The Ras-related Protein Rheb Is Farnesylated and Antagonizes Ras Signaling and Transformation

Presently, nothing is known about the function of the Ras-related protein Rheb. Since Rheb shares significant sequence identity with the core effector domains of Ras and KRev-1/Rap1A, it may share functional similarities with these two structurally related, yet functionally distinct, small GTPases. Furthermore, since like Ras, Rheb terminates with a COOH terminus that is likely to signal for farnesylation, it may be a target for the farnesyltransferase inhibitors that block Ras processing and function. To compare Rheb function with those of Ras and KRev-1, we introduced mutations into Rheb that generate constitutively active or dominant negative forms of Ras and Ras-related proteins and were designated Rheb(64L) and Rheb(20N), respectively. Expression of wild type or mutant Rheb did not alter the morphology or growth properties of NIH 3T3 cells. Thus, aberrant Rheb function is distinct from that of Ras and fails to cause cellular transformation. Instead, similar to KRev-1, co-expression of Rheb antagonized oncogenic Ras transformation and signaling. In vitro and in vivo analyses showed that like Ras, Rheb proteins are farnesylated and are sensitive to farnesyltransferase inhibition. Thus, it is possible that Rheb function may be inhibited by farnesyltransferase inhibitors treatment and, consequently, may contribute to the ability of these inhibitors to impair Ras transformation. Presently, nothing is known about the function of the Ras-related protein Rheb. Since Rheb shares significant sequence identity with the core effector domains of Ras and KRev-1/Rap1A, it may share functional similarities with these two structurally related, yet functionally distinct, small GTPases. Furthermore, since like Ras, Rheb terminates with a COOH terminus that is likely to signal for farnesylation, it may be a target for the farnesyltransferase inhibitors that block Ras processing and function. To compare Rheb function with those of Ras and KRev-1, we introduced mutations into Rheb that generate constitutively active or dominant negative forms of Ras and Ras-related proteins and were designated Rheb(64L) and Rheb(20N), respectively. Expression of wild type or mutant Rheb did not alter the morphology or growth properties of NIH 3T3 cells. Thus, aberrant Rheb function is distinct from that of Ras and fails to cause cellular transformation. Instead, similar to KRev-1, co-expression of Rheb antagonized oncogenic Ras transformation and signaling. In vitro and in vivo analyses showed that like Ras, Rheb proteins are farnesylated and are sensitive to farnesyltransferase inhibition. Thus, it is possible that Rheb function may be inhibited by farnesyltransferase inhibitors treatment and, consequently, may contribute to the ability of these inhibitors to impair Ras transformation. Mutated forms of the three ras genes (H-, K-, and N-ras) are associated with 30% of all human cancers and encode potent transforming and oncogenic mutant proteins (1Clark G.J. Der C.J. Dickey B.F. Birnbaumer L. GTPases in Biology I. Springer-Verlag, Berlin1993: 259-288Google Scholar). Normal Ras proteins function as GDP/GTP-regulated molecular switches (2Boguski M.S. McCormick F. Nature. 1993; 366: 643-654Crossref PubMed Scopus (1762) Google Scholar). Guanine nucleotide exchange factors (SOS and RasGRF/CDC25) promote formation of the active, GTP-bound state (2Boguski M.S. McCormick F. Nature. 1993; 366: 643-654Crossref PubMed Scopus (1762) Google Scholar, 3Quilliam L.A. Khosravi-Far R. Huff S.Y. Der C.J. BioEssays. 1995; 17: 395-404Crossref PubMed Scopus (193) Google Scholar, 4Feig L.A. Science. 1993; 260: 767-768Crossref PubMed Scopus (163) Google Scholar), whereas GTPase activating proteins (p120- and NF1-GTPase activating proteins) promote formation of inactive, GDP-bound Ras (5Bollag G. McCormick F. Cancer Biol. 1992; 3: 199-208PubMed Google Scholar). Mutated Ras proteins contain single amino acid substitutions (at residues 12, 13, or 61) that render the proteins insensitive to GTPase activating protein stimulation and, consequently, persist as constitutively activated proteins. Ras proteins serve as key intermediate relay switches in diverse signaling pathways that control cell growth and differentiation (6Bourne H.R. Sanders D.A. McCormick F. Nature. 