The Switch I Region of Rheb Is Critical for Its Interaction with FKBP38

The Ras-like small GTPase Rheb is an upstream activator of the mammalian target of rapamycin (mTOR). It has recently been shown that Rheb activates mTOR by binding to its endogenous inhibitor FKBP38 and preventing it from association with mTOR. The interaction of Rheb with FKBP38 is controlled by its guanine nucleotide binding states, which are responsive to growth factor and amino acid conditions. In this study, we show that Rheb interacts with FKBP38 through a section within its switch I region that is equivalent to the effector domain of other Ras-like small GTPases. We find that the ability for Rheb to interact with FKBP38 correlates with its activity for mTOR activation. Our findings suggest that FKBP38 is a bona fide effector of Rheb and that the ability to interact with FKBP38 is important for Rheb as an activator of mTOR. The Ras-like small GTPase Rheb is an upstream activator of the mammalian target of rapamycin (mTOR). It has recently been shown that Rheb activates mTOR by binding to its endogenous inhibitor FKBP38 and preventing it from association with mTOR. The interaction of Rheb with FKBP38 is controlled by its guanine nucleotide binding states, which are responsive to growth factor and amino acid conditions. In this study, we show that Rheb interacts with FKBP38 through a section within its switch I region that is equivalent to the effector domain of other Ras-like small GTPases. We find that the ability for Rheb to interact with FKBP38 correlates with its activity for mTOR activation. Our findings suggest that FKBP38 is a bona fide effector of Rheb and that the ability to interact with FKBP38 is important for Rheb as an activator of mTOR. Rheb is a Ras-related small GTPase that functions as an upstream activator of the mammalian target of rapamycin (mTOR) 2The abbreviations used are: mTORmammalian target of rapamycinS6KS6 kinaseFKBPFK506-binding proteinCaMcalmodulinTMtransmembraneTPRtetratricopeptide repeatPBSphosphate-buffered salineGSTglutathione S-transferase. 2The abbreviations used are: mTORmammalian target of rapamycinS6KS6 kinaseFKBPFK506-binding proteinCaMcalmodulinTMtransmembraneTPRtetratricopeptide repeatPBSphosphate-buffered salineGSTglutathione S-transferase. (1Li Y. Corradetti M.N. Inoki K. Guan K.L. Trends Biochem. Sci. 2004; 29: 32-38Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 2Manning B.D. Cantley L.C. Trends Biochem. Sci. 2003; 28: 573-576Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). Like other members of the Ras superfamily of small GTPases, the activity of Rheb is regulated by its guanine nucleotide binding states. It is active upon GTP bound but becomes inactive following hydrolysis of the bound GTP to GDP (3Aspuria P.J. Tamanoi F. Cell. Signal. 2004; 16: 1105-1112Crossref PubMed Scopus (164) Google Scholar). The nucleotide binding states of Rheb are controlled mainly by the TSC1-TSC2 complex, which acts as a GTPase-activating protein that stimulates GTP hydrolysis of Rheb and prevents its activation (4Garami A. Zwartkruis F.J. Nobukuni T. Joaquin M. Roccio M. Stocker H. Kozma S.C. Hafen E. Bos J.L. Thomas G. Mol. Cell. 2003; 11: 1457-1466Abstract Full Text Full Text PDF PubMed Scopus (825) Google Scholar, 5Zhang Y. Gao X. Saucedo L.J. Ru B. Edgar B.A. Pan D. Nat. Cell Biol. 2003; 5: 578-581Crossref PubMed Scopus (703) Google Scholar, 6Saucedo L.J. Gao X. Chiarelli D.A. Li L. Pan D. Edgar B.A. Nat. Cell Biol. 2003; 5: 566-571Crossref PubMed Scopus (524) Google Scholar, 7Stocker H. Radimerski T. Schindelholz B. Wittwer F. Belawat P. Daram P. Breuer S. Thomas G. Hafen E. Nat. Cell Biol. 2003; 5: 559-565Crossref PubMed Scopus (423) Google Scholar). A complex signaling network converges both growth factor and energy signals to the TSC1-TSC2 complex, altering its GTPase-activating protein activity and consequently the guanine nucleotide binding states of Rheb (8Avruch J. Hara K. Lin Y. Liu M. Long X. Ortiz-Vega S. Yonezawa K. Oncogene. 2006; 25: 6361-6372Crossref PubMed Scopus (253) Google Scholar). Changes in amino acid conditions also regulate Rheb activity through mechanisms independent of the TSC1-TSC2 complex (9Long X. Ortiz-Vega S. Lin Y. Avruch J. J. Biol. Chem. 2005; 280: 23433-23436Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 10Nobukuni T. Joaquin M. Roccio M. Dann S.G. Kim S.Y. Gulati P. Byfield M.P. Backer J.M. Natt F. Bos J.L. Zwartkruis F.J. Thomas G. