Nacusi LP, Segovis CM, Medeiros RB, Mitchell JS, Shimizu Y, et al. The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1. J Cell Biol. 2008;182:1231–44.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Nosaka Y, Arai A, Miyasaka N, Miura O. 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. J Biol Chem. 1999;274:30154–62.CrossRefPubMedGoogle Scholar
  21. Oh J, Seo DW, Diaz T, Wei B, Ward Y, Ray JM, et al. Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Res. 2004;64:9062–9.CrossRefPubMedGoogle Scholar
  22. Ohba Y, Ikuta K, Ogura A, Matsuda J, Mochizuki N, Nagashima K, et al. Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. EMBO J. 2001;20:3333–41.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Okino K, Nagai H, Nakayama H, Doi D, Yoneyama K, Konishi H, et al. Inactivation of Crk SH3 domain-binding guanine nucleotide-releasing factor (C3G) in cervical squamous cell carcinoma. Int J Gynecol Cancer. 2006;16:763–71.CrossRefPubMedGoogle Scholar
  24. Parker JD, Shen Y, Pleasance E, Li Y, Schein JE, Zhao Y, et al. Molecular etiology of an indolent lymphoproliferative disorder determined by whole-genome sequencing. Cold Spring Harb Mol Case Stud. 2016;2:a000679.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Peak JC, Jones NP, Hobbs S, Katan M, Eccles SA. Phospholipase C gamma 1 regulates the Rap GEF1-Rap1 signalling axis in the control of human prostate carcinoma cell adhesion. Oncogene. 2008;27:2823–32.CrossRefPubMedGoogle Scholar
  26. Radha V, Mitra A, Dayma K, Sasikumar K. Signalling to actin: role of C3G, a multitasking guanine-nucleotide-exchange factor. Biosci Rep. 2011;31:231–44.CrossRefPubMedGoogle Scholar
  27. Rufanova VA, Lianos E, Alexanian A, Sorokina E, Sharma M, McGinty A, et al. C3G overexpression in glomerular epithelial cells during anti-GBM-induced glomerulonephritis. Kidney Int. 2009;75:31–40.CrossRefPubMedGoogle Scholar
  28. Sakakibara A, Ohba Y, Kurokawa K, Matsuda M, Hattori S. Novel function of Chat in controlling cell adhesion via Cas-Crk-C3G-pathway-mediated Rap1 activation. J Cell Sci. 2002;115:4915–24.CrossRefPubMedGoogle Scholar
  29. Sakkab D, Lewitzky M, Posern G, Schaeper U, Sachs M, Birchmeier W, et al. Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL. J Biol Chem. 2000;275:10772–8.CrossRefPubMedGoogle Scholar
  30. Samuelsson J, Alonso S, Ruiz-Larroya T, Cheung TH, Wong YF, Perucho M. Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer. Int J Oncol. 2011;38:1575–7.PubMedGoogle Scholar
  31. Sasi Kumar K, Ramadhas A, Nayak SC, Kaniyappan S, Dayma K, Radha V. C3G (RapGEF1), a regulator of actin dynamics promotes survival and myogenic differentiation of mouse mesenchymal cells. Biochim Biophys Acta. 2015;1853:2629–39.CrossRefPubMedGoogle Scholar
  32. Schonherr C, Yang HL, Vigny M, Palmer RH, Hallberg B. Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells. Oncogene. 2010;29:2817–30.CrossRefPubMedGoogle Scholar
  33. Sekine K, Kawauchi T, Kubo K, Honda T, Herz J, Hattori M, et al. Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin alpha5beta1. Neuron. 2012;76:353–69.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Shah B, Lutter D, Bochenek ML, Kato K, Tsytsyura Y, Glyvuk N, et al. C3G/Rapgef1 is required in multipolar neurons for the transition to a bipolar morphology during cortical development. PLoS One. 2016;11:e0154174.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Shirinian M, Popovic M, Grabbe C, Varshney G, Hugosson F, Bos H, et al. The Rap1 guanine nucleotide exchange factor C3G is required for preservation of larval muscle integrity in Drosophila melanogaster. PLoS One. 2010;5:e9403.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Tanaka S, Morishita T, Hashimoto Y, Hattori S, Nakamura S, Shibuya M, et al. C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Proc Natl Acad Sci USA. 1994;91:3443–7.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Tanaka S, Ouchi T, Hanafusa H. Downstream of Crk adaptor signaling pathway: activation of Jun kinase by v-Crk through the guanine nucleotide exchange protein C3G. Proc Natl Acad Sci USA. 1997;94:2356–61.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Tsukamoto N, Hattori M, Yang H, Bos JL, Minato N. Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. J Biol Chem. 1999;274:18463–9.CrossRefPubMedGoogle Scholar
  39. Utreras E, Henriquez D, Contreras-Vallejos E, Olmos C, Di Genova A, Maass A, et al. Cdk5 regulates Rap1 activity. Neurochem Int. 2013;62:848–53.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Voss AK, Gruss P, Thomas T. The guanine nucleotide exchange factor C3G is necessary for the formation of focal adhesions and vascular maturation. Development. 2003;130:355–67.CrossRefPubMedGoogle Scholar
  41. Voss AK, Krebs DL, Thomas T. C3G regulates the size of the cerebral cortex neural precursor population. EMBO J. 2006;25:3652–63.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Voss AK, Britto JM, Dixon MP, Sheikh BN, Collin C, Tan SS, et al. C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment. Development. 2008;135:2139–49.CrossRefPubMedGoogle Scholar
  43. Wang SF, Aoki M, Nakashima Y, Shinozuka Y, Tanaka H, Taniwaki M, et al. Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling. Blood. 2008;111:2878–86.CrossRefPubMedGoogle Scholar
  44. Wu C, Lai CF, Mobley WC. Nerve growth factor activates persistent Rap1 signaling in endosomes. J Neurosci Off J Soc Neurosci. 2001;21:5406–16.Google Scholar
  45. Yang JJ, Cho LY, Ma SH, Ko KP, Shin A, Choi BY, et al. Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study. PLoS One. 2011;6:e21155.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Yip YP, Thomas T, Voss AK, Yip JW. Migration of sympathetic preganglionic neurons in the spinal cord of a C3G deficient mouse suggests that C3G acts in the reelin signaling pathway. J Comp Neurol. 2012;520:3194–202.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media LLC 2016

Authors and Affiliations

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