p120 gtpase activating protein


Summary: A 120-kDa RAS GTPase-activating protein that binds to tyrosine phosphoproteins through its SH2 domains. The 100-kDa RNA-splicing variant (p100 GAP protein) is expressed in placenta.

Top Publications

  1. Tomar A, Lim S, Lim Y, Schlaepfer D. A FAK-p120RasGAP-p190RhoGAP complex regulates polarity in migrating cells. J Cell Sci. 2009;122:1852-62 pubmed publisher
  2. Bradley W, Hernandez S, Settleman J, Koleske A. Integrin signaling through Arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane. Mol Biol Cell. 2006;17:4827-36 pubmed
    ..Our results demonstrate that integrin signaling through Arg activates p190 by promoting its association with p120, resulting in recruitment of p190 to the cell periphery where it inhibits Rho. ..
  3. Kim I, Ryu Y, Kwak H, Ahn S, Oh J, Yancopoulos G, et al. EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. FASEB J. 2002;16:1126-8 pubmed
  4. Gavard J, Marthiens V, Monnet C, Lambert M, Mège R. N-cadherin activation substitutes for the cell contact control in cell cycle arrest and myogenic differentiation: involvement of p120 and beta-catenin. J Biol Chem. 2004;279:36795-802 pubmed
    ..Our results demonstrate that N-cadherin adhesion may account for cell-cell contact-dependent cell cycle arrest and differentiation of myogenic cells, involving regulation through p120 and beta-catenins. ..
  5. Kulkarni S, Gish G, van der Geer P, Henkemeyer M, Pawson T. Role of p120 Ras-GAP in directed cell movement. J Cell Biol. 2000;149:457-70 pubmed
    ..This observation suggests a specific function for Ras-GAP separate from Ras regulation in cell motility. ..
  6. Pamonsinlapatham P, Hadj Slimane R, Lepelletier Y, Allain B, Toccafondi M, Garbay C, et al. p120-Ras GTPase activating protein (RasGAP): a multi-interacting protein in downstream signaling. Biochimie. 2009;91:320-8 pubmed publisher
    ..Here, we summarize, in angiogenesis and cancer, the various functional roles played by p120-RasGAP domains and their effector partners in downstream signaling. ..
  7. Anand S, Majeti B, Acevedo L, Murphy E, Mukthavaram R, Scheppke L, et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med. 2010;16:909-14 pubmed publisher
  8. Lu Y, Yang H, Yuan L, Liu G, Zhang C, Hong M, et al. Overexpression of miR-335 confers cell proliferation and tumour growth to colorectal carcinoma cells. Mol Cell Biochem. 2016;412:235-45 pubmed publisher
    ..Together, miR-335-RASA1 contributes to cell growth in CRC, and elucidation of downstream pathway will provide new insights into the molecular mechanisms of CRC progression. ..
  9. Burrows P, Gonzalez Garay M, Rasmussen J, Aldrich M, Guilliod R, Maus E, et al. Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci U S A. 2013;110:8621-6 pubmed publisher

More Information


  1. Brunton V, MacPherson I, Frame M. Cell adhesion receptors, tyrosine kinases and actin modulators: a complex three-way circuitry. Biochim Biophys Acta. 2004;1692:121-44 pubmed
    ..Deregulation of many aspects of these signalling pathways in cancer highlights the need for a better understanding of the complexities involved. ..
  2. Ahmadian M, Kiel C, Stege P, Scheffzek K. Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP. J Mol Biol. 2003;329:699-710 pubmed
    ..The alpha7/variable loop uses several conserved residues including two lysine residues, which are involved in numerous interactions with the switch I region of Ras. This region determines the specificity of the Ras-RasGAP interaction. ..
  3. Woodcock S, Hughes D. p120 Ras GTPase-activating protein associates with fibroblast growth factor receptors in Drosophila. Biochem J. 2004;380:767-74 pubmed
    ..On the basis of these results, we propose that RasGAP is directly recruited into activated FGFRs in Drosophila and plays a role in regulating the strength of signalling through Ras and the mitogen-activated protein kinase pathway. ..
