Tuberous sclerosis is caused by mutations to either the TSC1 or TSC2 tumor suppressor gene. The disease is characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction, and dermatological abnormalities. TSC1 encodes a 130-kDa protein called hamartin, and TSC2 encodes a 200-kDa protein called tuberin. Although it has been shown that hamartin and tuberin form a complex and mediate phosphoinositide 3-kinase/Akt-dependent phosphorylation of the ribosomal protein S6, it is not yet clear how inactivation of either protein leads to tuberous sclerosis. Therefore, to obtain additional insight into tuberin and hamartin function, yeast two-hybrid screening experiments were performed to identify proteins that interact with tuberin. One of the proteins identified was 14-3-3ζ, a member of the 14-3-3 protein family. The interaction between tuberin and 14-3-3ζ was confirmed in vitro and by co-immunoprecipitation; multiple sites within tuberin for 14-3-3ζ binding were identified; and it was determined that 14-3-3ζ associated with the tuberin-hamartin complex. Finally, it was shown that the tuberin/14-3-3ζ interaction is regulated by Akt-mediated phosphorylation of tuberin, providing insight into how tuberin may regulate phosphorylation of S6. Tuberous sclerosis is caused by mutations to either the TSC1 or TSC2 tumor suppressor gene. The disease is characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction, and dermatological abnormalities. TSC1 encodes a 130-kDa protein called hamartin, and TSC2 encodes a 200-kDa protein called tuberin. Although it has been shown that hamartin and tuberin form a complex and mediate phosphoinositide 3-kinase/Akt-dependent phosphorylation of the ribosomal protein S6, it is not yet clear how inactivation of either protein leads to tuberous sclerosis. Therefore, to obtain additional insight into tuberin and hamartin function, yeast two-hybrid screening experiments were performed to identify proteins that interact with tuberin. One of the proteins identified was 14-3-3ζ, a member of the 14-3-3 protein family. The interaction between tuberin and 14-3-3ζ was confirmed in vitro and by co-immunoprecipitation; multiple sites within tuberin for 14-3-3ζ binding were identified; and it was determined that 14-3-3ζ associated with the tuberin-hamartin complex. Finally, it was shown that the tuberin/14-3-3ζ interaction is regulated by Akt-mediated phosphorylation of tuberin, providing insight into how tuberin may regulate phosphorylation of S6. tuberous sclerosis glutathione S-transferase fragile X mental retardation protein In humans, germ-line mutations to the TSC1 andTSC2 tumor suppressor genes cause the autosomal dominant disease tuberous sclerosis (TSC)1 (1The European Chromosome 16 Tuberous Sclerosis Consortium Cell. 1993; 75: 1305-1315Abstract Full Text PDF PubMed Scopus (1515) Google Scholar, 2van Slegtenhorst M. de Hoogt R. Hermans C. Nellist M. Janssen B. Verhoef S. Lindhout D. van den Ouweland A. Halley D. Young J. et al.Science. 1997; 277: 805-808Crossref PubMed Scopus (1404) Google Scholar). TheTSC1 gene encodes hamartin, a novel 130-kDa protein, whereasTSC2 encodes a 200-kDa protein called tuberin. Tuberin and hamartin interact to form a protein complex, and it has been suggested that inactivation of this complex leads to TSC (3van Slegtenhorst M. Nellist M. Nagelkerken B. Cheadle J. Snell R. van den Ouweland A. Reuser A. Sampson J. Halley D. van der Sluijs P. Hum. Mol. Genet. 1998; 7: 1053-1057Crossref PubMed Scopus (494) Google Scholar). Indeed, pathogenic tuberin amino acid substitutions interfere with tuberin-hamartin complex formation (4Aicher L.D. Campbell J.S. Yeung R.S. J. Biol. Chem. 2001; 276: 21017-21021Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 5Nellist M. Verhaaf B. Goedbloed M.A. Reuser A.J.J. van den Ouweland A.M.W. Halley D.J.J. Hum. Mol. Genet. 