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• W2085381292 abstract "TSC2, or tuberin, is the product of the tuberous sclerosis tumor suppressor gene TSC2 and acts downstream of the phosphatidylinositol 3-kinase-Akt signaling pathway to negatively regulate cellular growth. One mechanism underlying its function is to assemble into a heterodimer with the TSC1 gene product TSC1, or hamartin, resulting in a reduction in phosphorylation, and hence activation, of the ribosomal subunit S6 kinase (S6K). We identified a novel interaction between TSC2 and 14-3-3β. We found that 14-3-3β does not interfere with TSC1-TSC2 binding and can form a ternary complex with these two proteins. Association between 14-3-3β and TSC2 requires phosphorylation of TSC2 at a unique residue that is not a known Akt phosphorylation site. The overexpression of 14-3-3β compromises the ability of the TSC1-TSC2 complex to reduce S6K phosphorylation. The antagonistic activity of 14-3-3β toward TSC is dependent on the 14-3-3β-TSC2 interaction, since a mutant of TSC2 that is not recognized by 14-3-3β is refractory to 14-3-3β. We suggest that 14-3-3 proteins interact with the TSC1-TSC2 complex and negatively regulate the function of the TSC proteins. TSC2, or tuberin, is the product of the tuberous sclerosis tumor suppressor gene TSC2 and acts downstream of the phosphatidylinositol 3-kinase-Akt signaling pathway to negatively regulate cellular growth. One mechanism underlying its function is to assemble into a heterodimer with the TSC1 gene product TSC1, or hamartin, resulting in a reduction in phosphorylation, and hence activation, of the ribosomal subunit S6 kinase (S6K). We identified a novel interaction between TSC2 and 14-3-3β. We found that 14-3-3β does not interfere with TSC1-TSC2 binding and can form a ternary complex with these two proteins. Association between 14-3-3β and TSC2 requires phosphorylation of TSC2 at a unique residue that is not a known Akt phosphorylation site. The overexpression of 14-3-3β compromises the ability of the TSC1-TSC2 complex to reduce S6K phosphorylation. The antagonistic activity of 14-3-3β toward TSC is dependent on the 14-3-3β-TSC2 interaction, since a mutant of TSC2 that is not recognized by 14-3-3β is refractory to 14-3-3β. We suggest that 14-3-3 proteins interact with the TSC1-TSC2 complex and negatively regulate the function of the TSC proteins. tuberous sclerosis complex mammalian target of rapamcyin glutathione S-transferase hemagglutinin calf intestinal phosphatase subunit S6 kinase Tuberous sclerosis (TSC)1 is an inheritable disorder in which the brain, kidneys, skin, heart, and other organs may be affected by tumor-like growths, or hamartomas, that can result in seizures, mental retardation, and autism (1Gomez M. Sampson J. Whittemore V.H. Tuberous Sclerosis Complex. 3rd Ed. Oxford University Press, New York1999Google Scholar, 2Young J. Povey S. Mol. Med. Today. 1998; 4: 313-319Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). TSC affects roughly 1 in 6,000 newborns and is caused by mutations in either one of two genes. The TSC1 locus encodes a 130-kDa protein termed hamartin, or TSC1, and the TSC2 locus encodes a 180-kDa protein termed tuberin, or TSC2. Studies of hamartomas and tumors from TSC patients, as well as those of rodent models, support the categorization of both gene products as tumor suppressor proteins.The proteins TSC1 and TSC2 bind each other, and this association is compromised by many tumor-derived mutations found in either protein (3Hodges A.K., Li, S. Maynard J. Parry L. Braverman R. Cheadle J.P. DeClue J.E. Sampson J.R. Hum. Mol. Genet. 2001; 10: 2899-2905Crossref PubMed Scopus (99) Google Scholar). Studies in Drosophila melanogaster identified the TSC genes (dTSC1 and dTSC2) as important regulators of cell growth (4Gao X. Pan D. Genes Dev. 2001; 15: 1383-1392Crossref PubMed Scopus (387) Google Scholar, 5Tapon N. Ito N. Dickson B.J. Treisman J.E. Hariharan I.K. Cell. 2001; 105: 345-355Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 6Potter C.J. Huang H. Xu T. Cell. 2001; 105: 357-368Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar). Direct biochemical evidence linking the function of the TSC complex to cell growth control was recently provided by the finding that TSC1-TSC2 inhibits mTOR effectors and that phosphorylation of TSC2 by Akt suppresses TSC1-TSC2 activity (7Manning B.D. Tee