guanine nucleotide releasing factor 2


Summary: A 145-kDa guanine nucleotide exchange factor that is specific for rap1 and ras GTP-BINDING PROTEINS. It associates with SH3 domains of the crk family of signaling proteins.

Top Publications

  1. Voss A, Britto J, Dixon M, Sheikh B, Collin C, Tan S, et al. C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment. Development. 2008;135:2139-49 pubmed publisher
    ..In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration. ..
  2. Cho Y, Hemmeryckx B, Groffen J, Heisterkamp N. Interaction of Bcr/Abl with C3G, an exchange factor for the small GTPase Rap1, through the adapter protein Crkl. Biochem Biophys Res Commun. 2005;333:1276-83 pubmed
    ..These data suggest a role for C3G-mediated Rap1 activation in Bcr/Abl-induced leukemia development. ..
  3. Fukuyama T, Ogita H, Kawakatsu T, Inagaki M, Takai Y. Activation of Rac by cadherin through the c-Src-Rap1-phosphatidylinositol 3-kinase-Vav2 pathway. Oncogene. 2006;25:8-19 pubmed
    ..This effect of Rap1 on Vav2 was mediated by phosphatidylinositol 3-kinase. We describe here the signaling pathway from trans-interacting cadherin to the activation of Rac. ..
  4. Jenei V, Andersson T, Jakus J, Dib K. E3B1, a human homologue of the mouse gene product Abi-1, sensitizes activation of Rap1 in response to epidermal growth factor. Exp Cell Res. 2005;310:463-73 pubmed
    ..Accordingly, we propose that overexpression of e3B1 in NIH3T3/EGFR cells leads to mobilization of Src tyrosine kinases that participate in EGF-induced activation of Rap1 and inhibition of cell proliferation. ..
  5. Tian X, Feig L. Age-dependent participation of Ras-GRF proteins in coupling calcium-permeable AMPA glutamate receptors to Ras/Erk signaling in cortical neurons. J Biol Chem. 2006;281:7578-82 pubmed
    ..Thus, Ras/Erk signaling and CREB activity induced by AMPARs occur through age-dependent mechanisms that likely make unique developmentally dependent contributions to synaptic function. ..
  6. Radha V, Rajanna A, Mitra A, Rangaraj N, Swarup G. C3G is required for c-Abl-induced filopodia and its overexpression promotes filopodia formation. Exp Cell Res. 2007;313:2476-92 pubmed
    ..We suggest that C3G and c-Abl function in an interdependent manner, in linking external signals to remodeling the cytoskeleton to induce filopodia. ..
  7. Buensuceso C, O Toole T. The association of CRKII with C3G can be regulated by integrins and defines a novel means to regulate the mitogen-activated protein kinases. J Biol Chem. 2000;275:13118-25 pubmed
    ..Thus, these data suggest the involvement of integrins in an ERK suppression pathway mediated by CRKII-C3G complex formation and downstream signaling from activated RAP1. ..
  8. Shivakrupa R, Radha V, Sudhakar C, Swarup G. Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain. J Biol Chem. 2003;278:52188-94 pubmed
    ..These results suggest that C3G and Hck interact physically and functionally in vivo to activate kinase-dependent and caspase-mediated apoptosis, which is independent of catalytic domain of C3G. ..
  9. 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 pubmed
    ..In conclusion, C3G-dependent activation of Rap1 is required for adhesion and spreading of embryonic fibroblasts and for the early embryogenesis of the mouse. ..

More Information


  1. Wu C, Lai C, Mobley W. Nerve growth factor activates persistent Rap1 signaling in endosomes. J Neurosci. 2001;21:5406-16 pubmed
    ..We propose that endosomes are a site from which NGF induces the prolonged activation of Rap1 and MAPK. ..
  2. Zhai B, Huo H, Liao K. C3G, a guanine nucleotide exchange factor bound to adapter molecule c-Crk, has two alternative splicing forms. Biochem Biophys Res Commun. 2001;286:61-6 pubmed
    ..These results indicate that two C3G mRNAs and proteins result from alternative RNA splicing. ..
  3. 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 pubmed
    ..These data indicate that the CrkL-C3G complex plays a role in Epo- or IL-3-induced, Ras-dependent activation of the Raf/ERK pathway leading to the activation of Elk-1 and the c-fos gene transcription. ..
  4. Ling L, Zhu T, Lobie P. Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities. J Biol Chem. 2003;278:27301-11 pubmed
    ..In addition, we demonstrated that C3G-Rap1 mediated CrkII enhancement of GH-stimulated JNK/SAPK activity. We have therefore identified a linear JAK2-independent pathway switching GH-stimulated p44/42 MAP kinase and JNK/SAPK activities. ..