1990; 349: 117-127Crossref Scopus (2698) Google Scholar, 7Khosravi-Far R. Der C.J. Cancer Metastasis Rev. 1994; 13: 67-89Crossref PubMed Scopus (310) Google Scholar, 8Prendergast G.C. Gibbs J.B. Adv. Cancer Res. 1993; 62: 19-63Crossref PubMed Scopus (60) Google Scholar). Consequently, mutated Ras proteins cause constitutive, ligand-independent activation of these pathways, thereby promoting to the aberrant growth of tumor cells. Ras proteins are prototypes for a large superfamily of Ras-related proteins (>60 mammalian members) that function as GDP/GTP-regulated molecular switches (2Boguski M.S. McCormick F. Nature. 1993; 366: 643-654Crossref PubMed Scopus (1762) Google Scholar, 6Bourne H.R. Sanders D.A. McCormick F. Nature. 1990; 349: 117-127Crossref Scopus (2698) Google Scholar, 9Bourne H.R. Sanders D.A. McCormick F. Nature. 1990; 348: 125-132Crossref PubMed Scopus (1844) Google Scholar). However, despite their strong amino acid sequence identity with Ras proteins (30–55%), the majority of these small GTPases lack the potent transforming potential of Ras proteins. Exceptions include TC21/R-Ras2 (10Chan A.M.L. Miki T. Meyers K.A. Aaronson S.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7558-7562Crossref PubMed Scopus (86) Google Scholar, 11Graham S.M. Cox A.D. Drivas G. Rush M.R. D'Eustachio P. Der C.J. Mol. Cell. Biol. 1994; 14: 4108-4115Crossref PubMed Scopus (93) Google Scholar), R-Ras (12Saez R. Chan A.M.-L. Miki T. Aaronson S.A. Oncogene. 1994; 9: 2977-2982PubMed Google Scholar, 13Cox A.D. Brtva T.R. Lowe D.G. Der C.J. Oncogene. 1994; 9: 3281-3288PubMed Google Scholar), RhoA (14Avraham H. Weinberg R.A. Mol. Cell. Biol. 1989; 9: 2058-2066Crossref PubMed Scopus (95) Google Scholar, 15Paterson H.F. Self A.J. Garrett M.D. Just I. Aktories K. Hall A. J. Cell Biol. 1990; 111: 1001-1007Crossref PubMed Scopus (571) Google Scholar, 16Perona R. Esteve P. Jiménez B. Ballestero R.P. Ramón y Cajal S. Lacal J.C. Oncogene. 1993; 8: 1285-1292PubMed Google Scholar, 17Khosravi-Far R. Solski P.A. Clark G.J. Kinch M.S. Der C.J. Mol. Cell. Biol. 1995; 15: 6443-6453Crossref PubMed Scopus (641) Google Scholar, 18Qiu R.-G. Chen J. McCormick F. Symons M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11781-11785Crossref PubMed Scopus (488) Google Scholar), RhoB (19Prendergast G.C. Khosravi-Far R. Solski P.A. Kurzawa H. Lebowitz P.F. Der C.J. Oncogene. 1995; 10: 2289-2296PubMed Google Scholar), and Rac1 (17Khosravi-Far R. Solski P.A. Clark G.J. Kinch M.S. Der C.J. Mol. Cell. Biol. 1995; 15: 6443-6453Crossref PubMed Scopus (641) Google Scholar, 20Qiu R.-G. Chin J. Kirn D. McCormick F. Symons M. Nature. 1995; 374: 457-459Crossref PubMed Scopus (813) Google Scholar), where constitutively activated versions of these Ras-related proteins can cause tumorigenic transformation of NIH 3T3 cells. The transforming activities of TC21 and R-Ras reflect the fact that these two Ras-related proteins share complete identity with the core Ras effector domain (Ras residues 32–40) and, consequently, may activate downstream signaling pathways in common with those that mediate Ras transforming potential (21Marshall M.S. Trends Biochem. Sci. 1993; 18: 250-254Abstract Full Text PDF PubMed Scopus (194) Google Scholar). However, although the Raf-1 serine/threonine kinase is clearly a critical effector important for Ras signaling and transformation (22Kolch W. Heidecker G. Lloyd P. Rapp U.R. Nature. 1991; 349: 426-428Crossref PubMed Scopus (355) Google Scholar, 23Cowley S. Paterson H. Kemp P. Marshall C.J. Cell. 1994; 77: 841-852Abstract Full Text PDF PubMed Scopus (1854) Google Scholar, 24Pagès G. Lenormand P. L'Allemain G. Chambard J.-C. Meloche S. Pouysségur J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8319-8323Crossref PubMed Scopus (926) Google Scholar, 25Westwick J.K. Cox A.D. Der C.J. Cobb M.H. Hibi M. Karin M. Brenner D.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6030-6034Crossref PubMed Scopus (168) Google Scholar, 26Troppmair J. Bruder J.T. Munoz H. Lloyd P.A. Kyriakis J. Banerjee P. Avruch J. Rapp U.R. J. Biol. Chem. 1994; 269: 7030-7035Abstract Full Text PDF PubMed Google Scholar, 27Brtva T.R. Drugan J.K. Ghosh S. Terrell R.S. Campbell-Burk S. Bell R.M. Der C.J. J. Biol. Chem. 1995; 270: 9809-9812Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar), neither TC21 nor R-Ras cause activation of Raf-1 (28Graham S.M. Vojtek A.B. Huff S.Y. Cox A.D. Clark G.J. Cooper J.A. Der C.J. Mol. Cell. Biol. 1996; 16: 6132-6140Crossref PubMed Scopus (54) Google Scholar, 29Huff S.Y. Quilliam L.A. Cox A.D. Der C.J. Oncogene. 