Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_534


Historical Background

The small, membrane-tethered G-protein Ras plays an important role in many cellular processes, including growth, differentiation, and survival (Wennerberg et al. 2005). Ras acts as a molecular switch and is bound to GDP in its inactive state, and GTP in its active state. When Ras is active, it can directly associate with the serine/threonine kinase Raf, which can be activated by phosphorylation upon recruitment to the membrane. Raf can then activate the dual-specificity protein kinase MEK1/2, which in turn activates the mitogen-activated protein kinase (MAPK) ERK1/2. Since Ras controls multiple cellular outcomes, its activity is tightly regulated. Inactive, GDP-bound Ras can be activated by interaction with guanine-nucleotide exchange factors (GEFs), which eject GDP from the nucleotide binding site of Ras and allow GTP to bind, which is present at a much higher molar concentration than GDP in the cytoplasm. Examples of Ras...

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  1. Bernards A. GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta. 2003;1603(2):47–82.PubMedPubMedCentralGoogle Scholar
  2. Boon LM, Mulliken JB, et al. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15(3):265–9.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Burrows PE, Gonzalez-Garay ML, et al. Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci USA. 2013;110(21):8621–6.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Ekman S, Thuresson ER, et al. Increased mitogenicity of an alphabeta heterodimeric PDGF receptor complex correlates with lack of RasGAP binding. Oncogene. 1999;18(15):2481–8.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Friedman E, Gejman PV, et al. Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours. Nat Genet. 1993;5(3):242–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Gideon P, John J, et al. Mutational and kinetic analyses of the GTPase-activating protein (GAP)-p21 interaction: the C-terminal domain of GAP is not sufficient for full activity. Mol Cell Biol. 1992;12(5):2050–6.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Giglione C, Gonfloni S, et al. 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(11):3275–83.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Henkemeyer M, Rossi DJ, et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature. 1995;377(6551):695–701.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Iwashita S, Song SY. RasGAPs: a crucial regulator of extracellular stimuli for homeostasis of cellular functions. Mol BioSyst. 2008;4(3):213–22.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Khalil H, Loukili N, et al. The caspase-3-p120-RasGAP module generates a NF-kappaB repressor in response to cellular stress. J Cell Sci. 2015;128(18):3502–13.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Kulkarni SV, Gish G, et al. Role of p120 Ras-GAP in directed cell movement. J Cell Biol. 2000;149(2):457–70.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Lapinski PE, Qiao Y, et al. A role for p120 RasGAP in thymocyte positive selection and survival of naive T cells. J Immunol. 2011;187(1):151–63.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Lapinski PE, Kwon S, et al. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest. 2012;122(2):733–47.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Lubeck BA, Lapinski PE, et al. Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation. Am J Pathol. 2014;184(12):3163–9.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Lubeck BA, Lapinski PE, et al. Cutting edge: codeletion of the Ras GTPase-activating proteins (RasGAPs) neurofibromin 1 and p120 RasGAP in T cells results in the development of T cell acute lymphoblastic leukemia. J Immunol. 2015;195(1):31–5.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Macmurdo CF, Wooderchak-Donahue W, et al. RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet A. 2016;170(6):1450–4.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Margolis B, Li N, et al. The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma. EMBO J. 1990;9(13):4375–80.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Marshall MS, Hill WS, et al. A C-terminal domain of GAP is sufficient to stimulate ras p21 GTPase activity. EMBO J. 1989;8(4):1105–10.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Revencu N, Boon LM, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29(7):959–65.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Revencu N, Boon LM, et al. RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation. Hum Mutat. 2013;34(12):1632–41.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Scheffzek K, Ahmadian MR, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. 1997;277(5324):333–8.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Takai Y, Sasaki T, et al. Small GTP-binding proteins. Physiol Rev. 2001;81(1):153–208.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238(4826):542–5.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Trahey M, Wong G, et al. Molecular cloning of two types of GAP complementary DNA from human placenta. Science. 1988;242(4886):1697–700.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Vogel US, Dixon RA, et al. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature. 1988;335(6185):90–3.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Wennerberg, K., K. L. Rossman, et al.. The Ras superfamily at a glance. J Cell Sci. 2005;118 Pt 5:843–6.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Yang JY, Walicki J, et al. Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157. Mol Biol Cell. 2005;16(8):3511–20.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyUniversity of Michigan Medical SchoolAnn ArborUSA