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Gene Review

RAP1A  -  RAP1A, member of RAS oncogene family

Homo sapiens

Synonyms: C21KG, G-22K, GTP-binding protein smg p21A, KREV-1, KREV1, ...
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Disease relevance of RAP1A


Psychiatry related information on RAP1A

  • We have recently reported altered levels of protein kinase A and Rap1 in patients with bipolar disorder [5].
  • The cAMP-dependent protein kinase substrate Rap1 in platelets from patients with obsessive compulsive disorder or schizophrenia [6].
  • Previous studies have reported that the cAMP-dependent protein kinase and one of its substrates, namely Rap1, are altered in patients with affective disorders [6].

High impact information on RAP1A


Chemical compound and disease context of RAP1A


Biological context of RAP1A

  • Moreover, incubation of similar extracts with the catalytic subunit of cAMP-dependent protein kinase did not cause phosphorylation of RAP2B, as had been observed for the closely homologous proteins, RAP1A and RAP1B [15].
  • Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis [16].
  • The accelerated cell migration was suppressed by the expression of active Rap1, Rap2 and R-Ras [16].
  • LC2 is therefore a biological enhancer of EPAC1 activity toward Rap1 and associated downstream signaling mechanisms [17].
  • These findings show that activation of MAP kinase by cAMP requires a SRC family kinase that lies downstream of protein kinase A. A role for RAP1, as documented for the beta(2)-adrenergic receptor, is apparently contingent on receptor endocytosis [18].

Anatomical context of RAP1A

  • To carry on our study, we raised stable myogenic cell lines overexpressing wild-type or mutated forms of RAP1A [19].
  • Myoblasts overexpressing the GTP-bound mutant did not display specific changes of RAP1A and of late endocytic compartments locations [19].
  • In conclusion, C3G-dependent activation of Rap1 is required for adhesion and spreading of embryonic fibroblasts and for the early embryogenesis of the mouse [16].
  • Nitric Oxide Produced in Response to Engagement of beta2 Integrins on Human Neutrophils Activates the Monomeric GTPases Rap1 and Rap2 and Promotes Adhesion [20].
  • Thus, Epac2 can respond to costimulation by agonists that jointly elevate Ras-GTP and cyclic AMP levels, activating a specific pool of Rap1 at the plasma membrane [21].

Associations of RAP1A with chemical compounds

  • Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway [22].
  • Furthermore, prostacyclin and forskolin induced cortical actin rearrangement in a Rap1-dependent manner [22].
  • Together, these results suggest that JAM1 regulates epithelial cell morphology and beta1 integrin expression by modulating activity of the small GTPase Rap1 [23].
  • Also, the activation of Rap1 was blocked by PP1, SU6656, LY294002, GF109203X, or BAPTA-AM, which indicates that the downstream signaling events in Rap1 activation involve Src tyrosine kinases, phosphoinositide 3-kinase, protein kinase C, and release of calcium [20].
  • Characterization of GFR, a novel guanine nucleotide exchange factor for Rap1 [24].

Physical interactions of RAP1A

  • Krit1 interacted strongly with Krev-1 but only weakly with Ras, suggesting it might specifically regulate Krev-1 activities [25].
  • We found that engagement of beta2 integrins on human neutrophils increased the levels of GTP-bound Rap1 and Rap2 [20].
  • Stimulation of the G(i)-coupled m2-muscarinic receptor translocates rap1GAPII from the cytosol to the membrane and decreases the amount of GTP-bound Rap1 [26].
  • The inactivation of Rap1 was associated with an insulin-stimulated decrease in the amount of Rap1 that was bound to Raf1 [27].
  • We have developed a novel assay to monitor the active, GTP-bound form of Rap1 based on the differential affinity of Rap1GTP and Rap1GDP for the Rap binding domain of RalGDS (RBD) [28].

Regulatory relationships of RAP1A


Other interactions of RAP1A

  • A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK [30].
  • Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene [31].
  • Activation of Rap1 resulted in a decrease in permeability and enhancement of VE-cadherin-dependent cell adhesion, whereas inactivation of Rap1 had the counter effect [22].
  • However, overexpression of a RAP1 GTPase-activating protein (RAP1GAP), which efficiently clamped cellular RAP1 in the inactive GDP-bound form, did not affect A(2A)-agonist-mediated MAP kinase stimulation [18].
  • In CHO-A(2A) cells, the stimulation of the A(2A)-receptor resulted in an activation of RAP1 and formation of RAP1-B-RAF complexes [18].