  5. Zhang W, Shao Y, Fang D, Huang J, Jeon M, Liu Y. Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J Biol Chem. 2003;278:23978-83 pubmed
    ..Thus, Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells. ..
  6. Lekmine F, Sassano A, Uddin S, Majchrzak B, Miura O, Druker B, et al. The CrkL adapter protein is required for type I interferon-dependent gene transcription and activation of the small G-protein Rap1. Biochem Biophys Res Commun. 2002;291:744-50 pubmed
  7. Abassi Y, Vuori K. Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling. EMBO J. 2002;21:4571-82 pubmed
    ..Together, these results indicate that the Y221 site in CrkII regulates Rac membrane translocation upon cell adhesion, which is necessary for activation of downstream Rac signaling pathways. ..
  8. Chung J, Serezani C, Huang S, Stern J, Keskin D, Jagirdar R, et al. Rap1 activation is required for Fc gamma receptor-dependent phagocytosis. J Immunol. 2008;181:5501-9 pubmed
    ..Taken together, our data demonstrate a novel role for Rap1 and its exchange factor C3G in mediating Fc gammaR-dependent phagocytosis. ..
  9. Radha V, Rajanna A, Gupta R, Dayma K, Raman T. The guanine nucleotide exchange factor, C3G regulates differentiation and survival of human neuroblastoma cells. J Neurochem. 2008;107:1424-35 pubmed publisher
    ..These findings demonstrate a novel function for C3G in regulating survival and differentiation of human neuroblastoma cells. ..
  10. Yokoyama W. Inhibitory receptors signal activation. Immunity. 2008;29:515-7 pubmed publisher
    ..However, in this issue of Immunity, Peterson and Long show that inhibitory receptors also signal tyrosine phosphorylation, an event usually indicating cellular activation. ..
  11. 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 pubmed
    ..These results indicate that Rap1 is activated by nectins through the c-Src-Crk-C3G signaling and involved in the nectin-induced, c-Src- and FRG-mediated activation of Cdc42 and formation of AJs. ..
  12. Radha V, Rajanna A, Swarup G. Phosphorylated guanine nucleotide exchange factor C3G, induced by pervanadate and Src family kinases localizes to the Golgi and subcortical actin cytoskeleton. BMC Cell Biol. 2004;5:31 pubmed
    ..C3G is activated upon phosphorylation at tyrosine 504 and therefore, determining the localization of phosphorylated C3G would provide an insight into its site of action in the cellular context...
  13. Shi S, Noda M, Kitayama H. Rap1 mutants with increased affinity for the guanine-nucleotide exchange factor C3G. Oncogene. 2004;23:8711-9 pubmed
    ..These results suggest that Rap1-AGE acts as a dominant interfering factor against C3G and serves as a useful tool in analyzing the roles of C3G-Rap1 signaling pathway in various biological processes. ..
  14. Nolz J, Nacusi L, Segovis C, Medeiros R, Mitchell J, 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 pubmed publisher
    ..These findings identify a previously unknown mechanism by which the WAVE2 complex regulates TCR signaling to Rap1 and integrin activation. ..
  15. Sydor J, Scalf M, Sideris S, Mao G, Pandey Y, Tan M, et al. Chip-based analysis of protein-protein interactions by fluorescence detection and on-chip immunoprecipitation combined with microLC-MS/MS analysis. Anal Chem. 2003;75:6163-70 pubmed
  16. 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 pubmed
    ..These data indicate that amplification and increased expression of the C3G gene may play some role in human lung carcinogenesis through derangement of the CRK-Rap1 signaling pathway. ..
  17. Rufanova V, 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 pubmed publisher
    ..We found that C3G was overexpressed in accelerated anti-GBM antibody-induced glomerulonephritis and suggest that this modulates glomerular epithelial cell morphology and behavior. ..
  18. 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 pubmed publisher
    ..These findings identify C3G as a novel target of c-Abl and also show that FABD of c-Abl is essential for regulation of its restricted activation to induce apoptosis. ..
  19. Asuri S, Yan J, Paranavitana N, Quilliam L. E-cadherin dis-engagement activates the Rap1 GTPase. J Cell Biochem. 2008;105:1027-37 pubmed publisher
    ..We hereby show that Rap1 plays a role in the maintenance and repair of E-cadherin junctions and is activated via an "outside-in" signaling pathway initiated by E-cadherin and mediated at least in part by PDZ-GEF I. ..