1997; 14: 133-143Crossref PubMed Scopus (43) Google Scholar). Thus, despite possessing complete identity with the core Ras effector domain, these two Ras-related proteins must cause transformation by activation of Raf-independent effector pathways. Therefore, while the core effector domain sequences of Ras, TC21, and R-Ras are clearly critical for effector interactions, sequences flanking this core region are likely to influence specific effector interactions. Consistent with this, recent mutagenesis studies have extended the boundaries of the Ras effector domain to include Ras residues 25–45 K. M. Science. 1990; PubMed Scopus Google Scholar, K. M. F. K. F. A. M. M. S. T. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). shares complete identity with the core Ras effector domain, it transforming potential and, the ability of Ras to H. T. M. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar, H. T. M. Proc. Natl. Acad. Sci. U. S. A. 1990; PubMed Scopus Google Scholar, B. I. McCormick F. J. 1993; PubMed Scopus Google Scholar). Since can with the Raf-1 serine/threonine kinase J. Kyriakis Marshall M.S. Bruder J.T. Rapp U.R. Avruch J. Nature. 1993; PubMed Scopus Google Scholar), as as Ras and proteins) M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, L. Brtva T.R. T. P. Der C.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar), it is not clearly is not transforming and it Ras function. is that fails to Ras important for Ras transformation. Thus, may with and Ras thereby their with Consistent with this fails to activate or downstream signaling activities that are by Rheb (Ras in is a of the Ras superfamily K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). The sequence of Rheb is distinct from Ras-related it shares amino acid with human and human Rheb sequence in common with Ras and proteins. Rheb strong identity with the Ras and core effector that Rheb may share common effector with Ras and The region of Rheb is similar to Ras with the amino Rheb terminates with a amino that is likely to signal for by the J. 1990; PubMed Scopus Google Scholar, A.D. Der C.J. Cell Biol. 1992; PubMed Scopus Google Scholar, T. J. Biochem. 1992; PubMed Scopus Google Scholar). for the Ras and two proteins and P. Marshall C.J. Hall A. P.A. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, K. Biochem. J. 1993; PubMed Scopus Google Scholar, R. J. J. Mol. Cell. Biol. 1996; 16: PubMed Scopus Google Scholar), all Ras superfamily proteins are by the Rheb function may be antagonized by that block Ras function I. F. H. of the R. G. Scholar). In the we introduced or of function mutations into Rheb and their properties in NIH 3T3 cells. that of wild type or mutant Rheb to cause or growth transformation of NIH 3T3 cells. Instead, like KRev-1, we that Rheb co-expression inhibited oncogenic Ras signaling and transformation and that Rheb with Raf-1 in However, whereas is by the like Ras, we that Rheb is by farnesylation, and this processing is by Rheb a that is similar to that of Ras the with these that Rheb function is similar to that of Ras and that of Rheb function may be a of of Ras transformation. to sequences to from a of T. of the to of of and that contain the sequences for the or Rheb protein sequence K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar), with flanking sequences that to into of the The of the sequence by into of the for from the or the mammalian for of protein farnesyltransferase protein from the B. Cell. Full Text PDF PubMed Scopus (641) Google Scholar, M. W. Cell. 1990; Full Text PDF PubMed Scopus Google Scholar). sequence into the to encode a mutagenesis to generate mutant or mutated sequences were to NIH 3T3 were in with and were by that we have G.J. Cox A.D. S.M. Der C.J. 1995; PubMed Scopus Google Scholar). formation were by NIH 3T3 in with oncogenic by and a of The of To the of introduced wild type or mutant Rheb protein the growth of NIH 3T3 with wild type or mutant Rheb proteins were by of in growth with were to cell with and were for in vitro growth