Regulators and effectors of ras proteins.

Annu. Rev. Cell Bioi. 1991. 7:601-32 Copyright © 1991 by Annual Reviews Inc. All rights reserved

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REGULATORS AND EFFECTORS

Annu. Rev. Cell. Biol. 1991.7:601-632. Downloaded from www.annualreviews.org Access provided by University of Adelaide on 12/10/14. For personal use only.

OF

ras

PROTEINS

Gideon Bollag and Frank McCormick Department of Molecular Biology, Cetus Corporation, Emeryville, California 94608 KEY

WORDS:

oncogenes, GTPase-activating proteins, signaling

CONTENTS INTRODUCTION..............................................................................................................

/

601

THE GDP GTP CyCLE......................................................................................................

602

STRUCTURE AND MECHANISM OF ras PROTEINS.................................................................

605

GENES ................................................................................................

608

Mammals .. ..... . . ..... . ... ................................. . ........... . . .... .. . ......................................... yeasts . . . . . . . ...... . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... . . . . . . . . . . . . . . . . . . ..... Other Organisms .................. . ............... . . ................ . ................... . ............. . . .. . .......... .

608 609 610

BIOCHEMICAL TARGETS OF ras PROTEINS ..... . . . . . . . .... . . . .. . . . ............. . . ..... . . . ............ . . . . ...........

612

FUNCTIONS OF

ras

EXCHANGE FACTORS ......................................................................................................

613

Mammals ...... . . . .... .... . . ..... . . . . . . ..... . . . . . . . . . . . . . ... . .. . . . . ...... . . . . . . ..... .... . . . .. . . . . . ... . . .. . . . . ...... . .. ... . yeasts. . . . . . . . .. . . . . . . . . . ... . . . . . . . . .. . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

613 614

GTPASE-ACTIVATING PROTEINS.......................................................................................

615

Identification ofras GAPs .............. . ...... . ..................................... . ... . ......... . ......... . . . . . Biochemical Characterization ofras GAPs .............................. . . . . .... . ..... . . ................ . Tyrosine Phosphorylation andras GAPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation afras GAPs .. . . ......... . . . . . . ..... . . . . . .......... . . . ....... . . . . . ........... . ........ . ................. IRA Genes in Yeast ............... . ........ . ......................... . ...................... . ........... . ............ GAPs forras-Related Proteins ............................. . .. . ....................... . ....................... . GAPs as Effectors ............................................. . . . ........ ............................................

615 616 617 618 619 619 620

FUTURE PROSPECTS........................................................................................................

623

REFERENCES............................................... . . . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . ... . ... . . . ....... .............. ....

623

INTRODUCTION The three proteins encoded by human ras genes (H-ras, K-ras, N-ras) are GTPases (Barbacid 1 987). These 2 1 -kd proteins bind guanine nucleotides 60 1 0743-4634/9 1 / 1 1 1 5-060 1 $02.00


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with high affinity and hydrolyze GTP with low catalytic efficiency. They serve as signal transducers by switching from an active GTP-bound form to an inactive GDP-bound form. The biological functions of these switches remain a mystery. Mutations in ras genes that result in proteins that are trapped in the GTP-bound form are oncogenic. M uch of the momentum that propels research into the function of ras oncogenes comes from the realization that they play a major causal role in at least 30% of all human cancers (Bos 1989). It seems likely that a full understanding of ras function will eventually lead to new approaches towards cancer therapy. Since ras proteins play important roles in signal transduction, the regu lation of ras activity is tightly controlled. Two types of protein determine whether ras proteins are bound to GDP or GTP. Guanine nucleotide releasing proteins (GNRPs) facilitate the release of GDP thereby allowing GTP to bind. GTPase-activating proteins (GAPs) accelerate the hydrolysis of GTP. These proteins lie upstream of ras proteins in signal transduction pathways. Downstream of ras are the effectors of ras action. So far, ras effectors are understood only in the yeast Saccharomyces cerevisiae. In this review, we summarize current understanding of the biological roles of ras proteins, the regulation of ras activity, and the potential ras effector pathways. Past reviews have highlighted other aspects of ras action (Bar bacid 1987; Bos 1989; Gibbs & Marshall 1989; Santos & Nebreda 1989; Broach & Deschenes 1990), and readers are referred to these for complete references. THE GDP/GTP CYCLE