2001; 10: 2889-2898Crossref PubMed Scopus (88) Google Scholar). TSC is characterized by a variety of hamartomatous growths in different organs and tissues. The defects in cell proliferation, migration, and differentiation that these lesions display indicate that theTSC1 and TSC2 gene products participate in the control of cell growth and division (6). Overexpression of either tuberin or hamartin lengthens G1 and inhibits cell proliferation, whereas G1 is shortened and tissues become hypertrophic when either gene is inactivated (7Jin F. Wienecke R. Xiao G.H. Maize J.C. DeClue J.E. Yeung R.S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9154-9159Crossref PubMed Scopus (119) Google Scholar, 8Soucek T. Pusch O. Wienecke R. DeClue J.E. Hengstschlager M. J. Biol. Chem. 1997; 272: 29301-29308Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 9Soucek T. Yeung R.S. Hengstchlager M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15653-15658Crossref PubMed Scopus (156) Google Scholar, 10Miloloza A. Rosner M. Nellist M. Halley D. Bernaschek G. Hengstschlager M. Hum. Mol. Genet. 2000; 9: 1721-1727Crossref PubMed Scopus (112) Google Scholar, 11Tapon N. Ito N. Dickson B.J. Treisman J.E. Hariharan I.K. Cell. 2001; 105: 345-355Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar, 12Potter C.J. Huanh H. Xu T. Cell. 2001; 105: 357-368Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar). Genetic studies in Drosophila provided the first evidence that tuberin and hamartin are involved in the phosphoinositide 3-kinase/protein kinase B (Akt) signal transduction pathway (11Tapon N. Ito N. Dickson B.J. Treisman J.E. Hariharan I.K. Cell. 2001; 105: 345-355Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar, 12Potter C.J. Huanh H. Xu T. Cell. 2001; 105: 357-368Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 13Gao X. Pan D. Genes Dev. 2001; 15: 1383-1392Crossref PubMed Scopus (390) Google Scholar). More recently, it was shown that Akt interacts with and phosphorylates tuberin (14Manning 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 (1286) Google Scholar, 15Potter C.J. Pedraza L.G. Xu T. Nat. Cell. Biol. 2002; 4: 658-665Crossref PubMed Scopus (781) Google Scholar) and that tuberin and hamartin regulate p70 S6 kinase activity and ribosomal protein S6 phosphorylation (16Kwiatkowski D.J. Zhang H. Bandura J.L. Heiberger K.M. Glogauer M. el-Hashemite N. Onda H. Hum. Mol. Genet. 2002; 11: 525-534Crossref PubMed Scopus (540) Google Scholar, 17Goncharova E.A. Goncharov D.A. Eszterhas A. Hunter D.S. Glassberg M.K. Yeung R.S. Walker C.L. Noonan D. Kwiatkowski D.J. Chou M.M. Panettieri Jr., R.A. Krymskaya V.P. J. Biol. Chem. 2002; 277: 30958-30967Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). However, despite these exciting findings, it is not yet clear exactly how phosphoinositide 3-kinase/Akt signaling defects lead to the wide variety of lesions associated with TSC. Previous work indicated that tuberin and hamartin interact within a large cytoplasmic complex, possibly containing other protein components (18Nellist M. van Slegtenhorst M.A. Goedbloed M. van den Ouweland A.M.W. Halley D.J.J. van der Sluijs P. J. Biol. Chem. 1999; 274: 35647-35652Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). To identify the components of this complex and thereby obtain new clues toward the functions of tuberin and hamartin, yeast two-hybrid screening experiments were performed. An interaction between tuberin and 14-3-3ζ was identified. 14-3-3ζ belongs to a family of abundant 28–33-kDa acidic polypeptides (19Tzivion G. Avruch J. J. Biol. Chem. 2002; 277: 3061-3064Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). 14-3-3 proteins are broadly expressed and conserved in a wide range of eukaryotes. At least seven different isoforms have been identified in mammalian cells, and 14-3-3 proteins have also been shown to be essential for both budding and fission yeast viability (20Gelperin D. Weigle J. Nelson K. Roseboom P. Irie K. Matsumoto K. Lemmon S. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 11539-11543Crossref PubMed Scopus (147) Google Scholar). 14-3-3 proteins have been implicated in cell cycle control (21Ford J.C. al Khodairy F. Fotou E. Sheldrick K.S. Griffiths D.J. Carr A.M. Science. 