6bcu

Structural highlights

Function

[4EBP1_HUMAN] Regulates eIF4E activity by preventing its assembly into the eIF4F complex. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.^[1] [RPTOR_HUMAN] Involved in the control of the mammalian target of rapamycin complex 1 (mTORC1) activity which regulates cell growth and survival, and autophagy in response to nutrient and hormonal signals; functions as a scaffold for recruiting mTORC1 substrates. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Involved in ciliogenesis.^{[2] [3] [4]} [LST8_HUMAN] Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'.^{[5] [6]} [RHEB_HUMAN] Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Activates the protein kinase activity of mTORC1. Has low intrinsic GTPase activity.^{[7] [8] [9] [10] [11] [12]}

See Also

• Raptor

References

1. ↑ Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature. 1994 Oct 27;371(6500):762-7. PMID:7935836 doi:http://dx.doi.org/10.1038/371762a0
2. ↑ Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002 Jul 26;110(2):163-75. PMID:12150925
3. ↑ Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002 Jul 26;110(2):177-89. PMID:12150926
4. ↑ Cardenas-Rodriguez M, Irigoin F, Osborn DP, Gascue C, Katsanis N, Beales PL, Badano JL. The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex. Hum Mol Genet. 2013 Oct 15;22(20):4031-42. doi: 10.1093/hmg/ddt253. Epub 2013 May, 31. PMID:23727834 doi:http://dx.doi.org/10.1093/hmg/ddt253
5. ↑ Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003 Apr;11(4):895-904. PMID:12718876
6. ↑ Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004 Nov;6(11):1122-8. Epub 2004 Oct 3. PMID:15467718 doi:10.1038/ncb1183
7. ↑ Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13571-6. Epub 2002 Sep 23. PMID:12271141 doi:10.1073/pnas.202476899
8. ↑ Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003 Aug 1;17(15):1829-34. Epub 2003 Jul 17. PMID:12869586 doi:10.1101/gad.1110003
9. ↑ Li Y, Inoki K, Guan KL. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol. 2004 Sep;24(18):7965-75. PMID:15340059 doi:10.1128/MCB.24.18.7965-7975.2004
10. ↑ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005 Apr 26;15(8):702-13. PMID:15854902 doi:S0960-9822(05)00226-5
11. ↑ Tee AR, Blenis J, Proud CG. Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS Lett. 2005 Aug 29;579(21):4763-8. PMID:16098514 doi:10.1016/j.febslet.2005.07.054
12. ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
13. ↑ Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, Dhar A, Pavletich NP. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 2017 Dec 13. pii: nature25023. doi: 10.1038/nature25023. PMID:29236692 doi:http://dx.doi.org/10.1038/nature25023