A.R. Logsdon M.N. Blenis J. Cantley L.C. Mol. Cell. 2002; 10: 151-162Abstract Full Text Full Text PDF PubMed Scopus (1258) Google Scholar, 8Inoki K., Li, Y. Zhu T., Wu, J. Guan K.L. Nat. Cell Biol. 2002; 4: 648-657Crossref PubMed Scopus (2363) Google Scholar, 9Potter C.J. Pedraza L.G. Xu T. Nat. Cell Biol. 2002; 4: 658-665Crossref PubMed Scopus (771) Google Scholar, 10Gao X. Zhang Y. Arrazola P. Hino O. Kobayashi T. Yeung R.S., Ru, B. Pan D. Nat. Cell Biol. 2002; 4: 699-704Crossref PubMed Scopus (565) Google Scholar). In an effort to elucidate the function and regulation of TSC proteins, we searched for cellular protein(s) that interact with TSC2 and have identified 14-3-3 as a novel TSC2-interacting protein. We show that 14-3-3 selectively interacts with phosphorylated TSC2 and interferes with the function of TSC1-TSC2. Our findings identify a novel regulation of the TSC complex and provide further insight into the mechanisms that control TSC activity in cell signaling. Tuberous sclerosis (TSC)1 is an inheritable disorder in which the brain, kidneys, skin, heart, and other organs may be affected by tumor-like growths, or hamartomas, that can result in seizures, mental retardation, and autism (1Gomez M. Sampson J. Whittemore V.H. Tuberous Sclerosis Complex. 3rd Ed. Oxford University Press, New York1999Google Scholar, 2Young J. Povey S. Mol. Med. Today. 1998; 4: 313-319Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). TSC affects roughly 1 in 6,000 newborns and is caused by mutations in either one of two genes. The TSC1 locus encodes a 130-kDa protein termed hamartin, or TSC1, and the TSC2 locus encodes a 180-kDa protein termed tuberin, or TSC2. Studies of hamartomas and tumors from TSC patients, as well as those of rodent models, support the categorization of both gene products as tumor suppressor proteins. The proteins TSC1 and TSC2 bind each other, and this association is compromised by many tumor-derived mutations found in either protein (3Hodges A.K., Li, S. Maynard J. Parry L. Braverman R. Cheadle J.P. DeClue J.E. Sampson J.R. Hum. Mol. Genet. 2001; 10: 2899-2905Crossref PubMed Scopus (99) Google Scholar). Studies in Drosophila melanogaster identified the TSC genes (dTSC1 and dTSC2) as important regulators of cell growth (4Gao X. Pan D. Genes Dev. 2001; 15: 1383-1392Crossref PubMed Scopus (387) Google Scholar, 5Tapon N. Ito N. Dickson B.J. Treisman J.E. Hariharan I.K. Cell. 2001; 105: 345-355Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 6Potter C.J. Huang H. Xu T. Cell. 2001; 105: 357-368Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar). Direct biochemical evidence linking the function of the TSC complex to cell growth control was recently provided by the finding that TSC1-TSC2 inhibits mTOR effectors and that phosphorylation of TSC2 by Akt suppresses TSC1-TSC2 activity (7Manning B.D. Tee A.R. Logsdon M.N. Blenis J. Cantley L.C. Mol. Cell. 2002; 10: 151-162Abstract Full Text Full Text PDF PubMed Scopus (1258) Google Scholar, 8Inoki K., Li, Y. Zhu T., Wu, J. Guan K.L. Nat. Cell Biol. 2002; 4: 648-657Crossref PubMed Scopus (2363) Google Scholar, 9Potter C.J. Pedraza L.G. Xu T. Nat. Cell Biol. 2002; 4: 658-665Crossref PubMed Scopus (771) Google Scholar, 10Gao X. Zhang Y. Arrazola P. Hino O. Kobayashi T. Yeung R.S., Ru, B. Pan D. Nat. Cell Biol. 2002; 4: 699-704Crossref PubMed Scopus (565) Google Scholar). In an effort to elucidate the function and regulation of TSC proteins, we searched for cellular protein(s) that interact with TSC2 and have identified 14-3-3 as a novel TSC2-interacting protein. We show that 14-3-3 selectively interacts with phosphorylated TSC2 and interferes with the function of TSC1-TSC2. Our findings identify a novel regulation of the TSC complex and provide further insight into the mechanisms that control TSC activity in cell signaling. We are grateful to Kun-Liang Guan for generously providing TSC2 expression constructs and for the exchange of unpublished data. We thank Sima Zacharek for discussion and reading of the manuscript, Yizhou He for technical assistance, and other members of the Xiong laboratory for helpful criticisms." @default.
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• W2085381292 title "14-3-3β Binds to and Negatively Regulates the Tuberous Sclerosis Complex 2 (TSC2) Tumor Suppressor Gene Product, Tuberin" @default.
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