Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning

Journal of Cell Biology

Volumn 173, Issue 2, 2006, Pages 279-289

  Cai, Sheng Li ^a   Tee, Andrew R ^b   Short, John D ^a   Bergeron, Judith M ^a   Kim, Jinhee ^a   Shen, Jianjun ^a   Guo, Ruifeng ^a   Johnson, Charles L ^a   Kiguchi, Kaoru ^a   Walker, Cheryl Lyn ^a  

^a UNIVERSITY OF TEXAS   (United States)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; HAMARTIN; MAMMALIAN TARGET OF RAPAMYCIN; PROTEIN; PROTEIN KINASE B; RHEB PROTEIN; TUBERIN; TUMOR SUPPRESSOR PROTEIN; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ARTICLE; CELL MEMBRANE; CONTROLLED STUDY; CYTOSOL; EMBRYO; ENZYME ACTIVITY; FEMALE; HUMAN; HUMAN CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION;

CELL LINE; CELL MEMBRANE; GROWTH SUBSTANCES; HELA CELLS; HUMANS; MICROSCOPY, CONFOCAL; MODELS, BIOLOGICAL; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS C-AKT; RAS PROTEINS; TUMOR SUPPRESSOR PROTEINS;

MAMMALIA;

EID: 33646111903     PISSN: 00219525     EISSN: 00219525     Source Type: Journal    
DOI: 10.1083/jcb.200507119     Document Type: Article

References (48)