Ras proteins are part of a large and diverse family of GTPases, whose functional and structural properties have been recently reviewed (Bourne et al 1990, 1991; Hall 1990). The essential feature of these proteins is their ability to cycle between inactive and active forms by switching between GDP- and GTP-bound forms (Figure I ) . X-ray structural analysis has revealed differences between these two forms that must account for their different biological activities. These differences are briefly summarized in the following section. In Figure I , the GTP/GDP cycle is schematized to highlight possible regulators and effectors. The conversion of the inactive, GDP-bound form to the active GTP-bound form is dependent on cellular exchange factors, the GNRPs, and presents a likely point of regulation. Candidates for mammalian and yeast factors have been reported (see section on Exchange Factors). The GNRP catalyzes the release of GDP, and the dissociation rate is designated k I (Figure I ) . Since GTP is present in excess con-

ras PROTEINS

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putative effectors (Sigal et al 1986a; see also Figure 2). p120-GAP binds weakly to these effector mutants (Vogel et a1 1 988; Schaber et al 1989) and only poorly catalyzes their GTPase activity (Adari et al 1988; Cales et al 1988). (d) p120-GAP binds tightly to Krev-1 (a ras homologue, see section on GAPs as Effectors), yet fails to catalyze GTP hydrolysis (Frech et al 1990; Rata et al 1 990). (e) Binding of an anti-ras monoclonal antibody (Y1 3-2S9) blocks the action of pI20-GAP on ras proteins (Trahey & McCormick 1 987). Mutations in the region to which this antibody binds (amino acids 63 to 73) also fail to interact with GAP (Srivastava et al 1989). While binding of NF l -GAP to Krev- l has not yet been examined, all of the other properties listed above apply to NF l -GAP as well as p 1 20GAP (Xu et al 1 990a; Martin et al 1990; Ballester et al 1 990; Bollag & McCormick 1991); however, some interesting differences have been observed. NF l -GAP binds to wild-type ras proteins with a 30-fold higher affinity than does p 1 20-GAP (Martin et al 1 990). In contrast, the specific activity of p120-GAP is about 30-fold higher than that of N F l -GAP. Furthermore, the affinity of some mutated ras proteins is up to 300-fold higher for NF l-GAP than for p120-GAP (Bollag & McCormick 199 1 ) . Indeed, the affinity o f NF l-GAP for GTP-bound mutant H-ras (glutamine at amino acid position 6 1 replaced by leucine) is about 2 nM, which suggests that this oncogenic protein will be tightly associated with NF1GAP in transformed cells. Tyrosine Phosphorylation and

ras

GAPs

Recently, much attention has focused on the interactions of p 1 20-GAP with tyrosine kinases. Among the growth factor receptors shown to phos phorylate GAP on tyrosine are those for platelet-derived growth factor (PDGF ; Molloy et a1 1989 ; Kaplan et a1 1 990), epidermal growth factor (EGF ; Ellis et a1 1 990; Margolis et aI1 990), acd colony-stimulating factor 1 (CSF 1 ; Reedijk et al 1 990). In addition, the tyrosine kinase oncogenes, v-src, v-fps, and v-abl, are also able to phosphorylate p 1 20-GAP (Ellis et aI 1990). F urthermore, pI20-GAP binds tightly to many of these tyrosine kinases, but only when they have been activated (Anderson et al 1 990 ; Kaplan et al 1990; Kazlauskas et al 1990; Margolis et a1 1 990; Reedijk et al 1990; Brott et al 1991). Interestingly, the PDGF -induced phos phorylation/association of p 1 20-GAP by the PDGF receptor is blocked in cells transformed by oncogenic ras proteins. Activated tyrosine kinases have been shown to bind to other signaling molecules as well. The other proteins that interact with the PDGF and EGF receptors include phos pholipase C (Margolis et al 1 989; Meisenhelder et al 1 989; Wahl et al 1 989), phosphatidylinositol (PI) 3'-kinase (Kaplan et al 1 987), and the


