Ras activation revisited: role of GEF and GAP systems

Abstract

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.

The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions

“…RAS-effector interaction essentially requires RAS association with membranes [25] and its activation by specific regulatory proteins ( e . g ., guanine nucleotide exchange factors or GEFs), leading to the formation of GTP-bound, active RAS [26,27,28]. Notably, RAS proteins change their conformation mainly at two highly mobile regions, designated as switch I (residues 30–40) and switch II (residues 60–68) [29,30].…”

The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells

“…RAS proteins respond to extracellular signals and transform them into intracellular responses through interaction with effector proteins. The activity of RAS proteins is highly controlled through two sets of specific regulators with opposite functions, the guanine nucleotide exchange factors and the GTPase-activating proteins (GAPs), as activators and inactivators of RAS signaling, respectively (18). In the present study, we analyzed the expression profile of different Ras isoforms in HSCs and found embryonic stem cell-expressed RAS (ERas) specifically expressed in quiescent HSCs.…”

RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines

“…This result confirms previous findings for T cells 22,23 and suggests that immune cells that express RasGRP family members (RasGRP4 in U937 and RasGRP1 in Jurkat and human primary T cells; Roose et al . 17 ) have exceptionally high basal rates of nucleotide exchange on Ras (some 30-fold higher than the intrinsic exchange rate of Ras 24 ) (Figure 6d). …”

“…This mode of GTPase activation, that is, via receptor-induced inactivation of GAP, has been recently shown for Rheb, a Ras-related GTPase, and some evidence points out that it may also be the case for Ras (reviewed in Hennig et al . 24 and Laplante and Sabatini 27 ). It has previously been shown that certain growth factors such as platelet-derived growth factor or epidermal growth factor induce proteolytic degradation of NF1, one of the RasGAPs.…”

“…Based on mathematical modeling one consequence of high flux through RasGDP/GTP cycle at basal state would be much faster accumulation of RasGTP after receptor triggering as compared with the settings with low basal flux. 24 …”