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Licensed Unlicensed Requires Authentication Published by De Gruyter March 12, 2015

Ras activation revisited: role of GEF and GAP systems

  • Anne Hennig , Robby Markwart , Manuel A. Esparza-Franco , Graham Ladds and Ignacio Rubio EMAIL logo
From the journal Biological Chemistry


Ras is a prototypical small G-protein and a central regulator of growth, proliferation and differentiation processes in virtually every nucleated cell. As such, Ras becomes engaged and activated by multiple growth factors, mitogens, cytokines or adhesion receptors. Ras activation comes about by changes in the steady-state equilibrium between the inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states of Ras, resulting in the mostly transient accumulation of Ras-GTP. Three decades of intense Ras research have disclosed various families of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) as the two principal regulatory elements of the Ras-GDP/GTP loading status. However, with the possible exception of the GEF Sos, we still have only a rudimentary knowledge of the precise role played by many GEF and GAP members in the signalling network upstream of Ras. As for GAPs, we even lack the fundamental understanding of whether they function as genuine signal transducers in the context of growth factor-elicited Ras activation or rather act as passive modulators of the Ras-GDP/GTP cycle. Here we sift through the large body of Ras literature and review the relevant data for understanding the participation and precise role played by GEFs and GAPs in the process of Ras activation.

Corresponding author: Ignacio Rubio, Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Hans-Knöll-Str. 2 D-07745 Jena, Germany; and Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany, e-mail:


We acknowledge funding by the German research council (DFG), grant # RU860/4-1 (A.H.), by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1002 (I.R., R.M.), by the BBSRC through the Midlands Interdisciplinary BioSciences Training Partnership (M.A.E.-F.) and grant number BB/G01227X/1 (G.L.) and the National Council on Science and Technology of Mexico (CONACYT) (M.A.E.-F.).


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Received: 2014-10-2
Accepted: 2015-3-9
Published Online: 2015-3-12
Published in Print: 2015-8-1

©2015 by De Gruyter

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