  4. Wang D, Li Z, Messing E, Wu G. The SPRY domain-containing SOCS box protein 1 (SSB-1) interacts with MET and enhances the hepatocyte growth factor-induced Erk-Elk-1-serum response element pathway. J Biol Chem. 2005;280:16393-401 pubmed
  5. de Wijn R, Oduber C, Breugem C, Alders M, Hennekam R, van der Horst C. Phenotypic variability in a family with capillary malformations caused by a mutation in the RASA1 gene. Eur J Med Genet. 2012;55:191-5 pubmed publisher
    ..The cause of this wide intramutational phenotypic variability remains to be elucidated. ..
  6. Sanchez Margalet V, Najib S. Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling. Mol Cell Endocrinol. 2001;183:113-21 pubmed
    ..e. p120GAP. In this way, these signaling complexes may modulate other signaling cascades of IR, such as p21Ras pathway. ..
  7. Koehler J, Moran M. Regulation of extracellular signal-regulated kinase activity by p120 RasGAP does not involve its pleckstrin homology or calcium-dependent lipid binding domains but does require these domains to regulate cell proliferation. Cell Growth Differ. 2001;12:551-61 pubmed
    ..Our results, therefore, suggest that p120GAP functions not only by down-regulating the Ras/MAPK pathway after growth factor stimulation but is also important in regulating cell proliferation that involves its PH and CaLB domains. ..
  8. Puri R, Fan Y, Rattan S. Role of pp60(c-src) and p(44/42) MAPK in ANG II-induced contraction of rat tonic gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol. 2002;283:G390-9 pubmed
    ..We conclude that pp60(c-src) and p(44/42) MAPKs play an important role in ANG II-induced contraction of LES and IAS smooth muscles. ..
  9. Kennedy D, French J, Guitard E, Ru K, Tocque B, Mattick J. Characterization of G3BPs: tissue specific expression, chromosomal localisation and rasGAP(120) binding studies. J Cell Biochem. 2001;84:173-87 pubmed
    ..Furthermore, we have characterized the protein expression of both G3BP-1 and G3BP-2a/b in adult mouse tissues, and show them to be both tissue and isoform specific. ..
  10. Yang X, Guan M, Vigil D, Der C, Lowy D, Popescu N. p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene. 2009;28:1401-9 pubmed publisher
    ..Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610 ..
  11. Chow A, Gawler D. Mapping the site of interaction between annexin VI and the p120GAP C2 domain. FEBS Lett. 1999;460:166-72 pubmed
  12. Vikkula M. [Pathogenesis and genetics of vascular anomalies]. Ann Chir Plast Esthet. 2006;51:282-6 pubmed
    ..This should provide development of new-targeted therapies...
  13. Ger M, Zitkus Z, Valius M. Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity. Cell Signal. 2011;23:1651-8 pubmed publisher
    ..This leads to the complex dissipation, decrease of RasGAP activity and the increase of H-Ras-GTP level in the detached cells. Our findings reveal unexpected feature of adaptor protein Nck1 as the regulator of RasGAP activity. ..
  14. Hecker T, Ding Q, Rege T, Hanks S, Gladson C. Overexpression of FAK promotes Ras activity through the formation of a FAK/p120RasGAP complex in malignant astrocytoma cells. Oncogene. 2004;23:3962-71 pubmed
  15. Buhl T, Shoukier M, Grzmil P, Revencu N, Schön M, Seitz C. Multifocal capillary malformations due to RASA1 mutation misdiagnosed as cutaneous mastocytosis. Arch Dermatol. 2012;148:1334-5 pubmed publisher
  16. Khalil H, Peltzer N, Walicki J, Yang J, Dubuis G, Gardiol N, et al. Caspase-3 protects stressed organs against cell death. Mol Cell Biol. 2012;32:4523-33 pubmed publisher
    ..Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response. ..