  20. Gutierrez Berzal J, Castellano E, Martín Encabo S, Gutiérrez Cianca N, Hernandez J, 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 pubmed
  21. Peterson M, Long E. Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk. Immunity. 2008;29:578-88 pubmed publisher
  22. Arai A, Kanda E, Miura O. Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene. 2002;21:2641-51 pubmed
    ..Together, these results indicate that Rac is activated by Epo or IL-3 at downstream of the Ras/PI3K pathway in parallel with Akt and plays a role in activation of the Erk/Elk-1 signaling pathway in hematopoietic cells. ..
  23. Rufanova V, Alexanian A, Wakatsuki T, Lerner A, Sorokin A. Pyk2 mediates endothelin-1 signaling via p130Cas/BCAR3 cascade and regulates human glomerular mesangial cell adhesion and spreading. J Cell Physiol. 2009;219:45-56 pubmed publisher
    ..Our data suggest that ET-1 stimulated the GTPase Rap1 (but neither RhoA nor Ras) by a mechanism involving Pyk2 activation and recruitment of the p130Cas/BCAR3 complex in GMC. ..
  24. Guerrero C, Martín Encabo S, Fernández Medarde A, Santos E. C3G-mediated suppression of oncogene-induced focus formation in fibroblasts involves inhibition of ERK activation, cyclin A expression and alterations of anchorage-independent growth. Oncogene. 2004;23:4885-93 pubmed
  25. Voss A, 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 pubmed
  26. Deevi R, Koney Dash M, Kissenpfennig A, Johnston J, Schuh K, Walter U, et al. Vasodilator-stimulated phosphoprotein regulates inside-out signaling of beta2 integrins in neutrophils. J Immunol. 2010;184:6575-84 pubmed publisher
  27. Huang X, Wu D, Jin H, Stupack D, Wang J. Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling. J Cell Biol. 2008;183:711-23 pubmed publisher
    ..Our results establish Rap1 as another downstream target of the Abl-CrkII signaling module and show that Abl-CrkII collaborates with Rho-ROCK1 to stimulate cell retraction. ..
  28. Wang Z, Dillon T, Pokala V, Mishra S, Labudda K, Hunter B, et al. Rap1-mediated activation of extracellular signal-regulated kinases by cyclic AMP is dependent on the mode of Rap1 activation. Mol Cell Biol. 2006;26:2130-45 pubmed
    ..We propose a model that specific GEFs activate distinct pools of Rap1 that are differentially coupled to downstream effectors. ..
  29. Martín Encabo S, Santos E, Guerrero C. C3G mediated suppression of malignant transformation involves activation of PP2A phosphatases at the subcortical actin cytoskeleton. Exp Cell Res. 2007;313:3881-91 pubmed
    ..We hypothesize that C3G triggers PP2A activation and binding to MEK and ERK at the subcortical actin cytoskeleton, thus favouring ERK dephosphorylation. ..
  30. Tamada M, Sheetz M, Sawada Y. Activation of a signaling cascade by cytoskeleton stretch. Dev Cell. 2004;7:709-18 pubmed
    ..We suggest that mechanical force on Triton cytoskeletons activates local tyrosine phosphorylation, which provides docking sites for cytosolic proteins, and initiates signaling to activate Rap1. ..
  31. Arai A, Nosaka Y, Kanda E, Yamamoto K, Miyasaka N, Miura O. Rap1 is activated by erythropoietin or interleukin-3 and is involved in regulation of beta1 integrin-mediated hematopoietic cell adhesion. J Biol Chem. 2001;276:10453-62 pubmed
  32. Riese M, Wittinghofer A, Barbieri J. ADP ribosylation of Arg41 of Rap by ExoS inhibits the ability of Rap to interact with its guanine nucleotide exchange factor, C3G. Biochemistry. 2001;40:3289-94 pubmed
    ..This identifies a second member of the Ras GTPase subfamily that can be ADP ribosylated by ExoS and indicates that ExoS can inhibit both Ras and Rap signaling pathways in eukaryotic cells. ..
  33. Liu Y, Hiraiwa Y, Liu E, Kurata H, Thant A, Matsuda S, et al. Suppression of cell spreading by v-Crk requires Ras-MEK-MAP kinase signaling. Oncogene. 2001;20:5908-12 pubmed
    ..Taken together, our results suggest that, among multiple signaling pathways activated by v-Crk, the Ras-MEK1-MAP kinase cascade plays a pivotal role in the suppression of cell spreading on fibronectin, but C3G and the PI3 kinase do not. ..
  34. Wang S, 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 pubmed publisher
    ..The results suggested that deregulated constitutive Rap1 activation caused abnormal expansion of DP thymocytes, bypassing the pre-T-cell receptor and eventually leading to Notch1 mutations and Notch-dependent T-ALL. ..
  35. Hisata S, Sakisaka T, Baba T, Yamada T, Aoki K, Matsuda M, et al. Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth. J Cell Biol. 2007;178:843-60 pubmed
    ..Thus, the interaction of PDZ-GEF1 with an internalized neurotrophin receptor transported to late endosomes induces sustained activation of both Rap1 and ERK and neurite outgrowth. ..