1. Alessi, D.R., F.B. Caudwell, M. Andjelkovic, B.A. Hemmings, and P. Cohen. 1996. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 399:333-338.
2. Ballif, B.A., P.P. Roux, S.A. Gerber, J.P. MacKeigan, J. Blenis, and S.P. Gygi. 2005. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc. Natl. Acad. Sci. USA. 102:667-672.
3. Bjornsti, M.A., and P.J. Houghton. 2004. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer. 4:335-348.
4. Cheadle, J.P., M.P. Reeve, J.R. Sampson, and D.J. Kwiatkowski. 2000. Molecular genetic advances in tuberous sclerosis. Hum. Genet. 107:97-114.
5. Clark, G.J., M.S. Kinch, K. Rogers-Graham, S.M. Sebti, A.D. Hamilton, and C.J. Der. 1997. The Ras-related protein Rheb is farnesylated and antagonizes Ras signaling and transformation. J. Biol. Chem. 272:10608-10615.
6. Dan, H.C., M. Sun, L. Yang, R.I. Feldman, X.M. Sui, C.C. Ou, M. Nellist, R.S. Yeung, D.J. Halley, S.V. Nicosia, et al. 2002. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277:35364-35370.
7. DeGraffenried, L.A., W.E. Friedrichs, L. Fulcher, G. Fernandes, J.M. Silva, J.M. Peralba, and M. Hidalgo. 2003. Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity. Ann. Oncol. 14:1051-1056.
8. The European Chromosome 16 Tuberous Sclerosis Consortium. 1993. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 75:1305-1315.
9. Garami, A., F.J. Zwartkruis, T. Nobukuni, M. Joaquin, M. Roccio, H. Stocker, S.C. Kozma, E. Hafen, J.L. Bos, and G. Thomas. 2003. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell. 11:1457-1466.
10. Gomez, M.R., J.R. Sampson, and V.H. Whittemore. 1999. Tuberous sclerosis complex. In Developmental Perspectives in Psychiatry. J.C. Harris, editor. Oxford University Press, Oxford, UK. 10-23, 275-312.
11. Hengstschlager, M., D.M. Rodman, A. Miloloza, E. Hengstschlager-Ottnad, M. Rosner, and M. Kubista. 2001. Tuberous sclerosis gene products in proliferation control. Mutat. Res. 488:233-239.
12. Hermeking, H. 2003. The 14-3-3 cancer connection. Nat. Rev. Cancer. 3:931-943.
13. Hodges, A.K., S. Li, J. Maynard, L. Parry, R. Braverman, J.P. Cheadle, J.E. DeClue, and J.R. Sampson. 2001. Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin. Hum. Mol. Genet. 10:2899-2905.
14. Inoki, K., Y. Li, T. Zhu, J. Wu, and K.L. Guan. 2002. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4:648-657.
15. Inoki, K., M.N. Corradetti, and K.L. Guan. 2005. Dysregulation of the TSC-mTOR pathway in human disease. Nat. Genet. 37:19-24.
16. Jin, J., F.D. Smith, C. Stark, C.D. Wells, J.P. Fawcett, S. Kulkarni, P. Metalnikov, P. O'Donnell, P. Taylor, L. Taylor, et al. 2004. Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr. Biol. 14:1436-1450.
17. Li, Y., K. Inoki, R. Yeung, and K.L. Guan. 2002. Regulation of TSC2 by 14-3-3 binding. J. Biol. Chem. 277:44593-44596.
18. Li, Y., K. Inoki, P. Vacratsis, and K.L. Guan. 2003. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. J. Biol. Chem. 278:13663-13671.
19. Li, Y., M.N. Corradetti, K. Inoki, and K.L. Guan. 2004a. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem. Sci. 29:32-38.
20. Li, Y., K. Inoki, and K.L. Guan. 2004b. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol. Cell. Biol. 24:7965-7975.
21. Liu, M.Y., S. Cai, A. Espejo, M.T. Bedford, and C.L. Walker. 2002. 14-3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s). Cancer Res. 62:6475-6480.
22. Lou, D., N. Griffith, and D.J. Noonan. 2001. The tuberous sclerosis 2 gene product can localize to nuclei in a phosphorylation-dependent manner. Mol. Cell Biol. Res. Commun. 4:374-380.
23. Manning, B.D., and L.C. Cantley. 2003. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Trans. 31:573-578.
24. Manning, B.D., A.R. Tee, M.N. Logsdon, J. Blenis, and L.C. Cantley. 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell. 10:151-162.
25. Martin, K.A., S.S. Schalm, C. Richardson, A. Romanelli, K.L. Keon, and J. Blenis. 2001. Regulation of ribosomal S6 kinase 2 by effectors of the phosphoinositide 3-kinase pathway. J. Biol. Chem. 276:7884-7891.
26. Marygold, S.J., and S.J. Leevers. 2002. Growth signaling: TSC takes its place. Curr. Biol. 12:R785-R787.
27. Muslin, A.J., and H. Xing. 2000. 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell. Signal. 12:703-709.
28. Nellist, M., M.A. van Slegtenhorst, M. Goedbloed, A.M. van den Ouweland, D.J. Halley, and P. van der Sluijs. 1999. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J. Biol. Chem. 274:35647-35652.
29. Nellist, M., M.A. Goedbloed, and D.J. Halley. 2003. Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins. Biochem. Soc. Trans. 31:587-591.
30. Obata, T., M.B. Yaffe, G.G. Leparc, E.T. Piro, H. Maegawa, A. Kashiwagi, R. Kikkawa, and L.C. Cantley. 2000. Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J. Biol. Chem. 275:36108-36115.
31. Pearson, R.B., P.B. Dennis, J.W. Han, N.A. Williamson, S.C. Kozma, R.E. Wettenhall, and G. Thomas. 1995. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. EMBO J. 14:5279-5287.
32. Plank, T.L., R.S. Yeung, and E.P. Henske. 1998. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res. 58:4766-4770.
33. Potter, C.J., L.G. Pedraza, and T. Xu. 2002. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4:658-665.
34. Roux, P.P., B.A. Ballif, R. Anjum, S.P. Gygi, and J. Blenis. 2004. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA. 101:13489-13494.
35. Takahashi, K., M. Nakagawa, S.G. Young, and S. Yamanaka. 2005. Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J. Biol. Chem. 280:32768-32774.
36. Tee, A.R., D.C. Fingar, B.D. Manning, D.J. Kwiatkowski, L.C. Cantley, and J. Blenis. 2002. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl. Acad. Sci. USA. 99:13571-13576.
37. Tee, A.R., B.D. Manning, P.P. Roux, L.C. Cantley, and J. Blenis. 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13:1259-1268.
38. Tee, A.R., J. Blenis, and C.G. Proud. 2005. Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS Lett. 579:4763-4768.
39. Tzivion, G., Y.H. Shen, and J. Zhu. 2001. 14-3-3 proteins; bringing new definitions to scaffolding. Oncogene. 20:6331-6338.
40. van Slegtenhorst, M., R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, J. Young, et al. 1997. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 277:805-808.
41. van Slegtenhorst, M., M. Nellist, B. Nagelkerken, J. Cheadle, R. Snell, A. van den Ouweland, A. Reuser, J. Sampson, D. Halley, and P. van der Sluijs. 1998. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet. 7:1053-1057.
42. Walker, C., and J. Ginsler. 1992. Development of a quantitative in vitro transformation assay for kidney epithelial cells. Carcinogenesis. 13:25-32.
43. Wienecke, R., A. Konig, and J.E. DeClue. 1995. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J. Biol. Chem. 270:16409-16414.
44. Yaffe, M.B. 2002. How do 14-3-3 proteins work? - Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett. 513:53-57.
45. Yaffe, M.B., and A.E. Elia. 2001. Phosphoserine/threonine-binding domains. Curr. Opin. Cell Biol. 13:131-138.
46. Yaffe, M.B., G.G. Leparc, J. Lai, T. Obata, S. Volinia, and L.C. Cantley. 2001. A motif-based profile scanning approach for genome-wide prediction of signaling pathways. Nat. Biotechnol. 19:348-353.
47. Young, J., and S. Povey. 1998. The genetic basis of tuberous sclerosis. Mol. Med. Today. 4:313-319.
48. Zhang, Y., X. Gao, L.J. Saucedo, B. Ru, B.A. Edgar, and D. Pan. 2003. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5:578-581.