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serine/threonine protein kinase encoded by the raj oncogene (Morrison et al 1989). The CSF 1 receptor appears to bind only to p I20-GAP and PI 3'-kinase (Reedijk et al 1990). The role of ras in these signaling complexes is currently being inves tigated. Some interesting links with phospholipase C-y have been reported. In mouse fibroblasts, microinjection of either ras or phospholipase C-y induces a mitogenic response (Smith et aI1989). Tyrosine phosphorylation directly stimulates the activity of phospholipase C-y (Nishibe et al 1990). Inhibitory antibodies to phospholipase C-y block the mitogenic induction by both phospholipase C-y and ras. However, ras antibodies block only ras responses, which suggests that ras acts upstream of phospholipase C-y in the mitogenic pathway (Smith et al 1990). Interpretation of these results are complicated by the fact that G protein-coupled receptors also modulate phospholipase C activity (Stryer & Bourne 1986; Gilman 1987; Birnbaumer 1990; Bourne et al 1990) . In addition to binding to activated tyrosine kinases, p I20-GAP forms an alternative complex with two other tyrosine-phosphorylated proteins of molecular weights 62 and 190 K [hence termed p62 and p190 (Bouton et a11991; Ellis et al 1990)]. More recently it was shown that isolated SH2 domains derived from p I 20-GAP are sufficient to direct binding to these phosphotyrosine-containing proteins as well as to autophosphorylated tyrosine kinases (Anderson et al 1990; Moran et al 1990). Other SH2containing proteins also associate with tyrosine phosphorylated proteins, albeit with different specificities (Mayer et al 1991). This suggests that these domains, which comprise the amino-terminal one-third of the p120GAP protein, direct the oligomerization of p 120-GAP with other phos phoproteins, presumably forming large signaling complexes. Regulation of ras GAPs

While it is clear that GAPs regulate the activity of ras proteins, it is the regulation of GAP activity that is apparently the target of extracellular signals. As mentioned above (The GDP/GTP Cycle), several studies, which have explored the regulation of the nucleotide state of ras, suggest that the accumulation of ras in its GTP state is, in part, a consequence of GAP inhibition. In response to T-cell activation, the activity of GAP is inhibited, thus leading to the activation of ras (Downward et al 1990a). This inhi bition apparently proceeds via protein kinase C activation: independent activation of protein kinase C by phorbol esters also inhibits GAP activity. In fibroblasts that overproduce the insulin receptor, insulin is able to activate ras, although the effect is protein kinase C-independent (Burgering et al 1991). Direct in vitro assays have identified mitogenic lipids that can inhibit


ras PROTEINS

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GAP activity directly (Tsai et al 1 9 89a,b; Y u et a l 1 990). Phosphatidyl inositol-4,5-diphosphate, phosphatidic acid, arachidonic acid, and other phospholipids with arachidonate at the sn2 position are all capable of inhibiting GAP activity in crude extracts (Tsai et al 1989a,b). It appears that rho-specific GAP is also inhibited by lipids (Tsai et aI 1 9 89a). F urther more, a lipoxygenase metabolite of arachidonic acid is more potent than arachidonic acid in inhibiting GAP activity (Yu et al 1 990). In addition, a cytoplasmic protein has been found that may mediate the lipid-dependent inhibition of intrinsic or GAP-stimulated ras GTPase activity (Tsai et al 1 990). It appears that the lipid inhibition primarily affects NFl-GAP activity (Bollag & McCormick 1 991). Furthermore, the inhibition is non competitive, which indicates that lipid-inhibited NF l-GAP is still com petent to interact with ras proteins. Recently it was found that cyclooxygenase metabolites of arachidonic acid actually stimulate pI20-GAP activity (Han et al 1 99 l ). While arachi donic acid can inhibit both p 1 20-GAP and NF l -GAP, the stimulation by these eicosanoids is specific for p120-GAP. It appears that this stimulation is rather selective, since the prostaglandins 9a-PGF 2, and PGA2 stimulated the activity while 9f3-PGF 2" PGF la and thromboxane B2 did not. IRA Genes in Yeast In the yeast Saccharomyces cerevisiae, IRA genes have an antagonistic function to that of the CDC25 gene: while CDC25 gene disruptions result in decreased levels of cAMP, IRA mutations result in increased levels (Tanaka et al 1 989). In addition, IRA disruptions suppress the lethality of CDC25 mutations. As described previously, IRA] and IRA2 share significant homology with p 1 20-GAP and more extensive homology with N F l -GAP. Recombinant mammalian pI20-GAP expression suppresses the phenotype of these mutations (Ballester et a1 1 989; Tanaka et aI 1 990a). Furthermore, a fragment of NF l -GAP encoding the GAP-related domain also suppresses the IRA defect (Xu et a1 1 990a; Martin et a1 1 990; Ballester et al 1990). GAPs for ras-Related Proteins