1994; 265: 533-535Crossref PubMed Scopus (301) Google Scholar) and shown to interact with a wide range of signaling proteins (22Yaffe M.B. FEBS Lett. 2002; 513: 53-57Crossref PubMed Scopus (557) Google Scholar). Many of these interactions are mediated through the binding of the 14-3-3 protein to two specific phosphoserine-containing sequences, RSXpSXP and RXXXpSXP, in the target protein (23Muslin A.J. Tanner J.W. Allen P.M. Shaw A.S. Cell. 1996; 84: 889-897Abstract Full Text Full Text PDF PubMed Scopus (1195) Google Scholar). The involvement of 14-3-3ζ in phosphorylation-dependent regulation of signal transduction pathways made it an interesting candidate for a tuberin binding partner, and the interaction between tuberin and 14-3-3ζ was investigated in more detail. The interaction between tuberin and 14-3-3ζ conformed to the pattern of binding of 14-3-3ζ to many other target proteins, and the interaction was shown to be representative of the binding between tuberin and the 14-3-3 protein family in general. The tuberin/14-3-3ζ interaction was shown to be dependent on Akt-mediated phosphorylation of tuberin, and evidence for multiple putative 14-3-3ζ-binding sites in tuberin was obtained. The full-length TSC1 andTSC2 expression constructs have been described previously (3van Slegtenhorst M. Nellist M. Nagelkerken B. Cheadle J. Snell R. van den Ouweland A. Reuser A. Sampson J. Halley D. van der Sluijs P. Hum. Mol. Genet. 1998; 7: 1053-1057Crossref PubMed Scopus (494) Google Scholar). Truncated TSC2 expression constructs encoding tuberin amino acids 1–607 (NruI truncation), 1–1099 (XmaI truncation), 1–252 plus 1536–1784 and and the TSC2 and expression constructs have also been described M. Verhaaf B. Goedbloed M.A. Reuser A.J.J. van den Ouweland A.M.W. Halley D.J.J. Hum. Mol. Genet. 2001; 10: 2889-2898Crossref PubMed Scopus (88) Google Scholar). The TSC2 expression was by of the TSC2 expression the the yeast two-hybrid screening the full-length TSC2 was into the of the was called The two full-length TSC2 constructs for the yeast two-hybrid experiments and were by of the the a full-length 14-3-3ζ identified in the yeast two-hybrid screening was a into the sites of the and mammalian expression of a protein, the full-length 14-3-3ζ was an the expression into the of the constructs were encoding proteins of the and isoforms of 14-3-3 were provided by J. of and the binding was provided by M. van and J. of The expression constructs encoding and Akt isoforms were yeast two-hybrid a tuberin protein was performed on a into the the of the that on were by a The of the were by to the and and the constructs were the yeast by the into by and The constructs were the To that the interactions were the were also a (3van Slegtenhorst M. Nellist M. Nagelkerken B. Cheadle J. Snell R. van den Ouweland A. Reuser A. Sampson J. Halley D. van der Sluijs P. Hum. Mol. Genet. 1998; 7: 1053-1057Crossref PubMed Scopus (494) Google a a and two tuberin constructs and experiments were performed described previously (3van Slegtenhorst M. Nellist M. Nagelkerken B. Cheadle J. Snell R. van den Ouweland A. Reuser A. Sampson J. Halley D. van der Sluijs P. Hum. Mol. Genet. 1998; 7: 1053-1057Crossref PubMed Scopus (494) Google Scholar, M. van Slegtenhorst M.A. Goedbloed M. van den Ouweland A.M.W. Halley D.J.J. van der Sluijs P. J. Biol. Chem. 1999; 274: 35647-35652Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). were in containing and were into and to a of constructs were into the by the the were and in and described previously (18Nellist M. van Slegtenhorst M.A. Goedbloed M. van den Ouweland A.M.W. Halley D.J.J. van der Sluijs P. J. Biol. Chem. 1999; 274: 35647-35652Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). were in protein and for on and the was by for and were to the was for a the was for protein and in the of different and the binding protein expression was for in a of E. by the of The was in of containing and and was to a of for the was for The protein in the was to of for The were with to proteins, and the and of the protein to the were by or cell were to of the and by for The were by with and in to was in of containing and for for the was and with specific for 14-3-3ζ on for the of of protein for the were with of by The and in this have been described previously (3van Slegtenhorst M. Nellist M. Nagelkerken B. Cheadle J. Snell R. van den Ouweland A. Reuser A. Sampson J. Halley D. van der Sluijs P. Hum. Mol. Genet. 