Analytical, diagnostic and therapeutic context of RAP1A


  1. Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes. Fujita, H., Fukuhara, S., Sakurai, A., Yamagishi, A., Kamioka, Y., Nakaoka, Y., Masuda, M., Mochizuki, N. J. Biol. Chem. (2005) [Pubmed]
  2. Cannabinoid receptor-induced neurite outgrowth is mediated by Rap1 activation through G(alpha)o/i-triggered proteasomal degradation of Rap1GAPII. Jordan, J.D., He, J.C., Eungdamrong, N.J., Gomes, I., Ali, W., Nguyen, T., Bivona, T.G., Philips, M.R., Devi, L.A., Iyengar, R. J. Biol. Chem. (2005) [Pubmed]
  3. Rap1A and rap1B ras-family proteins are prominently expressed in the nucleus of squamous carcinomas: nuclear translocation of GTP-bound active form. Mitra, R.S., Zhang, Z., Henson, B.S., Kurnit, D.M., Carey, T.E., D'Silva, N.J. Oncogene (2003) [Pubmed]
  4. Mutation in RAP1 is a rare event in myelodysplastic syndromes. Gyan, E., Frew, M., Bowen, D., Beldjord, C., Preudhomme, C., Lacombe, C., Mayeux, P., Dreyfus, F., Porteu, F., Fontenay, M. Leukemia (2005) [Pubmed]
  5. Protein kinase A and Rap1 levels in platelets of untreated patients with major depression. Perez, J., Tardito, D., Racagni, G., Smeraldi, E., Zanardi, R. Mol. Psychiatry (2001) [Pubmed]
  6. The cAMP-dependent protein kinase substrate Rap1 in platelets from patients with obsessive compulsive disorder or schizophrenia. Tardito, D., Maina, G., Tura, G.B., Bogetto, F., Pioli, R., Ravizza, L., Racagni, G., Perez, J. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2001) [Pubmed]
  7. Force Sensing by Mechanical Extension of the Src Family Kinase Substrate p130Cas. Sawada, Y., Tamada, M., Dubin-Thaler, B.J., Cherniavskaya, O., Sakai, R., Tanaka, S., Sheetz, M.P. Cell (2006) [Pubmed]
  8. Meiotic proteins bqt1 and bqt2 tether telomeres to form the bouquet arrangement of chromosomes. Chikashige, Y., Tsutsumi, C., Yamane, M., Okamasa, K., Haraguchi, T., Hiraoka, Y. Cell (2006) [Pubmed]
  9. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Laberge-le Couteulx, S., Jung, H.H., Labauge, P., Houtteville, J.P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.F., Tournier-Lasserve, E. Nat. Genet. (1999) [Pubmed]
  10. Molecular cloning of a GTPase activating protein specific for the Krev-1 protein p21rap1. Rubinfeld, B., Munemitsu, S., Clark, R., Conroy, L., Watt, K., Crosier, W.J., McCormick, F., Polakis, P. Cell (1991) [Pubmed]
  11. Ras-associated protein-1 regulates extracellular signal-regulated kinase activation and migration in melanoma cells: two processes important to melanoma tumorigenesis and metastasis. Gao, L., Feng, Y., Bowers, R., Becker-Hapak, M., Gardner, J., Council, L., Linette, G., Zhao, H., Cornelius, L.A. Cancer Res. (2006) [Pubmed]
  12. Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression. Lau, N., Uhlmann, E.J., Von Lintig, F.C., Nagy, A., Boss, G.R., Gutmann, D.H., Guha, A. Int. J. Oncol. (2003) [Pubmed]
  13. Expression of human Krev-1 gene in lungs of transgenic mice and subsequent reduction in multiplicity of ethyl carbamate-induced lung adenomas. Damak, S., Harnboonsong, Y., George, P.M., Bullock, D.W. Mol. Carcinog. (1996) [Pubmed]
  14. Partial growth suppression of human prostate cancer cells by the Krev-1 suppressor gene. Burney, T.L., Rockove, S., Eiseman, J.L., Jacobs, S.C., Kyprianou, N. Prostate (1994) [Pubmed]
  15. RAP2B: a RAS-related GTP-binding protein from platelets. Ohmstede, C.A., Farrell, F.X., Reep, B.R., Clemetson, K.J., Lapetina, E.G. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  16. 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, B.J., Maki, K., Miyazaki , J., Matsuda, M. EMBO J. (2001) [Pubmed]
  17. MAP1A light chain 2 interacts with exchange protein activated by cyclic AMP 1 (EPAC1) to enhance Rap1 GTPase activity and cell adhesion. Gupta, M., Yarwood, S.J. J. Biol. Chem. (2005) [Pubmed]