Since the GAPs for ras proteins are exquisitely selective, different GAPs should exist for other small guanine nucleotide-binding proteins with low intrinsic GTPase activity. Much effort has been focused on the GAP specific for Krev-1, since Krev-l has been shown to bind non-productively to p I20-GAP (Frech et al 1 990; Hata et aI1 990). Both cytosolic (Kikuchi et al 1 989; Veda et al 1 989) and membrane-bound (Polakis et al 1 99 1 ) forms of Krev-l GAP have been described. The membrane-bound form has been purified to homogeneity, revealing a monomeric molecular weight of


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88 K (Polakis et al 1991). This Krev- l GAP is inactive toward ras proteins as well as other small guanine nucleotide binding proteins including rho, G25K and rae-I. Recent cloning and sequencing of the gene encoding this GAP has revealed no regions of significant homology to any of the ras GAPs (Rubinfeld et al 1991). GAPs for other proteins have also been identified. Two groups have reported the partial purification of rho GAP from human spleen (Garrett et a1 1989) and bovine brain (Yamamoto et aI 1990). Sizing results suggest that the rho GAP from human spleen may be about 29 kd and the one from bovine brain is between 37 and 200 kd, although it is not yet clear that these are unrelated GAPs. A specific ral GAP of molecular weight > 150 K has also been reported in brain and testis cytosols (Emkey et al 1 9 9 1 ). Both cytosolic and membrane-bound forms of a GAP specific for rab3A have been reported (Burstein et al 1991). A GAP has also been identified in porcine liver for the yptl protein, and this GAP interacts with the yptl effector region (Becker et aI1 99 l ). A further exciting development has been the demonstration that the homologous human proteins ber and n-chimerin are GAPs for rae proteins (Diekmann et al 1991). It is likely that each small GTP-binding protein may have its own specific GAP or GAPs. GAPs as Effectors

A growing volume of evidence suggests that the GAPs, which down regu late ras proteins by stimulating their GTPase activity, also have a second role as effectors. As described previously, the GAPs bind to oncogenic mutants of ras without catalyzing their GTPase activity (Vogel et al 1988; Krengel et al 1990; Bollag & McCormick 1991) . While the lack of catalysis explains the fact that these oncogenic proteins accumulate in their GTP bound state, the observation that some of these mutants bind to GAP with a higher affinity than wild-type ras proteins is consistent with a downstream role for GAP. Furthermore, ras proteins mutated at the effector-binding site interact poorly with GAP (Adari et al 1988; Cales et a1 1 988; Vogel et al 1988; Rey et al 1 989; Schaber et al 1989). Therefore, GAP fulfills this criterion for ras effector: it binds well to activated ras proteins and poorly to proteins with impaired signaling function. These arguments have recently been strengthened by the observation that certain cffcctor mutations reduce the transforming ability of activated but not normal ras: reduced binding to the effector (e.g. pI20-GAP) was compensated for by reduced GTPase activity for the normal proteins, while no compensatory effect occurred with the activated proteins since their GTPase was unaffected


