6qdt

Structural highlights

Disease

[RPGF2_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.

Function

[1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression. [RPGF2_HUMAN] Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Acts also as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP (PubMed:23800469, PubMed:10801446) or not (PubMed:10608844, PubMed:10548487, PubMed:11359771). Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s)-alpha signaling pathway. Involved in the cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Provides also inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor (NGF)-induced sustained activation of Rap1 at late endosomes and in brain-derived neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]}

References

1. ↑ Ohtsuka T, Hata Y, Ide N, Yasuda T, Inoue E, Inoue T, Mizoguchi A, Takai Y. nRap GEP: a novel neural GDP/GTP exchange protein for rap1 small G protein that interacts with synaptic scaffolding molecule (S-SCAM). Biochem Biophys Res Commun. 1999 Nov;265(1):38-44. PMID:10548487 doi:http://dx.doi.org/10.1006/bbrc.1999.1619
2. ↑ Liao Y, Kariya K, Hu CD, Shibatohge M, Goshima M, Okada T, Watari Y, Gao X, Jin TG, Yamawaki-Kataoka Y, Kataoka T. RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a Ras/Rap1A-associating domain, is conserved between nematode and humans. J Biol Chem. 1999 Dec 31;274(53):37815-20. doi: 10.1074/jbc.274.53.37815. PMID:10608844 doi:http://dx.doi.org/10.1074/jbc.274.53.37815
3. ↑ de Rooij J, Boenink NM, van Triest M, Cool RH, Wittinghofer A, Bos JL. PDZ-GEF1, a guanine nucleotide exchange factor specific for Rap1 and Rap2. J Biol Chem. 1999 Dec 31;274(53):38125-30. doi: 10.1074/jbc.274.53.38125. PMID:10608883 doi:http://dx.doi.org/10.1074/jbc.274.53.38125
4. ↑ Pham N, Cheglakov I, Koch CA, de Hoog CL, Moran MF, Rotin D. The guanine nucleotide exchange factor CNrasGEF activates ras in response to cAMP and cGMP. Curr Biol. 2000 May 4;10(9):555-8. doi: 10.1016/s0960-9822(00)00473-5. PMID:10801446 doi:http://dx.doi.org/10.1016/s0960-9822(00)00473-5
5. ↑ Rebhun JF, Castro AF, Quilliam LA. Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction. J Biol Chem. 2000 Nov 10;275(45):34901-8. PMID:10934204 doi:http://dx.doi.org/10.1074/jbc.M005327200
6. ↑ Liao Y, Satoh T, Gao X, Jin TG, Hu CD, Kataoka T. RA-GEF-1, a guanine nucleotide exchange factor for Rap1, is activated by translocation induced by association with Rap1*GTP and enhances Rap1-dependent B-Raf activation. J Biol Chem. 2001 Jul 27;276(30):28478-83. doi: 10.1074/jbc.M101737200. Epub 2001, May 18. PMID:11359771 doi:http://dx.doi.org/10.1074/jbc.M101737200
7. ↑ Pak Y, Pham N, Rotin D. Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Mol Cell Biol. 2002 Nov;22(22):7942-52. PMID:12391161
8. ↑ Amsen EM, Pham N, Pak Y, Rotin D. The guanine nucleotide exchange factor CNrasGEF regulates melanogenesis and cell survival in melanoma cells. J Biol Chem. 2006 Jan 6;281(1):121-8. doi: 10.1074/jbc.M507595200. Epub 2005 Nov , 4. PMID:16272156 doi:http://dx.doi.org/10.1074/jbc.M507595200
9. ↑ Hisata S, Sakisaka T, Baba T, Yamada T, Aoki K, Matsuda M, Takai Y. 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 Aug 27;178(5):843-60. doi: 10.1083/jcb.200610073. PMID:17724123 doi:http://dx.doi.org/10.1083/jcb.200610073
10. ↑ Pannekoek WJ, van Dijk JJ, Chan OY, Huveneers S, Linnemann JR, Spanjaard E, Brouwer PM, van der Meer AJ, Zwartkruis FJ, Rehmann H, de Rooij J, Bos JL. Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control. Cell Signal. 2011 Dec;23(12):2056-64. doi: 10.1016/j.cellsig.2011.07.022. Epub, 2011 Aug 4. PMID:21840392 doi:http://dx.doi.org/10.1016/j.cellsig.2011.07.022
11. ↑ Emery AC, Eiden MV, Mustafa T, Eiden LE. Rapgef2 connects GPCR-mediated cAMP signals to ERK activation in neuronal and endocrine cells. Sci Signal. 2013 Jun 25;6(281):ra51. doi: 10.1126/scisignal.2003993. PMID:23800469 doi:http://dx.doi.org/10.1126/scisignal.2003993