Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity

Molecular and Cellular Biology

Volumn 24, Issue 18, 2004, Pages 7965-7975

  Li, Yong ^a,b   Inoki, Ken ^a,b   Guan, Kun Liang ^a,b,c  

^a UNIVERSITY OF MICHIGAN   (United States)

^b UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF MICHIGAN HEALTH SYSTEM   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARGININE; ASPARAGINE; GUANOSINE TRIPHOSPHATASE; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; RAS PROTEIN; RHEB PROTEIN; S6 KINASE; TUBERIN; UNCLASSIFIED DRUG;

ARTICLE; CATALYSIS; CELL CULTURE; CELL FUNCTION; COMPLEX FORMATION; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME SUBSTRATE; GENE MUTATION; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; TSC1 GENE; TSC2 GENE; TUBEROUS SCLEROSIS; TUMOR SUPPRESSOR GENE;

BINDING SITES; CELL LINE; GTPASE-ACTIVATING PROTEINS; HUMANS; MONOMERIC GTP-BINDING PROTEINS; MUTAGENESIS, SITE-DIRECTED; MUTATION; NEUROPEPTIDES; PHOSPHORYLATION; PROTEIN ISOPRENYLATION; PROTEIN KINASES; PROTEINS; RECOMBINANT PROTEINS; REPRESSOR PROTEINS; RIBOSOMAL PROTEIN S6 KINASES; SIGNAL TRANSDUCTION; TUBEROUS SCLEROSIS; TUMOR SUPPRESSOR PROTEINS;

EID: 4444276510     PISSN: 02707306     EISSN: None     Source Type: Journal    
DOI: 10.1128/MCB.24.18.7965-7975.2004     Document Type: Article

References (59)