or in G.J. Cox A.D. S.M. Der C.J. 1995; PubMed Scopus Google Scholar). were by were to Rheb can activate or block oncogenic Ras stimulation of from the R. J.K. Solski P.A. M. L. M.H. Der C.J. Mol. Cell. Biol. 1996; 16: PubMed Scopus Google Scholar). of NIH 3T3 were with the where is by and the Rheb Ras the were and for as R. J.K. Solski P.A. M. L. M.H. Der C.J. Mol. Cell. Biol. 1996; 16: PubMed Scopus Google Scholar). To generate we Rheb sequences that are distinct from the sequences of sequences of Ras, and Ras-related proteins K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). to sequences to the Rheb amino acid residues into the for of the protein into by a with Rheb to and the were for of Rheb protein To Rheb to activated human were with Raf-1 and activated Ras of J. in and by proteins Ras, KRev-1, and Rheb sequences were with and with of the Raf-1 cell in for The proteins were and The proteins were to with and by and activated Ras protein were as J. Rapp U.R. Cell 1996; Google Scholar). and proteins were with to the with of and were and and for their ability to protein as G.J. Drugan J.K. Terrell R.S. Der C.J. Bell R.M. Campbell-Burk S. Proc. Natl. Acad. Sci. U. S. A. 1995; Scopus Google Scholar). in R. Der C.J. 1995; PubMed Scopus Google Scholar), of and proteins were to of with or and with or the of the that can farnesyltransferase in is for farnesyltransferase and can of not KRev-1, in A. J. Cox A.D. Der C.J. A.D. S.M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). in NIH 3T3 wild type Ras or Rheb were with of for The were into and as A.D. Solski P.A. Der C.J. 1995; PubMed Scopus Google Scholar), by and for to or protein were for and with in and with in To the of the and to the for The were in and with for were a and were Rheb strong sequence with the Ras effector domain To Rheb function cell we mutant Rheb proteins with mutations to those that Ras and Ras-related proteins into constitutively active or proteins. Rheb(64L) a that is to the that Ras proteins constitutively active and transforming (1Clark G.J. Der C.J. Dickey B.F. Birnbaumer L. GTPases in Biology I. Springer-Verlag, Berlin1993: 259-288Google Scholar), a that is to the that in dominant negative of Ras and Ras-related proteins (28Graham S.M. Vojtek A.B. Huff S.Y. Cox A.D. Clark G.J. Cooper J.A. Der C.J. Mol. Cell. Biol. 1996; 16: 6132-6140Crossref PubMed Scopus (54) Google Scholar, L.A. Cooper Mol. Cell. Biol. 8: PubMed Scopus Google Scholar, A.J. Paterson H.F. D. Hall A. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, K. J.C. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). To the of Rheb protein the growth properties of NIH 3T3 in we NIH 3T3 with that wild type or mutant Rheb proteins. To that may we of of for these cell the introduced Rheb a that the amino acid sequence of Rheb Consistent with the of this of Rheb with Ras-related proteins A. P. A. 1991; PubMed Scopus Google Scholar), this did not the KRev-1, or TC21/R-Ras2 proteins not protein in the that Rheb is in NIH 3T3 The a to of protein this whereas a in the cells. is the is introduced into Ras and Ras-related proteins. with did not nor forms of is similar to with mutant versions of Ras and Ras-related where is that with the wild type protein S.Y. Quilliam L.A. Cox A.D. Der C.J. Oncogene. 1997; 14: 133-143Crossref PubMed Scopus (43) Google Scholar, L.A. Cooper Mol. Cell. Biol. 8: PubMed Scopus Google Scholar). may be to a of the protein to the fact that of this mutant is not by NIH 3T3 cells. and G.J. Cox A.D. S.M. Der C.J. 1995; PubMed Scopus Google have that constitutively activated of Ras cause and growth transformation of NIH 3T3 cells. In we that with wild type or mutant sequences showed that were from that of NIH 3T3 not in to with NIH 3T3 L.A. Cooper Mol. Cell. Biol. 8: PubMed Scopus Google Scholar), significant in the of for not the growth of NIH 3T3 were by of introduced in the growth of wild type or cell were from those by the cells. Furthermore, whereas NIH 3T3 in growth with not G.J. Cox A.D. S.M. Der C.J. 1995; PubMed Scopus Google Scholar), all three showed a for growth with we their ability to in and to be negative not Thus, in to Ras, aberrant wild type or mutant Rheb function did not cause growth or of NIH 3T3 cells. Since Rheb the growth promoting with constitutively activated of Ras, TC21, or we Rheb similar to and, Ras function H. T. M. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar, H. T. M. Proc. Natl. Acad. Sci. U. S. A. 1990; PubMed Scopus Google Scholar). these we the constitutively activated mutant as a control for these formation H. T. M. Proc. Natl. Acad. Sci. U. S. A. 1990; PubMed Scopus Google Scholar). the of of of or Rheb(64L) a in oncogenic In with did not cause a significant in Ras transformation since neither with or in the ability of Rheb to the ability of oncogenic Ras to from a this we a where is by a activated Ras from this with with wild type or mutant Rheb. of a of oncogenic of or Rheb(64L) a in oncogenic activation Rheb oncogenic Ras activation of have to contain all the cellular to mediate oncogenic Ras activation of in vitro A.J. M. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar). Therefore, we the ability of Rheb to this the of Ras protein with the activation of as by the ability to protein G.J. Drugan J.K. Terrell R.S. Der C.J. Bell R.M. Campbell-Burk S. Proc. Natl. Acad. Sci. U. S. A. 1995; Scopus Google Scholar). of Rheb(64L) or with a of a in Ras activation of with the ability of Rheb to block Ras transformation and that Rheb shares the Ras as Rheb shares sequence identity with the core Ras effector domain, the of Rheb to activate from the or in that Rheb fails to activate Ras important for Ras function. Instead, the ability of Rheb to Ras may be a of Rheb formation of with Ras as can not Raf-1 J. Kyriakis Marshall M.S. Bruder J.T. Rapp U.R. Avruch J. Nature. 1993; PubMed Scopus Google Scholar). To this we the ability of proteins activated Rheb(64L) or to Raf-1 in and not with Raf-1 in vitro Thus, like KRev-1, Rheb may Ras function by with key Ras effector proteins as Ras and KRev-1, Rheb terminates with a K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Since the of the amino acid the sequence for for is or or for is or A.D. Der C.J. Cell Biol. 1992; PubMed Scopus Google Scholar), we that Rheb may be To the of Rheb we a Rheb protein R. Der C.J. 1995; PubMed Scopus Google Scholar). and proteins were as for and respectively. with the for the and and that are the for the for protein all three proteins showed of and Rheb showed significant of In Furthermore, of to and Rheb in the Thus, like Ras, Rheb is by in To Rheb farnesylated in we Rheb be in with In to be in the whereas of Rheb were in the and of with and Rheb to to the that Rheb is farnesylated in vivo and that this Rheb Ras proteins are associated with the of the A.D. Der C.J. Cell Biol. 1992; PubMed Scopus Google Scholar), to and F. B. A. J. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar, H. McCormick F. Cancer Res. 1994; Google Scholar). To compare the of Rheb with Ras and KRev-1, we NIH 3T3 that versions of wild type and analyses were the In with we that showed In Ras and Rheb showed a with of in Thus, the of Rheb is similar to that of as a that and by in the in the by stimulation of 3T3 and by growth and growth stimulation of K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). Since Rheb protein amino acid identity with and Ras it that Rheb may important in signaling pathways in and cells. To Rheb we of Rheb that mutations to those that in constitutively activated or dominant negative of Ras and Ras-related proteins. In to Ras, we that aberrant Rheb did not cause or growth transformation of NIH 3T3 cells. Instead, we that Rheb inhibited oncogenic Ras signaling and transformation. Thus, Rheb the similar to that with the growth promoting of However, like Ras, we that Rheb by the and that inhibited by Rheb sequence with and human and K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). In Rheb strong sequence identity with residues that the core effector domain of Ras (Ras residues 32–40) and K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google and protein not by growth promoting we that Rheb may the growth promoting associated with Ras proteins. However, NIH 3T3 with wild type Rheb or mutant Rheb did not the or growth growth in or in transformation that is with constitutively activated of Furthermore, a dominant negative mutant of to the dominant negative did not the potent growth of NIH 3T3 that is by L.A. Cooper Mol. Cell. Biol. 8: PubMed Scopus Google Scholar). Thus, Rheb not to influence the growth