  17. Hatzfeld M. The p120 family of cell adhesion molecules. Eur J Cell Biol. 2005;84:205-14 pubmed
    ..Thus, p120 proteins may not only be master regulators of cadherin abundance and activity but play additional roles in regulating cell polarity. This review focuses on the putative roles of p120 proteins in cell polarity. ..
  18. Diao X, Shen E, Wang X, Hu B. Differentially expressed microRNAs and their target genes in the hearts of streptozotocin-induced diabetic mice. Mol Med Rep. 2011;4:633-40 pubmed publisher
    ..These results demonstrate that miRNAs may mediate cardiac hypertrophy and myocardial fibrosis in diabetic cardiomyopathy via their targets, and provide insights into the pathogenesis of diabetic cardiomyopathy. ..
  19. Puttgen K, Lin D. Neurocutaneous vascular syndromes. Childs Nerv Syst. 2010;26:1407-15 pubmed publisher
    ..This paper is meant to update clinicians and researchers about important advances in these rare, important vascular syndromes, to improve care, and lay the foundation for future directions for research...
  20. Grewal T, Evans R, Rentero C, Tebar F, Cubells L, de Diego I, et al. Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. Oncogene. 2005;24:5809-20 pubmed
    ..These findings demonstrate an important role for annexin A6 in regulating plasma membrane localization of p120GAP and hence Ras activity. ..
  21. Adam A, Sharenko A, Pumiglia K, Vincent P. Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers. J Biol Chem. 2010;285:7045-55 pubmed publisher
  22. Carr C, Zimmerman H, Martin C, Vikkula M, Byrd A, Abdul Rahman O. 5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C. Am J Med Genet A. 2011;155A:1640-5 pubmed publisher
    ..3 neurocutaneous syndrome. This finding highlights the need to assess for CM-AVM in patients with neurologic features consistent with MEF2C haploinsufficiency, and vice versa. ..
  23. Frigerio A, Stevenson D, Grimmer J. The genetics of vascular anomalies. Curr Opin Otolaryngol Head Neck Surg. 2012;20:527-32 pubmed publisher
    ..Variable gene expression of infantile hemangioma during proliferation and involution may offer new therapeutic targets for treatment. ..
  24. Mashima R, Hishida Y, Tezuka T, Yamanashi Y. The roles of Dok family adapters in immunoreceptor signaling. Immunol Rev. 2009;232:273-85 pubmed publisher
    ..Here, we review the physiological roles and underlying mechanisms of Dok family proteins. ..
  25. Harrington E, Shannon C, Morin N, Rowlett H, Murphy C, Lu Q. PKCdelta regulates endothelial basal barrier function through modulation of RhoA GTPase activity. Exp Cell Res. 2005;308:407-21 pubmed
    ..Thus, PKCdelta may regulate basal endothelial barrier function by stabilizing microfilaments and focal contacts by regulating RhoA GTPase activity through upstream modulators, p190RhoGAP and p120RasGAP. ..
  26. Dai Y, Walker S, de Vet E, Cook S, Welch H, Lockyer P. Ca2+-dependent monomer and dimer formation switches CAPRI Protein between Ras GTPase-activating protein (GAP) and RapGAP activities. J Biol Chem. 2011;286:19905-16 pubmed publisher
    ..We propose that Ca(2+)-dependent dimerization of CAPRI may serve to coordinate Ras and Rap1 signaling pathways. ..
  27. Mihrshahi R, Barclay A, Brown M. Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J Immunol. 2009;183:4879-86 pubmed publisher
  28. Herbrand U, Ahmadian M. p190-RhoGAP as an integral component of the Tiam1/Rac1-induced downregulation of Rho. Biol Chem. 2006;387:311-7 pubmed
    ..This process is mediated by Rac1, but not by Rac2 or Rac3 isoforms. Our data provide evidence for a biochemical pathway of the reciprocal regulation of two related small GTPases, which are key elements in cell migration. ..