1. An, K. S., J. A. Rodriguez, J. L. Finch, K. A. Volcik, E. S. Roach, M. R. Delgado, E. Rodriguez, Jr., and H. Northrup. 1998. Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Am. J. Hum. Genet. 62:286-294.
2. Benvenuto, G., S. Li, S. J. Brown, R. Braverman, W. C. Vass, J. P. Cheadle, D. J. Halley, J. R. Sampson, R. Wienecke, and J. E. DeClue. 2000. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 19:6306-6316.
3. Bjornsti, M. A., and P. J. Houghton. 2004. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer 4:335-348.
4. Brinkmann, T., O. Daumke, U. Herbrand, D. Kuhlmann, P. Stege, M. R. Ahmadian, and A. Wittinghofer. 2002. Rap-specific GTPase activating protein follows an alternative mechanism. J. Biol. Chem. 277:12525-12531.
5. Brown, E. J., P. A. Beal, C. T. Keith, J. Chen, T. B. Shin, and S. L. Schreiber. 1995. Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature 377:441-446.
6. Brunn, G. J., C. C. Hudson, A. Sekulic, J. M. Williams, H. Hosoi, P. J. Houghton, J. C. Lawrence, Jr., and R. T. Abraham. 1997. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277:99-101.
7. Castro, A. F., J. F. Rebhun, G. G. Clark, and L. A. Quilliam. 2003. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem. 278:32493-32496.
8. 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.
9. Cherfils, J., and P. Chardin. 1999. GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem. Sci. 24:306-311.
10. 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.
11. Cox, A. D., and C. J. Der. 2002. Farnesyltransferase inhibitors: promises and realities. Curr. Opin. Pharmacol. 2:388-393.
12. Dabora, S. L., S. Jozwiak, D. N. Franz, P. S. Roberts, A. Nieto, J. Chung, Y. S. Choy, M. P. Reeve, E. Thiele, J. C. Egelhoff, J. Kasprzyk-Obara, D. Domanska-Pakiela, and D. J. Kwiatkowski. 2001. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am. J. Hum. Genet. 68:64-80.
13. Daumke, O., M. Weyand, P. P. Chakrabarti, I. R. Vetter, and A. Wittinghofer. 2004. The GTPase-activating protein Rap1GAP uses a catalytic asparagine. Nature 429:197-201.
14. Dennis, P. B., S. Fumagalli, and G. Thomas. 1999. Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Curr. Opin. Genet. Dev. 9:49-54.
15. Donovan, S., K. M. Shannon, and G. Bollag. 2002. GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602:23-45.
16. European Chromosome 16 Tuberous Sclerosis Consortium. 1993. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305-1315.
17. Fingar, D. C., and J. Blenis. 2004. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23:3151-3171.
18. Gao, X., Y. Zhang, P. Arrazola, O. Hino, T. Kobayashi, R. S. Yeung, B. Ru, and D. Pan. 2002. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol. 4:699-704.
19. 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.
20. Goncharova, E. A., D. A. Goncharov, A. Eszterhas, D. S. Hunter, M. K. Glassberg, R. S. Yeung, C. L. Walker, D. Noonan, D. J. Kwiatkowski, M. M. Chou, R. A. Panettieri, Jr., and V. P. Krymskaya. 2002. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J. Biol. Chem. 277:30958-30967.
21. Im, E., F. C. von Lintig, J. Chen, S. Zhuang, W. Qui, S. Chowdhury, P. F. Worley, G. R. Boss, and R. B. Pilz. 2002. Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 21:6356-6365.
22. Inoki, K., Y. Li, T. Xu, and K. L. Guan. 2003. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17:1829-1834.
23. 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.
24. Jacinto, E., and M. N. Hall. 2003. Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4:117-126.
25. Jones, A. C., M. M. Shyamsundar, M. W. Thomas, J. Maynard, S. Idziaszczyk, S. Tomkins, J. R. Sampson, and J. P. Cheadle. 1999. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 64:1305-1315.
26. Kenerson, H. L., L. D. Aicher, L. D. True, and R. S. Yeung. 2002. Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 62:5645-5650.
27. Krymskaya, V. P. 2003. Tumour suppressors hamartin and tuberin: intracellular signalling. Cell. Signal. 15:729-739.
28. Kwiatkowski, D. J. 2003. Tuberous sclerosis: from tubers to mTOR. Ann. Hum. Genet. 67:87-96.
29. Kwiatkowski, D. J., H. Zhang, J. L. Bandura, K. M. Heiberger, M. Glogauer, N. el-Hashemite, and H. Onda. 2002. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11:525-534.
30. Li, Y., M. N. Corradetti, K. Inoki, and K. L. Guan. 2004. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem. Sci. 29:32-38.
31. 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.
32. Mach, K. E., K. A. Furge, and C. F. Albright. 2000. Loss of Rhb1, a Rheb-related GTPase in fission yeast, causes growth arrest with a terminal phenotype similar to that caused by nitrogen starvation. Genetics 155:611-622.
33. Maheshwar, M. M., J. P. Cheadle, A. C. Jones, J. Myring, A. E. Fryer, P. C. Harris, and J. R. Sampson. 1997. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum. Mol. Genet. 6:1991-1996.
34. Maheshwar, M. M., R. Sandford, M. Nellist, J. P. Cheadle, B. Sgotto, M. Vaudin, and J. R. Sampson. 1996. Comparative analysis and genomic structure of the tuberous sclerosis 2 (TSC2) gene in human and pufferfish. Hum. Mol. Genet. 5:131-137.
35. Manning, B. D., and L. C. Cantley. 2003. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 28:573-576.
36. 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.
37. Maruta, H., J. Holden, A. Sizeland, and G. D'Abaco. 1991. The residues of Ras and Rap proteins that determine their GAP specificities. J. Biol. Chem. 266:11661-11668.
38. Marygold, S. J., and S. J. Leevers. 2002. Growth signaling: TSC takes its place. Curr. Biol. 12:R785-R787.
39. 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.
40. Onda, H., P. B. Crino, H. Zhang, R. D. Murphey, L. Rastelli, B. E. G. Rothberg, and D. J. Kwiatkowski. 2002. Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol. Cell. Neurosci. 21:561-574.
41. Patel, P. H., N. Thapar, L. Guo, M. Martinez, J. Maris, C. L. Gau, J. A. Lengyel, and F. Tamanoi. 2003. Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J. Cell Sci. 116:3601-3610.
42. 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.
43. Porfiri, E., T. Evans, P. Chardin, and J. F. Hancock. 1994. Prenylation of Ras proteins is required for efficient hSOS1-promoted guanine nucleotide exchange. J. Biol. Chem. 269:22672-22677.
44. Proud, C. G. 2002. Regulation of mammalian translation factors by nutrients. Eur. J. Biochem. 269:5338-5349.
45. Saucedo, L. J., X. Gao, D. A. Chiarelli, L. Li, D. Pan, and B. A. Edgar. 2003. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5:566-571.
46. Scheffzek, K., M. R. Ahmadian, W. Kabsch, L. Wiesmuller, A. Lautwein, F. Schmitz, and A. Wittinghofer. 1997. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:333-338.
47. Scheffzek, K., M. R. Ahmadian, and A. Wittinghofer. 1998. GTPase-activating proteins: helping hands to complement an active site. Trends Biochem. Sci. 23:257-262.
48. Seeburg, P. H., W. W. Colby, D. J. Capon, D. V. Goeddel, and A.D. Levinson. 1984. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312:71-75.
49. Stewart, S., and K. L. Guan. 2000. The dominant negative Ras mutant, N17Ras, can inhibit signaling independently of blocking Ras activation. J. Biol. Chem. 275:8854-8862.
50. Stocker, H., T. Radimerski, B. Schindelholz, F. Wittwer, P. Belawat, P. Daram, S. Breuer, G. Thomas, and E. Hafen. 2003. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5:559-565.
51. Tabancay, A. P., Jr., C. L. Gau, I. M. Machado, E. J. Uhlmann, D. H. Gutmann, L. Guo, and F. Tamanoi. 2003. Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J. Biol. Chem. 278:39921-39930.
52. 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.
53. 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.
54. Urano, J., C. Ellis, G. J. Clark, and F. Tamanoi. 2001. Characterization of Rheb functions using yeast and mammalian systems. Methods Enzymol. 333:217-231.
55. Yamagata, K., L. K. Sanders, W. E. Kaufmann, W. Yee, C. A. Barnes, D. Nathans, and P. F. Worley. 1994. rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J. Biol. Chem. 269:16333-16339.
56. Yang, W., A. P. Tabancay, Jr., J. Urano, and F. Tamanoi. 2001. Failure to farnesylate Rheb protein contributes to the enrichment of G0/G1 phase cells in the Schizosaccharomyces pombe farnesyltransferase mutant. Mol. Microbiol. 41:1339-1347.
57. Young, J., and S. Povey. 1998. The genetic basis of tuberous sclerosis. Mol. Med. Today 4:313-319.
58. Zhang, F. L., and P. J. Casey. 1996. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65:241-269.
59. 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.