  18. MAP kinase stimulation by cAMP does not require RAP1 but SRC family kinases. Klinger, M., Kudlacek, O., Seidel, M.G., Freissmuth, M., Sexl, V. J. Biol. Chem. (2002) [Pubmed]
  19. RAP1A GTP/GDP cycles determine the intracellular location of the late endocytic compartments and contribute to myogenic differentiation. Pizon, V., Méchali, F., Baldacci, G. Exp. Cell Res. (1999) [Pubmed]
  20. Nitric Oxide Produced in Response to Engagement of beta2 Integrins on Human Neutrophils Activates the Monomeric GTPases Rap1 and Rap2 and Promotes Adhesion. Jenei, V., Deevi, R.K., Adams, C.A., Axelsson, L., Hirst, D.G., Andersson, T., Dib, K. J. Biol. Chem. (2006) [Pubmed]
  21. The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. Li, Y., Asuri, S., Rebhun, J.F., Castro, A.F., Paranavitana, N.C., Quilliam, L.A. J. Biol. Chem. (2006) [Pubmed]
  22. Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Fukuhara, S., Sakurai, A., Sano, H., Yamagishi, A., Somekawa, S., Takakura, N., Saito, Y., Kangawa, K., Mochizuki, N. Mol. Cell. Biol. (2005) [Pubmed]
  23. Junctional adhesion molecule 1 regulates epithelial cell morphology through effects on beta1 integrins and Rap1 activity. Mandell, K.J., Babbin, B.A., Nusrat, A., Parkos, C.A. J. Biol. Chem. (2005) [Pubmed]
  24. Characterization of GFR, a novel guanine nucleotide exchange factor for Rap1. Ichiba, T., Hoshi, Y., Eto, Y., Tajima, N., Kuraishi, Y. FEBS Lett. (1999) [Pubmed]
  25. Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22. Serebriiskii, I., Estojak, J., Sonoda, G., Testa, J.R., Golemis, E.A. Oncogene (1997) [Pubmed]
  26. Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i). Mochizuki, N., Ohba, Y., Kiyokawa, E., Kurata, T., Murakami, T., Ozaki, T., Kitabatake, A., Nagashima, K., Matsuda, M. Nature (1999) [Pubmed]
  27. Insulin regulates the dynamic balance between Ras and Rap1 signaling by coordinating the assembly states of the Grb2-SOS and CrkII-C3G complexes. Okada, S., Matsuda, M., Anafi, M., Pawson, T., Pessin, J.E. EMBO J. (1998) [Pubmed]
  28. Rapid Ca2+-mediated activation of Rap1 in human platelets. Franke, B., Akkerman, J.W., Bos, J.L. EMBO J. (1997) [Pubmed]
  29. Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Murphy, M.M., Zayed, M.A., Evans, A., Parker, C.E., Ataga, K.I., Telen, M.J., Parise, L.V. Blood (2005) [Pubmed]
  30. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Enserink, J.M., Christensen, A.E., de Rooij, J., van Triest, M., Schwede, F., Genieser, H.G., Døskeland, S.O., Blank, J.L., Bos, J.L. Nat. Cell Biol. (2002) [Pubmed]
  31. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Sahoo, T., Johnson, E.W., Thomas, J.W., Kuehl, P.M., Jones, T.L., Dokken, C.G., Touchman, J.W., Gallione, C.J., Lee-Lin, S.Q., Kosofsky, B., Kurth, J.H., Louis, D.N., Mettler, G., Morrison, L., Gil-Nagel, A., Rich, S.S., Zabramski, J.M., Boguski, M.S., Green, E.D., Marchuk, D.A. Hum. Mol. Genet. (1999) [Pubmed]
  32. Mapping of the KREV1 transformation suppressor gene and its pseudogene (KREV1P) to human chromosome 1p13.3 and 14q24.3, respectively, by fluorescence in situ hybridization. Takai, S., Nishino, N., Kitayama, H., Ikawa, Y., Noda, M. Cytogenet. Cell Genet. (1993) [Pubmed]
  33. Rap1 regulates the formation of E-cadherin-based cell-cell contacts. Hogan, C., Serpente, N., Cogram, P., Hosking, C.R., Bialucha, C.U., Feller, S.M., Braga, V.M., Birchmeier, W., Fujita, Y. Mol. Cell. Biol. (2004) [Pubmed]
  34. Insulin and epidermal growth factor stimulate a conformational change in Rap1 and dissociation of the CrkII-C3G complex. Okada, S., Pessin, J.E. J. Biol. Chem. (1997) [Pubmed]
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