properties of However, Rheb is a of growth or differentiation of as a to be growth in not NIH M. T. T. A. Mol. Cell. Biol. 1992; PubMed Scopus Google Scholar). Instead, we that wild type and a constitutively activated mutant of Rheb showed the ability to oncogenic Ras stimulation of from activation of in and formation in NIH 3T3 transformation Thus, like KRev-1, Rheb may function as a negative of Ras function. The ability of wild type and Rheb(64L) to Ras function is not since Rheb and residues to Ras residues and residues and Ras and proteins contain residues and Ras proteins constitutively active and transforming (1Clark G.J. Der C.J. Dickey B.F. Birnbaumer L. GTPases in Biology I. Springer-Verlag, Berlin1993: 259-288Google Scholar). Thus, wild type Rheb may as a constitutively active protein and the may not have significant in Rheb In the mutant of is likely to render the protein constitutively L.A. Cooper Mol. Cell. Biol. 8: PubMed Scopus Google Scholar), the ability to Thus, we that the of Rheb is for The strong sequence identity the core Ras effector domain and the region of Rheb possible for Rheb of oncogenic Ras function. Since the Ras effector domain is critical for Ras of and (21Marshall M.S. Trends Biochem. Sci. 1993; 18: 250-254Abstract Full Text PDF PubMed Scopus (194) Google Scholar), Rheb may with Ras and, consequently, oncogenic Ras signaling and function. for this is by like KRev-1, Rheb can with Raf-1 in vitro and that Rheb inhibited oncogenic Ras activation of is a Furthermore, Rheb inhibited Ras stimulation of from the that Rheb can with Raf-1 in Rheb can with Ras as M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, A. Chen Mol. Cell. Biol. 1994; 14: PubMed Scopus Google Scholar, F. S. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google or kinase P. R. B. I. M.D. J. Nature. 1994; PubMed Scopus Google Scholar), be to However, it possible that Rheb may with and mediate signaling activities that the transforming of oncogenic Ras and the of to Ras transformation. Since Rheb antagonized oncogenic Ras transforming yet showed growth in it that Rheb not is similar to that with KRev-1, did not of NIH 3T3 H. T. M. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar). the dominant protein to oncogenic Ras function L.A. Gibbs J.B. Mol. Cell. Biol. 1991; PubMed Scopus Google Scholar). Thus, the of KRev-1, and are to for Ras important for these may not be critical for Ras function. their may be and cause a not of oncogenic Ras function to that are to cause transformation. for this is by that oncogenic Ras transformation of is a of Science. 1993; 260: PubMed Scopus Google Scholar). Ras transformation is not Furthermore, it is of Ras function is the of KRev-1, since of were to Ras transformation H. T. M. Cell. 1989; Full Text PDF PubMed Scopus Google Scholar). function for in Dickey B.F. Birnbaumer L. GTPases in Biology I. Springer-Verlag, Scholar). Therefore, while we have that Rheb can Ras this is the for this Ras-related protein or it a distinct from Ras to be of effector may important for Rheb function. of transformation can that are not to impair J. and A. Rev. in Scholar, C.J. Cox A.D. S.M. A.D. 1996; Scholar). Since is that may by a in the of M.S. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google A.D. S.M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), it that of transformation may as a of farnesylated proteins. key of target are that it by can be inhibited that transforming and that the function of this protein Ras transforming that Rheb is is sensitive to and can Ras transforming it as a possible target for of Ras transformation. that Rheb be a protein K. Sanders W. D. P.F. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar), in it not be a for to in of However, we have a of human by and Rheb to be in with in the and not Therefore, the of Rheb in vivo is with a in the to of a of To a for Rheb in it be to a of a the ability of to transforming In studies that Rheb function is distinct from Ras proteins and is similar to in NIH 3T3 cells. However, it possible that Rheb may growth or differentiation promoting in cell Thus, while studies that Rheb can function like like Ras in Rheb function in cell may to the of Rheb. since Rheb is the of in Rheb function of the of Rheb in cell Cox for critical and for and for of the and