  29. Cottet S, Corthesy Theulaz I, Spertini F, Corthesy B. Microaerophilic conditions permit to mimic in vitro events occurring during in vivo Helicobacter pylori infection and to identify Rho/Ras-associated proteins in cellular signaling. J Biol Chem. 2002;277:33978-86 pubmed
  30. Donovan S, Shannon K, Bollag G. GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta. 2002;1602:23-45 pubmed
  31. Chow A, Davis A, Gawler D. Identification of a novel protein complex containing annexin VI, Fyn, Pyk2, and the p120(GAP) C2 domain. FEBS Lett. 2000;469:88-92 pubmed
    ..Finally, co-immunoprecipitation studies in Rat-1 fibroblasts confirm that Fyn, Pyk2, annexin VI and RasGAP can form a protein complex in mammalian cells. ..
  32. King P, Lubeck B, Lapinski P. Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis. Sci Signal. 2013;6:re1 pubmed publisher
    ..Here, we discuss advances in understanding the role of RasGAPs in the maintenance of tissue integrity. ..
  33. Pixley F, Xiong Y, Yu R, Sahai E, Stanley E, Ye B. BCL6 suppresses RhoA activity to alter macrophage morphology and motility. J Cell Sci. 2005;118:1873-83 pubmed
    ..These results demonstrate that BCL6 suppresses RhoA activity, largely through upregulation of surface CSF1R expression, to modulate cytoskeletal and adhesion structures and increase the motility of macrophages. ..
  34. Zhu Y, Xu B, Xia W. Hsa-mir-182 downregulates RASA1 and suppresses lung squamous cell carcinoma cell proliferation. Clin Lab. 2014;60:155-9 pubmed
    ..Our data provide a possible mechanism for lung cancer cell proliferation in lung squamous cell cancer and may be helpful in discovering a new strategy to reveal lung squamous cell carcinoma progress. ..
  35. Eerola I, Boon L, Mulliken J, Burrows P, Dompmartin A, Watanabe S, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240-9 pubmed
  36. Whitaker S, Leech S, Taylor A, Splitt M, Natarajan S, Rajan N. Multifocal capillary malformations in an older, asymptomatic child with a novel RASA1 mutation. Clin Exp Dermatol. 2016;41:156-8 pubmed publisher
    ..We discuss the recent literature and our approach in the management of such a case. ..
  37. Tsubouchi A, Sakakura J, Yagi R, Mazaki Y, Schaefer E, Yano H, et al. Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration. J Cell Biol. 2002;159:673-83 pubmed
    ..We conclude that Tyr31/118-phosphorylated paxillin serves as a template for the localized suppression of RhoA activity and is necessary for efficient membrane spreading and ruffling in adhesion and migration of NMuMG cells. ..
  38. Rapoport M, Amit M, Aharoni D, Weiss M, Weissgarten J, Bruck N, et al. Constitutive up-regulated activity of MAP kinase is associated with down-regulated early p21Ras pathway in lymphocytes of SLE patients. J Autoimmun. 2002;19:63-70 pubmed
    ..Taken together, our data demonstrate for the first time a disease associated functional defect in p21Ras signalling in lymphocytes of SLE patients. ..
  39. Balanis N, Yoshigi M, Wendt M, Schiemann W, Carlin C. ?3 integrin-EGF receptor cross-talk activates p190RhoGAP in mouse mammary gland epithelial cells. Mol Biol Cell. 2011;22:4288-301 pubmed publisher
    ..Our data also suggest that EGFR expressed at high levels has a role in eliciting cell shape changes associated with epithelial-to-mesenchymal transition. ..
  40. Lapinski P, Kwon S, Lubeck B, Wilkinson J, Srinivasan R, Sevick Muraca E, et al. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest. 2012;122:733-47 pubmed publisher
  41. Hershkovitz D, Bercovich D, Sprecher E, Lapidot M. RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol. 2008;158:1035-40 pubmed publisher
    ..We have demonstrated that the spectrum of clinical manifestations due to mutations in RASA1 is wider than previously thought and also includes typical CMs not associated with AVM/AVF. ..
  42. Chan P, Chen H. p120RasGAP-mediated activation of c-Src is critical for oncogenic Ras to induce tumor invasion. Cancer Res. 2012;72:2405-15 pubmed publisher
    ..Collectively, our findings unveil a relationship between oncogenic Ras, p120RasGAP, and c-Src, suggesting a critical role for c-Src in cancers evoked by oncogenic mutations in Ras genes. ..
