Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi


  • Philip E. Lapinski
  • Philip D. King
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_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 which 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...

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  1. Anand S, Majeti BK, et al. MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat Med. 2010;16(8):909–14.PubMedCrossRefGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. Boon LM, Mulliken JB, et al. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15(3):265–9.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. Iwashita S, Song SY. RasGAPs: a crucial regulator of extracellular stimuli for homeostasis of cellular functions. Mol Biosyst. 2008;4(3):213–22.PubMedCrossRefGoogle Scholar
  9. Kulkarni SV, Gish G, et al. Role of p120 Ras-GAP in directed cell movement. J Cell Biol. 2000;149(2):457–70.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. Takai Y, Sasaki T, et al. Small GTP-binding proteins. Physiol Rev. 2001;81(1):153–208.PubMedGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. Trahey M, Wong G, et al. Molecular cloning of two types of GAP complementary DNA from human placenta. Science. 1988;242(4886):1697–700.PubMedCrossRefGoogle Scholar
  18. Vogel US, Dixon RA, et al. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature. 1988;335(6185):90–3.PubMedCrossRefGoogle Scholar
  19. Wennerberg K, Rossman KL, et al. The Ras superfamily at a glance. J Cell Sci. 2005;118(Pt 5):843–6.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

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