Disease relevance of RAPGEF1

• The C3G protein expressed in Escherichia coli binds to CRK and GRB2/ASH proteins [1].
• We document here the amplification of C3G in five of 18 primary non-small cell lung cancers examined and its increased expression in 18 of 28 tumors in comparison to corresponding non-cancerous lung tissues [2].
• These results indicate that inactivation of C3G by de novo methylation plays an important role in the development of cervical squamous cell carcinoma [3] .
• Characterization of p87C3G, a novel, truncated C3G isoform that is overexpressed in chronic myeloid leukemia and interacts with Bcr-Abl [4].

High impact information on RAPGEF1

• The adapter protein CrkL was associated with both phosphorylated Cbl and the guanidine nucleotide-releasing factor C3G, which catalyzes guanosine triphosphate (GTP) exchange on Rap1 [5].
• C3G-deficient neuroepithelial cells accumulate nuclear beta-catenin and fail to exit the cell cycle in vivo [6].
• C3G regulates the size of the cerebral cortex neural precursor population [6].
• The Cre-expressing MEF-hC3G showed impaired cell adhesion, delayed cell spreading and accelerated cell migration [7].
• From the embryo of this mouse, we prepared fibroblast cell lines, MEF-hC3G [7].

Chemical compound and disease context of RAPGEF1

• Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers [2].
• A significant attenuation of hind paw inflammation characterized by fluid accumulation, uric acid production, and rheumatoid factors induced by carrageenan was observed following the intake of both ME (50 mg/kg of body weight) and C3G (10 mg/kg of body weight) [8].

Biological context of RAPGEF1

• Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis [7].
• 5. The lethality was rescued by the expression of the human C3G transgene, which could be excised upon the expression of Cre recombinase [7].
• The nucleotide sequence of a 4.1-kb C3G cDNA contains a 3.2-kb open reading frame encoding a 121-kDa protein, and antibodies against C3G have been shown to detect a protein of 130-140 kDa [1].
• T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G [9].
• While Sos binds to both Grb2 Src homology-3 (SH3) domains, Vav was found to associate selectively with the carboxyl-terminal SH3 domain, while C3G bound selectively to the amino-terminal SH3 domain of bacterially expressed Grb2 [10].

Anatomical context of RAPGEF1

• The mRNAs of both the C3G and CRK proteins are expressed ubiquitously in human adult and fetal tissues [1].
• Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G [11].
• Sos, Vav, and C3G participate in B cell receptor-induced signaling pathways and differentially associate with Shc-Grb2, Crk, and Crk-L adaptors [10].
• Similarly to previously identified Rap GEFs, C3G and Smg GDS, each of the newly identified exchange factors promoted the activation of Elk-1 in the LNCaP prostate tumor cell line where B-Raf can couple Rap1 to the extracellular receptor-activated kinase cascade [12].
• A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia [13].

Associations of RAPGEF1 with chemical compounds

• The adapter protein Crkl links Cbl to C3G after integrin ligation and enhances cell migration [14].
• A GRF2 mutant missing the IQ sequence was competent for Ras activation but failed to couple this to stimulation of the ERK pathway [15].
• C3G also stimulated binding of GTP-gamma S [guanosine 5'-3-O-(thio)triphosphate] to Rap1B [16].
• Furthermore, pretreatment of the cells with the tyrosine kinase inhibitor, genistein, decreased both the basal and insulin-stimulated tyrosine phosphorylation of CrkII that directly correlated with the amount of CrkII that was immunoprecipitated with C3G [17].
• A series of analysis with C3G deletion mutants revealed a proline-rich Cas-binding site (Ala0-Pro1-Pro2-Lys3-Pro4-Pro5-Leu6-Pro7) located NH2-terminal to the previously characterized Crk binding motifs in C3G [18].

Physical interactions of RAPGEF1

• Mutational analysis of C3G assigns the SH3 binding region to a 50-amino acid region containing a proline-rich sequence [1].
• We report here that the cytoplasmic domain of E-cadherin interacts with C3G, a guanine nucleotide exchange factor for Rap1 [19].
• Deletion of the amino terminus of C3G to amino acid 579 significantly reduced the Crk-dependent tyrosine phosphorylation of C3G and increased GTP-bound Rap1 irrespective of the presence of CrkI [20].

Regulatory relationships of RAPGEF1

• IFN-gamma activates the C3G/Rap1 signaling pathway [21].
• C-3-G treatment also induced increase of cAMP levels and up-regulation of tyrosinase expression and activity resulting in an enhanced melanin synthesis and melanosome maturation [22].

Other interactions of RAPGEF1

• Novel Rap1 dominant-negative mutants interfere selectively with C3G and Epac [23].
• In cellular models where Rap1 is activated via endogenous GEFs, the Rap1[S17A] mutant inhibits both the cAMP-Epac and EGF-C3G pathways, whereas Rap1[G15D] selectively interferes with the latter [23].
• In untransformed cells, three major proteins coprecipitated with CRKL, identified as C3G, SOS and c-ABL [24].
• Evidence is presented that Crk complexes with C3G in control cells, and VEGF treatment leads to the recruitment of the complex to the cell surface [25].
• Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras [26].

Analytical, diagnostic and therapeutic context of RAPGEF1

• Mapping of the human C3G gene coding a guanine nucleotide releasing protein for Ras family to 9q34.3 by fluorescence in situ hybridization [27].
• The association of Rap1-AGE with C3G in the cells was confirmed by co-immunoprecipitation experiments [28].

References