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 14238-14243Crossref PubMed Scopus (608) Google Scholar). In response to those diverse signals, Rheb cycles between active GTP-bound and inactive GDP-bound states, acting as a molecular switch to control mTOR activity (8Avruch J. Hara K. Lin Y. Liu M. Long X. Ortiz-Vega S. Yonezawa K. Oncogene. 2006; 25: 6361-6372Crossref PubMed Scopus (253) Google Scholar). mammalian target of rapamycin S6 kinase FK506-binding protein calmodulin transmembrane tetratricopeptide repeat phosphate-buffered saline glutathione S-transferase. mammalian target of rapamycin S6 kinase FK506-binding protein calmodulin transmembrane tetratricopeptide repeat phosphate-buffered saline glutathione S-transferase. How Rheb activates mTOR has been a key focus of current studies in mTOR signaling. mTOR elicits its rapamycin-sensitive function in the context of a multiple protein complex termed the mTOR complex 1 (mTORC1). Upon activation, mTORC1 promotes protein synthesis by phosphorylating S6 kinase (S6K) at position Thr389 and 4E-BP1 at positions Thr37/Thr46, two factors involved in translation initiation (11Martin D.E. Hall M.N. Curr. Opin. Cell Biol. 2005; 17: 158-166Crossref PubMed Scopus (437) Google Scholar). It has been recently shown that Rheb activates mTORC1 by antagonizing its endogenous inhibitor, FKBP38 (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar, 13Proud C.G. Science. 2007; 318: 926-927Crossref PubMed Scopus (35) Google Scholar). Under growth factor deprivation or amino acid starvation condition, FKBP38 binds directly to mTOR and down-regulates mTORC1 activity. When amino acids and growth factors are present, Rheb interacts with FKBP38 and releases mTORC1 for activation. The interaction of Rheb with FKBP38 is guanine nucleotide-dependent. It binds strongly to FKBP38 in GTP-bound form and weakly in GDP bound form. This GTP-dependent binding suggests that FKBP38 is an effector of Rheb in the mTOR pathway, which represents the first known effector of Rheb that is regulated by guanine nucleotide (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). FKBP38, also known as FKBP8, belongs to the peptidyl prolyl cis/trans-isomerase family of FK506-binding protein (FKBP) (14Harrar Y. Bellini C. Faure J.D. Trends Plant Sci. 2001; 6: 426-431Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). It contains a domain, referred to as FKBP-C, that is highly similar to FKBP12, the receptor for the immunosuppressive drug rapamycin (15Fischer G. Tradler T. Zarnt T. FEBS Lett. 1998; 426: 17-20Crossref PubMed Scopus (103) Google Scholar). It has been shown previously that the FKBP-C domain in FKBP38 is sufficient for its interaction with mTOR. Although the binding of FKBP12 to mTOR requires rapamycin, the binding of the FKBP-C domain of FKBP38 with mTOR is independent of the drug (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). In addition to the FKBP-C domain, FKBP38 also contains several other distinct domains, including a tetratricopeptide repeat (TPR) domain, a Ca2+/calmodulin (CaM) binding domain, and a transmembrane domain (TM) (16Maestre-Martinez M. Edlich F. Jarczowski F. Weiwad M. Fischer G. Lucke C. J. Biomol. NMR. 2006; 34: 197-202Crossref PubMed Scopus (31) Google Scholar, 17Nielsen J.V. Mitchelmore C. Pedersen K.M. Kjaerulff K.M. Finsen B. Jensen N.A. Genomics. 2004; 83: 181-192Crossref PubMed Scopus (24) Google Scholar, 18Pedersen K.M. Finsen B. Celis J.E. Jensen N.A. Electrophoresis. 1999; 20: 249-255Crossref PubMed Scopus (34) Google Scholar, 19Wang H.Q. Nakaya Y. Du Z. Yamane T. Shirane M. Kudo T. Takeda M. Takebayashi K. Noda Y. Nakayama K.I. Nishimura M. Hum. Mol. Genet. 2005; 14: 1889-1902Crossref PubMed Scopus (76) Google Scholar). The TM domain of FKBP38 is unique among all of the members of the FKBP protein family and is essential for targeting this protein to mitochondria, where it functions (20Shirane M. Nakayama K.I. Nat. Cell Biol. 2003; 5: 28-37Crossref PubMed Scopus (249) Google Scholar). The identification of FKBP38 as a target of Rheb allows us to examine how Rheb, a unique member of the Ras superfamily, relays its signaling activity downstream. It is well established that Ras, in GTP-bound form, interacts with its effectors through a section located in the switch I region of the protein. This section, commonly referred to as the effector domain, is critical for the signaling activity of Ras (21Marshall C.J. Curr. Opin. Cell Biol. 1996; 8: 197-204Crossref PubMed Scopus (470) Google Scholar, 22Wittinghofer A. Nassar N. Trends Biochem. Sci. 1996; 21: 488-491Abstract Full Text PDF PubMed Scopus (137) Google Scholar). Since the switch I region in Rheb is highly similar to that in Ras, it is possible