ras PROTEINS

62 1

by p I 20-GAP (Farnsworth et al 1 9 9 1 ) . Binding of GAP to ras is also GTP-dependent. In addition, studies with ras monoclonal antibodies have provided more data to support the GAP-as-effector hypothesis: The anti body Y 1 3-259 inhibits the action of GAP (Trahey & McCormick 1 987; Adari et al 1988; Rey et al 1 989; Srivastava et al 1 989; Martin et al 1 990) and ras (Mulcahy et al 1 985; Smith et al 1 986), while the antibody Y 1 3238 inhibits neither GAP activity (Adari et al 1 988; Rey et al 1 989), nor ras activity (Kung et al 1 986). Further evidence has come from the unexpected finding that a sup pressor of ras-induced transformation binds tightly to p l 20-GAP. In the search for proteins that could revert the transformed phenotype, a ras homologue was found and named Krev- l (Kitayama et al 1 989). Krev- l is identical to the independently isolated rap and smg p2 1 proteins (Kawata et a1 1 988; Pizon et al 1 988). Krev- l was found associated with cytochrome b in neutrophils (Quinn et a1 1 989) and is a substrate for cAMP-dependent protein kinase in platelets (White et al 1 990). Interestingly, while p 1 20GAP is ineffective in stimulating the Krev- l GTPase activity, it binds to Krev- l with higher affinity than to wild-type ras proteins (Frech et a1 1 990; Hata et al 1 990). Thus it has been proposed that Krev- l suppresses ras activity by binding to and sequestering p I 20-GAP. If the sole function of p I 20-GAP were to stimulate ras GTPase activity, then the sequestration of p l 20-GAP would result in an accumulation of GTP-bound ras. There fore, ras proteins would be activated by Krev- l overexpression. Since the opposite effect is observed, it is attractive to speculate that Krev- l depen dent suppression results from sequestering an effector of ras action. This idea is supported by evidence that activating mutations in Krev- l poten tiate its suppressing ability (Kitayama et al 1 990): these mutations result in an accumulation of Krev- l in its GTP-bound state, which increases its affinity for the ras effector. These data are consistent with the idea that this effector may be p I 20-GAP, since p 1 20-GAP does indeed bind with high affinity to the GTP-bound form of Krev- l (Frech et al 1 990). While these observations provide indirect evidence for the GAP-as effector hypothesis, recently direct evidence has been reported. In guinea pig atrial membranes, where a G protein (Gk) couples a muscarinic receptor to a potassium channel, ras and p I 20-GAP collaborate to inhibit this coupling (Yatani et al 1 990). These studies show that oncogenic mutants of ras are more effective and that antibodies to GAP block the ras effect. Furthermore, the p I 20-GAP effect requires more than simple binding to ras, since the isolated catalytic domain of p l 20-GAP is over 1 00-fold less effective in blocking the coupling. These data suggest that p 1 20-GAP plays a direct role in generating some sort of signal that impedes the interaction


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of Gk with the muscarinic receptor. Data from other G protein-coupled systems suggest a similar function for ras and GAP. In these other systems, ras activation apparently blocks the coupling of tyrosine kinase receptors with G protein signaling pathways (Tarpley et al 1 986; Benjamin et al 1 987, 1 988; Parries et al 1 987; Maly et a1 1 988; Alonso et a1 1988, 1 990). One recent study concluded that p 1 20-GAP is not the sole effector of ras proteins (Zhang et al 1 990). Overexpression of p 1 20-GAP was able to suppress transformation by overexpressed wild-type ras protein, but had no effect on the transformation produced by activated ras. It was suggested that p 1 20-GAP should potentiate the effect of activated ras proteins if p I 20-GAP were the only effector. Since the only effect of p I 20-GAP overexpression was the down regulation of wild-type ras, it was determined that p 1 20-GAP was not a dominant downstream element in the ras path way. The discovery of N F l -GAP, however, suggests that a reevaluation of this conclusion may be in order: the results are consistent with p 1 20GAP and NF l -GAP as dual downstream effectors. Consistent with this explanation, we have found that both p I 20-GAP-like and N F I -GAP-like activities can be found in clonal cell lines (Bollag & McCormick 1 99 1 ). The regulation and putative effector roles of the GAPs are highlighted in Figure 5. Both p I 20-GAP and NF l -GAP bind to GTP-bound ras proteins. This binding could serve dual purposes: down regulation of ras by catalyzing GTP hydrolysis and active signaling (signals A and B). Signal A, for example, could lead to uncoupling of certain G proteins from their receptors. Down regulation by the GAPs would be inhibited by certain lipids, by oncogenic activation , or by protein kinase C. This inhibition would lead to the accumulation of ras bound to GTP, thereby activating

Signal A Figure 5

Signal 8

Model of the putative effector functions of GTPase-activating proteins.

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the signaling pathways. In contrast, p 1 20-GAP activity would be stimu lated by certain prostaglandins and result in the inactivation of ras. Regen eration of the active form is catalyzed by GNRPs. In this model, both regulation of the nucleotide state of ras and signal transmission from ras are mediated by the GAP proteins. As depicted in Figure 1 , alternative models implicate regulation through the GNRPs and signaling by novel effector proteins.