  43. Mai A, Veltel S, Pellinen T, Padzik A, Coffey E, Marjomaki V, et al. Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration. J Cell Biol. 2011;194:291-306 pubmed publisher
  44. Chartier N, Lainé M, Ducarouge B, Oddou C, Bonaz B, Albiges Rizo C, et al. Enterocytic differentiation is modulated by lipid rafts-dependent assembly of adherens junctions. Exp Cell Res. 2011;317:1422-36 pubmed publisher
    ..A better understanding of the mechanism involved in the establishment of junctional complex and their role in enterocytic differentiation provides new insights into the regulation of intestinal homeostasis...
  45. Huang J, Chen C, Chuang N. P120-GAP associated with syndecan-2 to function as an active switch signal for Src upon transformation with oncogenic ras. Biochem Biophys Res Commun. 2005;329:855-62 pubmed
    ..japonicus. ..
  46. Buchs A, Chagag P, Weiss M, Kish E, Levinson R, Aharoni D, et al. Normal p21Ras/MAP kinase pathway expression and function in PBMC from patients with polycystic ovary disease. Int J Mol Med. 2004;13:595-9 pubmed
    ..These data indicate that the expression and overall function of the p21Ras/MAP kinase pathway remain intact in non-diabetic patients with PCOD. ..
  47. Kraemer A, Brinkmann T, Plettner I, Goody R, Wittinghofer A. Fluorescently labelled guanine nucleotide binding proteins to analyse elementary steps of GAP-catalysed reactions. J Mol Biol. 2002;324:763-74 pubmed
    ..Our data reveal marked differences in GAP/target interactions even between closely related systems and suggest that the fluorescent reporter group method might be generally applicable to many other GNBPs and their cognate GAPs. ..
  48. Giglione C, Gonfloni S, Parmeggiani A. Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. Eur J Biochem. 2001;268:3275-83 pubmed
    ..Our results suggest that phosphorylation by p60c-Src and Lck is a selective process that can modulate the activity of p120-GAP and CDC25Mm towards Ras proteins. ..
  49. Minami M, Koyama T, Wakayama Y, Fukuhara S, Mochizuki N. EphrinA/EphA signal facilitates insulin-like growth factor-I-induced myogenic differentiation through suppression of the Ras/extracellular signal-regulated kinase 1/2 cascade in myoblast cell lines. Mol Biol Cell. 2011;22:3508-19 pubmed publisher
    ..Collectively, these findings demonstrate that the ephrinA/EphA signal facilitates IGF-I-induced myogenesis by suppressing the Ras-ERK1/2 cascade through p120RasGAP in myoblast cell lines. ..
  50. Ross B, Kristensen O, Favre D, Walicki J, Kastrup J, Widmann C, et al. High resolution crystal structures of the p120 RasGAP SH3 domain. Biochem Biophys Res Commun. 2007;353:463-8 pubmed
    ..The RasGAP SH3 domain forms dimers in the crystal structures, which may provide new functional insight. The dimer interface involves residues also present in a peptide previously identified as an apoptotic sensitizer of tumor cells. ..
  51. Revencu N, Boon L, Mendola A, Cordisco M, Dubois J, Clapuyt P, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34:1632-41 pubmed publisher
    ..The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up. ..
  52. Grillner P, Söderman M, Holmin S, Rodesch G. A spectrum of intracranial vascular high-flow arteriovenous shunts in RASA1 mutations. Childs Nerv Syst. 2016;32:709-15 pubmed publisher
  53. Lapinski P, Lubeck B, Chen D, Doosti A, Zawieja S, Davis M, et al. RASA1 regulates the function of lymphatic vessel valves in mice. J Clin Invest. 2017;127:2569-2585 pubmed publisher
    ..Thus, RASA1 catalytic activity is essential for the function and development of LV valves. These data provide a partial explanation for LV leakage defects and potentially other LV abnormalities observed in CM-AVM. ..