that Rheb signals to its effector in the mTOR pathway through a mechanism similar to that of Ras. In this study, we investigated the role of the switch I region in Rheb for its interaction with FKBP38 and its ability to activate mTORC1. Reagents and Plasmids—Antibodies against Rheb, S6K, phospho-S6K (Thr389), 4E-BP1, and phospho-4E-BP1 (Thr37/Thr46) were purchased from Cell Signaling Inc. Anti-HA (12CA5) and c-Myc (9E10) antibodies were purchased from Roche Applied Science, and anti-FLAG M2 antibody was from Sigma. The pCMV-Myc-FKBP38 vector was constructed by PCR amplifying FKBP38 from pcDNA3–2×HA-FKBP38 (14Harrar Y. Bellini C. Faure J.D. Trends Plant Sci. 2001; 6: 426-431Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar) and cloning into pCMV-tag3 vector. The sources for pRK7-HA-S6K1 and Rheb constructs were described before (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). The FKBP52 gene was amplified by PCR from the FKBP52 cDNA clone (ID 3542330) obtained from OpenBiosystems and cloned into pcDNA3.1-Myc vector to create pcDNA3.1-Myc-FKBP52. pcDNA3.1-Myc-FKBP52TM was created by inserting the sequence for the transmembrane domain of FKBP38 at the 3′-end of FKBP52. Generation of Rheb and FKBP38 Mutants—Plasmids encoding all mutant versions of Rheb were generated by site-directed mutagenesis using QuikChange kit from Stratagene. The wild type Rheb in pcDNA-FLAG-Rheb vector was used as the template (6Saucedo L.J. Gao X. Chiarelli D.A. Li L. Pan D. Edgar B.A. Nat. Cell Biol. 2003; 5: 566-571Crossref PubMed Scopus (524) Google Scholar). Primers were designed to contain the desired mutations, and the mutagenesis was performed following the manufacturer's instruction. Deletion mutants of FKBP38 were generated by PCR from wild type FKBP38 construct with suitable primers and cloned into pcDNA3.1-Myc vector to create Myc-tagged truncated FKBP38 expression vectors. All mutations were verified by sequencing. Cell Culture and Transfection—HEK293 and HeLa cells were maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum from PAA Laboratories (Ontario, Canada). For amino acid starvation and repletion, HEK293 cells were incubated in Dulbecco's modified Eagle's medium free of amino acids for 1 h, amino acid stock mixture (50× the standard concentration) from Sigma was added to the culture to a final concentration of 1×. Cells were harvested and lysed after a 30-min incubation. For serum deprivation and restimulation, cells were shifted to Dulbecco's modified Eagle's medium containing 0.2% of fetal bovine serum for 16 h. Fetal bovine serum was then added back to the medium to a final concentration of 20%. Cells were harvested and lysed upon incubation for another 30 min. DNA transfection was performed using Lipofectamine™ 2000 following the manufacturer's instructions (Invitrogen). Coimmunoprecipitation—HEK293 cells were co-transfected with vectors expressing FKBP38 and Rheb. After incubation in Dulbecco's modified Eagle's medium for 30 h, transfected cells were washed with cold PBS on ice and lysed in buffer containing 50 mm Tris-HCl (pH 7.4), 150 mm NaCl, 1 mm EDTA, 1% Triton X-100, 1 mm phenylmethylsulfonyl fluoride, and 1× protease inhibitor mixture (Roche Applied Science). Lysates (0.5 mg) were incubated with anti-Myc antibody (9E10)-linked Protein A-agarose beads for 3 h at 4 °C with agitation. Beads were washed four times with lysis buffer and once with 20 mm Tris-Cl, pH 7.4. Washed beads were resuspended in 60 μl of 2× SDS sample buffer and boiled for 5 min. Samples were subjected to SDS-PAGE followed by Western cells on were with for 20 and with in PBS for min. cells were by with Triton in PBS for and with bovine serum in PBS for 30 min. Cells were then incubated at 4 °C with antibody followed by with Cells were washed and with and by All of the in this were are shown in the We previously shown that Rheb interacts with FKBP38, which suggests a of both Since FKBP38 is mainly on (20Shirane M. Nakayama K.I. Nat. Cell Biol. 2003; 5: 28-37Crossref PubMed Scopus (249) Google it is that Rheb on the this we of the endogenous Rheb using shown in Rheb to to which were with that was by This that Rheb is mainly to the association of Rheb, we the from HEK293 cells by and the of Rheb with the shown in we that the of Rheb in the that was by the of with findings (20Shirane M. Nakayama K.I. Nat. Cell Biol. 2003; 5: 28-37Crossref PubMed Scopus (249) Google FKBP38 was in the A small of Rheb and FKBP38 in the that was in the and In mTOR was also to in the which is in with that mTOR with Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D. Shen T. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). findings that Rheb, FKBP38, and mTOR on an to how Rheb the binding of FKBP38 with we the in FKBP38 that its interaction with Rheb. Since FKBP38 contains several distinct we constructed mutant of the and in of the mutant the transmembrane The interaction of the mutant with Rheb was using an in binding shown in we that a mutant FKBP38 protein the FKBP-C domain was to interact with Rheb those for the domain the tetratricopeptide repeat domain or the first amino acids mutants containing the first amino acids or the FKBP-C domain were to interact with Rheb. findings suggest that Rheb interacts with FKBP38 by binding to its FKBP-C domain, the region that is highly similar to were obtained by using FKBP38 mutants in mammalian cells We investigated the role for of the unique in the function of FKBP38 as an mTORC1 we the of at an in cells that the mutants of In with the (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google of wild type FKBP38 the on 1 and In a mutant FKBP38 protein the FKBP-C domain was in of the with the that this domain is for interaction with mTOR (6Saucedo L.J. Gao X. Chiarelli D.A. Li L. Pan D. Edgar B.A. Nat. Cell Biol. 2003; 5: 566-571Crossref PubMed Scopus (524) Google Scholar). the transmembrane domain, including the of amino acids amino acids and amino acids also the mutants were to with this suggests that the is essential for the activity of In the region containing the amino acids to important for FKBP38 a mutant protein the region was of to with In mutants the domain of the activity that this domain is essential for the activity of Although a mutant for the domain a of the activity is in with that of the mutant the transmembrane domain 3 and were for mutant FKBP38 in the amino at Thr389 findings in FKBP38 are critical for its activity mTORC1. are the amino the FKBP-C domain, and the transmembrane In the family of FK506-binding another similar with FKBP38, including the FKBP-C domain, the domain, and the binding J. Biochem. Cell Biol. 2005; PubMed Scopus Google Scholar). We FKBP52 a similar activity mTORC1. shown in of FKBP38 amino or of at that of FKBP52 to The of on mTORC1 to by its to to a of the protein containing the transmembrane domain from FKBP38 of mTORC1 that the FKBP38 is a unique member in the family of the FK506-binding that the ability to mTORC1 in the of The that Rheb interacts with FKBP38 and its activity in a GTP-dependent suggests that FKBP38 is an effector of Rheb. a small GTPase that is to Ras, Rheb is to a similar mechanism to interact and activate its We the switch I region in Rheb is for its interaction with FKBP38 and the ability to interact with FKBP38 is essential for Rheb signaling to mTORC1. studies a mutations within the switch I region of Rheb that its ability to activate mTORC1 but that for nucleotide including and X. Lin Y. Ortiz-Vega S. Yonezawa K. Avruch J. Curr. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, J. C.G. FEBS Lett. 2005; PubMed Scopus Google Scholar). We first mutations the binding of Rheb with we Myc-tagged FKBP38 with Rheb mutants in HEK293 cells and interaction by shown in we that the interaction of Rheb with FKBP38 was by and mutations 4 and and by the A or of from position to the binding and We the ability of Rheb mutants to the of FKBP38 on mTORC1 signaling activity. with we that of FKBP38 amino of at Thr389 and of 4E-BP1 at a expression of wild type Rheb the of FKBP38 1 and Although and mutants activity for the in the of FKBP38 4 and the and mutants were of activity and the ability of Rheb to with FKBP38 correlates with its ability to mTORC1 signaling. was a which bound strongly to FKBP38 to the A and a containing and was to interact with FKBP38, that the binding of with FKBP38 requires the switch I region was as a in cells and it to amino acids or growth factor L. Tamanoi F. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). We previously shown that binds to and FKBP38 on mTOR in a that the binding between FKBP38 and mTOR is to amino acids or growth factor (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). This a that the of the endogenous Rheb from its binding and this we the ability of to with FKBP38 its shown in we that the at Thr389 was to amino acid in cells 3 and it responsive in cells the mutant and which was of FKBP38 binding This suggests that the of is by its The region in Rheb that to the effector domain of Ras contains including amino acids We the role for of in its interaction with FKBP38 by with shown in we that the at position or the ability of the mutant Rheb to interact with that at position the those at position or the We the ability of the mutants to activate mTORC1 signaling in the of amino We that the mutants with FKBP38 binding including those with at positions and were in the of and 4E-BP1 This suggests that the interaction with FKBP38 is important for Rheb to activate mTORC1. the we the ability of mutants in antagonizing FKBP38 activity. We that mutants were of the of FKBP38 on mTORC1 the ability of Rheb to interact with FKBP38 correlates with its activity for mTORC1 studies shown that Rheb is in cells on that to the that Rheb with C. B. Biochem. 