FUTURE PROSPECTS Here we have reviewed the evidence that implicates ras as a switch along essential cellular pathways. Factors regulating this switch have been identi fied and are being characterized; however, the true function of this switch in mammalian cells remains undiscovered. While interactions with other signaling systems are evident, no unifying picture has emerged. We expect many of these mysteries will be solved in the near future. The roles of the GNRPs and GAPs will be clarified and more factors that interact directly with ras will be found. Biochemical activities will be assigned to the effectors of ras. And we hope that these developments will lead to new and better treatments for the diseases associated with ras. Literature Cited

Adari, H., Lowy, D. R., Willumsen, B. M., Der, C. 1 . , McCormick, F. 1988. Guano sine triphosphatase activating protein (GAP) interacts with the p21 ras effector binding domain. Science 240: 5 1 8-21 Allende, C. c., Hinrichs, M . V., Santos, E., Allende, 1. E. 1988. Oncogenic ras protein induces meiotic maturation of amphibian oocytes in the presence of protein syn thesis inhibitors. FEBS Lett. 234: 426-30 Alonso, T., Morgan, R. 0., Marvizon, 1. C., Zarbl, H., Santos, E. 1 988. Malignant transformation by ras and other onco genes produces common alterations in inositol phospholipid signaling pathways.

region of srn,q p 25 A in its interaction with membranes and the GDP/GTP exchange protein. Mol. Cell. Bioi. I I : 1 438--47 Araki, S., Kikuchi, A., Hata, Y., Isomura, M., Takai, Y. 1 990. Regulation of revers ible binding of srng p21 A, a ras p21-like GTP-binding protein, to synaptic plasma membranes and vesicles by its specific regu latory protein, GDP dissociation inhibi tor. J. Bioi. Chern. 265: 1 3007- 1 5 Aroian, R . V . , Koga, M . , Mendel, 1. E., Ohshima, Y., Sternberg, P. W. 1 990. The let-23 gene necessary for Caenorhabditis ele,qans vulval induction encodes a tyro sine kinase of the EGF receptor subfamily.

Alonso, T., Srivastava, S., Santos, E. 1 990. Alterations of G-protein coupling func tion in phosphoinositide signaling path ways of cells transformed by ras and other membrane-associated and cytoplasmic oncogenes. Mol. Cell. BiD!. 10: 3 1 1 7-24 Anderson, D., Koch, C. A., Grey, L., Ellis, c., Moran, M. F., Pawson, T. 1 990. Bind ing of SH2 domains of phospholipase C y I , GAP, and Src to activated growth factor receptors. Science 250: 979-82 Araki, S., Kaibuchi, K., Sasaki, T., Hata, Y., Takai, Y. 1 99 1 . Role ofthe C-terminal

Ballester, R., Marchuk, D., Boguski, M., Saulino, A., Letcher, R., et al. 1 990. The NFl locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63: 851-59 Ballester, R., Michaeli, T., Ferguson, K., Xu, H. P., McCormick, F., Wigler, M. 1 989. Genetic analysis of mammalian GAP expressed in yeast. ee1l 59: 68 1-86 Barbacid, M. 1 987. ras Genes. Annu. Rev.

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Regulators and Effectors of Arf GTPases in Neutrophils.

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Loss of negative regulators amplifies RAS signaling.

SGK-1 and PHLPP1: Ras-mediated effectors during ECM-detachment.

Phosphorylated proteins as physiological effectors.

LysM effectors: secreted proteins supporting fungal life.

Chondroitin sulfate-cell membrane effectors as regulators of growth factor-mediated vascular and cancer cell migration.

Upstream regulators and downstream effectors of NADPH oxidases as novel therapeutic targets for diabetic kidney disease.

Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system.

Ras signaling through RASSF proteins.

Ras proteins. Some signal developments.

Intrinsic disorder in plant proteins and phytopathogenic bacterial effectors.

Editorial: Memory T Cells: Effectors, Regulators, and Implications for Transplant Tolerance.

Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved.

Id proteins: small molecules, mighty regulators.

HnRNP-like proteins as post-transcriptional regulators.

Coevolution of RAC Small GTPases and their Regulators GEF Proteins.

Piezo proteins: regulators of mechanosensation and other cellular processes.

SR Proteins: Binders, Regulators, and Connectors of RNA.

Lipid modifications and function of the ras superfamily of proteins.

DTC-and-Me: Patient, Provider, Proteins and Regulators.

WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome.

Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering.

Rab proteins: the key regulators of intracellular vesicle transport.