  36. Voss A, Krebs D, Thomas T. C3G regulates the size of the cerebral cortex neural precursor population. EMBO J. 2006;25:3652-63 pubmed
    ..Our results show that the size of the cortical neural precursor population is controlled by C3G-mediated inhibition of the Ras signalling pathway. ..
  37. Li S, Tian X, Hartley D, Feig L. Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. J Neurosci. 2006;26:1721-9 pubmed
  38. Ballif B, Arnaud L, Arthur W, Guris D, Imamoto A, Cooper J. Activation of a Dab1/CrkL/C3G/Rap1 pathway in Reelin-stimulated neurons. Curr Biol. 2004;14:606-10 pubmed
    ..C3G and Rap1 regulate adhesion of fibroblasts and other cell types. Regulation of Crk/CrkL, C3G, and Rap1 by Reelin may be involved in coordinating neuron migrations during brain development. ..
  39. 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 pubmed
    ..These results indicate that inactivation of C3G by de novo methylation plays an important role in the development of cervical squamous cell carcinoma. ..
  40. Lents N, Irintcheva V, Goel R, Wheeler L, Baldassare J. The rapid activation of N-Ras by alpha-thrombin in fibroblasts is mediated by the specific G-protein Galphai2-Gbeta1-Ggamma5 and occurs in lipid rafts. Cell Signal. 2009;21:1007-14 pubmed publisher
    ..We thus report the molecular elucidation of an extremely specific and rapid signal transduction pathway linking alpha-thrombin stimulation to the activation of Ras. ..
  41. Schönherr C, Yang H, Vigny M, Palmer R, 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 pubmed publisher
    ..These results suggest that ALK activation of Rap1 may contribute to cell proliferation and oncogenesis of neuroblastoma driven by gain-of-function mutant ALK receptors. ..
  42. Mor A, Wynne J, Ahearn I, Dustin M, Du G, Philips M. Phospholipase D1 regulates lymphocyte adhesion via upregulation of Rap1 at the plasma membrane. Mol Cell Biol. 2009;29:3297-306 pubmed publisher
    ..Our data support a model whereby PLD1 regulates Rap1 activity by controlling exocytosis of a stored, vesicular pool of Rap1 that can be activated by C3G upon delivery to the plasma membrane. ..
  43. Gutierrez Uzquiza A, Arechederra M, Molina I, Baños R, Maia V, Benito M, et al. C3G down-regulates p38 MAPK activity in response to stress by Rap-1 independent mechanisms: involvement in cell death. Cell Signal. 2010;22:533-42 pubmed publisher
  44. Uemura N, Griffin J. The adapter protein Crkl links Cbl to C3G after integrin ligation and enhances cell migration. J Biol Chem. 1999;274:37525-32 pubmed
    ..These data suggest that Crkl is involved in signaling pathways that regulate migration, possibly through a complex with Cbl and C3G. ..
  45. Hogan C, Serpente N, Cogram P, Hosking C, Bialucha C, Feller S, et al. Rap1 regulates the formation of E-cadherin-based cell-cell contacts. Mol Cell Biol. 2004;24:6690-700 pubmed
    ..Furthermore, our data suggest that Cdc42 functions downstream of Rap1 in this process. We conclude that Rap1 plays a vital role in the establishment of E-cadherin-based cell-cell adhesion. ..
  46. Maia V, Sanz M, Gutierrez Berzal J, de Luis A, Gutierrez Uzquiza A, Porras A, et al. C3G silencing enhances STI-571-induced apoptosis in CML cells through p38 MAPK activation, but it antagonizes STI-571 inhibitory effect on survival. Cell Signal. 2009;21:1229-35 pubmed publisher
    ..Therefore, our results strongly suggest a dual regulatory role for C3G in CML cells, modulating both apoptosis and survival via Rap-dependent and independent mechanisms. ..
  47. Chiang S, Baumann C, Kanzaki M, Thurmond D, Watson R, Neudauer C, et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature. 2001;410:944-8 pubmed
    ..The activation of TC10 is essential for insulin-stimulated glucose uptake and GLUT4 translocation. The TC10 pathway functions in parallel with PI(3)K to stimulate fully GLUT4 translocation in response to insulin. ..
  48. Jeffress J, Page S, Royer S, Belden E, Blumenstiel J, Anderson L, et al. The formation of the central element of the synaptonemal complex may occur by multiple mechanisms: the roles of the N- and C-terminal domains of the Drosophila C(3)G protein in mediating synapsis and recombination. Genetics. 2007;177:2445-56 pubmed