2006; PubMed Scopus Google Scholar, K. M. S.G. S. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). of Rheb that the of Rheb is with that the protein is with the and are a it is possible that of the were The association of Rheb is also with the that Rheb directly interacts with FKBP38, which has been shown previously to a protein (20Shirane M. Nakayama K.I. Nat. Cell Biol. 2003; 5: 28-37Crossref PubMed Scopus (249) Google Scholar, G. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). The target of FKBP38, has been shown to to including and Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, D. Shen T. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, X. L. H. P.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biochem. PubMed Scopus Google Scholar, Liu X. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J.E. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Our that at a of mTOR is to mitochondria, where Rheb and FKBP38 This is by findings that mTOR with of Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). that are the of Rheb, and FKBP38 on is with the role of mTORC1 in and The FKBP-C domain of FKBP38 sequence with FKBP12 (16Maestre-Martinez M. Edlich F. Jarczowski F. Weiwad M. Fischer G. Lucke C. J. Biomol. NMR. 2006; 34: 197-202Crossref PubMed Scopus (31) Google Scholar). We previously shown that the FKBP-C domain in FKBP38 but FKBP12 is to interact with mTOR in the of rapamycin (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). with this we show in this that the FKBP-C domain of FKBP38 is essential for its activity mTORC1 signaling activity. the FKBP-C domain to sufficient for mTORC1 Deletion mutants of FKBP38 the transmembrane domain or the amino acids are in mTORC1 that are also important for FKBP38 Since the transmembrane domain is for targeting FKBP38 to (20Shirane M. Nakayama K.I. Nat. Cell Biol. 2003; 5: 28-37Crossref PubMed Scopus (249) Google the of this domain for FKBP38 function that association is important for FKBP38 the other the region containing the amino acids of FKBP38 is for its association with or for its interaction with Rheb and mTOR (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). role in FKBP38 function requires the FKBP-C domain of FKBP38 also its binding with Rheb the that Rheb with mTOR for FKBP38 the that the mutant of Rheb is to with FKBP38 mTOR from it suggests that the of FKBP38 with Rheb and mTOR are (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). It is that Rheb and mTOR to of the FKBP-C domain in a that Rheb is to FKBP38 and consequently its association with mTOR. of the of the and on the for the Upon GTP small of Ras family interact with effectors through the effector domain within the switch I region of the the effector domain of a small GTPase a critical role in its activity to effectors J.L. PubMed Scopus Google Scholar). studies a mutations within the switch I including and that the ability of Rheb to mTORC1 activity X. Lin Y. Ortiz-Vega S. Yonezawa K. Avruch J. Curr. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In the study, we find that mutations in Rheb its interaction with a between the ability to interact with FKBP38 and the ability to mTORC1 which is with the that Rheb activates mTORC1 by FKBP38 from mTOR (12Bai X. Ma D. Liu A. Shen X. Wang Q.J. Liu Y. Jiang Y. Science. 2007; 318: 977-980Crossref PubMed Scopus (304) Google Scholar). Our also two other in the effector domain that are important for the interaction of Rheb with FKBP38, including and at positions the ability of Rheb to interact with FKBP38 and to mTORC1. suggest that the interaction with FKBP38 is critical for Rheb to activate a that FKBP38 is a key factor that Rheb activity to mTORC1. the that Rheb interacts with FKBP38 through its effector domain in a GTP-dependent suggests that the signaling mechanism of Rheb is similar to that of other members of the Ras We Wang and members of the Jiang for with

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