1998; 7: 1053-1057Crossref PubMed Scopus (494) Google Scholar). The was provided by F. The and the was provided by E. van were and and the two-hybrid screening experiments were performed on the a encoding full-length tuberin. the that on were in a and were and full-length The interactions between the full-length 14-3-3ζ and the tuberin were in the yeast two-hybrid shown in the interaction between 14-3-3ζ and tuberin was and interaction between 14-3-3ζ and either a encoding the binding or a encoding a of the binding with the hamartin (3van Slegtenhorst M. Nellist M. Nagelkerken B. Cheadle J. Snell R. van den Ouweland A. Reuser A. Sampson J. Halley D. van der Sluijs P. Hum. Mol. Genet. 1998; 7: 1053-1057Crossref PubMed Scopus (494) Google Scholar) was the interaction between 14-3-3ζ and two different tuberin and was the and amino acid substitutions Previous work has that the inhibits tuberin phosphorylation and the interaction between tuberin and hamartin, whereas the not M. Verhaaf B. Goedbloed M.A. Reuser A.J.J. van den Ouweland A.M.W. Halley D.J.J. Hum. Mol. Genet. 2001; 10: 2889-2898Crossref PubMed Scopus (88) Google Scholar). shown in activity was when the constructs tuberin and the tuberin were with either or hamartin amino acids In activity was not when the was The the yeast two-hybrid experiments were with the on the interaction between hamartin and different tuberin M. Verhaaf B. Goedbloed M.A. Reuser A.J.J. van den Ouweland A.M.W. Halley D.J.J. Hum. Mol. Genet. 2001; 10: 2889-2898Crossref PubMed Scopus (88) Google Scholar) and indicated that the tuberin/14-3-3ζ interaction was to pathogenic tuberin amino acid between tuberin and in the yeast two-hybrid binding binding in a new To that the interaction between tuberin and 14-3-3ζ was were with a TSC2 expression the were and the was with a expressed protein to Tuberin by the was by shown in tuberin to the not to containing or containing protein binding B. J.L. J. 1997; PubMed Scopus Google Scholar). The binding between tuberin and the was with the binding of the tuberin and were with expression constructs encoding the different tuberin and the were with the described tuberin was also shown in the was by the tuberin and the and with the the yeast two-hybrid To the tuberin/14-3-3ζ interaction the interaction between tuberin and hamartin, tuberin, hamartin, or both proteins were with the shown in hamartin was by the when tuberin was either that the tuberin-hamartin complex was to interact with the or that hamartin interact with In cells, tuberin hamartin in the (18Nellist M. van Slegtenhorst M.A. Goedbloed M. van den Ouweland A.M.W. Halley D.J.J. van der Sluijs P. J. Biol. Chem. 1999; 274: 35647-35652Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Therefore, when a cell hamartin was in the binding the was was not by the it was not in the cell of hamartin by the in the of tuberin indicated that the interaction between tuberin and 14-3-3ζ was with the interaction between tuberin and of tuberin and hamartin was in a binding shown in both tuberin and hamartin were by the whereas a control protein was The of the tuberin-hamartin complex in the was by the of tuberin in the hamartin In the of the for tuberin and hamartin were in the In the tuberin signal in the was more the hamartin that a of the tuberin in the cell was associated with The hamartin signal in the is with the binding both tuberin and the tuberin-hamartin complex. To the interaction between tuberin and 14-3-3ζ in experiments were performed on of to tuberin and 14-3-3ζ were However, shown in tuberin was by specific for 14-3-3ζ, that tuberin and 14-3-3ζ in with the of the binding hamartin was also in the whereas was not by the protein that is to interact with 14-3-3ζ M. K. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google was also in the To tuberin interacts with 14-3-3ζ or also with additional of the 14-3-3 protein a cell was with containing proteins of the and isoforms of 14-3-3 J. H. M. R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). shown in both tuberin and hamartin were by of the 14-3-3 isoforms that tuberin interacts with a to the 14-3-3 protein family. between tuberin and the different 14-3-3 isoforms suggested that tuberin may a binding by 14-3-3 Indeed, the 14-3-3 protein family many target proteins through two specific phosphoserine-containing RSXpSXP and RXXXpSXP, is amino acid (23Muslin A.J. Tanner J.W. Allen P.M. Shaw A.S. Cell. 1996; 84: 889-897Abstract Full Text Full Text PDF PubMed Scopus (1195) Google Scholar). in of the amino acid of tuberin identified M.B. J. T. S. Cantley L.C. Nat. 2001; PubMed Scopus Google Scholar) acids acids acids acids acids acids acids and acids of a putative with to not tuberin binding to the with the that tuberin multiple The binding was with expression constructs encoding different of tuberin. shown in of the tuberin proteins containing a putative were by the To phosphorylation of tuberin the is for the tuberin/14-3-3ζ the of activity on the binding was cell were with protein with the The of these experiments are shown in for either with or the of protein tuberin was by the of tuberin be was in the of tuberin in the shown in the tuberin-hamartin complex was not by the The of tuberin/14-3-3ζ binding was with of tuberin by protein or binding to the were with of and not The binding was in the of the and PubMed Scopus Google Scholar). shown in of tuberin and hamartin by the was by the of either or to the cell with tuberin/14-3-3ζ binding dependent on tuberin the of the on binding were also shown in of the tuberin-hamartin complex was not by the of either or that the tuberin/14-3-3ζ interaction is more to tuberin with the The of tuberin binding to the However, of the the indicated that possibly to glutathione not PubMed Scopus Google Scholar). The tuberin-hamartin complex was also by the of was to the cell tuberin and hamartin not be by specific for either tuberin or However, of either protein was by the of indicated that a specific on the interaction between tuberin and hamartin, the interactions between the two proteins and studies have identified tuberin a target of Akt-mediated phosphorylation (14Manning 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 (1286) Google Scholar, 15Potter C.J. Pedraza L.G. Xu T. Nat. Cell. Biol. 2002; 4: 658-665Crossref PubMed Scopus (781) Google Scholar). To the interaction between tuberin and 14-3-3ζ is by Akt were with expression constructs encoding different tuberin and and or a Akt the cell were with the described shown in tuberin were expressed of the Akt the of tuberin and the on whereas the of the was is with studies that the tuberin is M. Verhaaf B. Goedbloed M.A. Reuser A.J.J. van den Ouweland A.M.W. Halley D.J.J. Hum. Mol. Genet. 2001; 10: 2889-2898Crossref PubMed Scopus (88) Google Scholar). the binding of tuberin and the to the was more the binding of the However, of Akt activity by expression of the Akt the binding of tuberin in to the to the binding when either Akt or the was Therefore, Akt activity tuberin/14-3-3ζ that the interaction is dependent Akt-mediated phosphorylation of tuberin. TSC is caused by the inactivation of either tuberin or that tuberin and hamartin are involved in the phosphoinositide 3-kinase/Akt signal transduction pathway (11Tapon N. Ito N. Dickson B.J. Treisman J.E. Hariharan I.K. Cell. 2001; 105: 345-355Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar, 12Potter C.J. Huanh H. Xu T. Cell. 2001; 105: 357-368Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar, 13Gao X. Pan D. Genes Dev. 2001; 15: 1383-1392Crossref PubMed Scopus (390) Google Scholar, 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 (1286) Google Scholar, 15Potter C.J. Pedraza L.G. Xu T. Nat. Cell. Biol. 2002; 4: 658-665Crossref PubMed Scopus (781) Google Scholar, D.J. Zhang H. Bandura J.L. Heiberger K.M. Glogauer M. el-Hashemite N. Onda H. Hum. Mol. Genet. 2002; 11: 525-534Crossref PubMed Scopus (540) Google Scholar, 17Goncharova E.A. Goncharov D.A. Eszterhas A. Hunter D.S. Glassberg M.K. Yeung R.S. Walker C.L. Noonan D. Kwiatkowski D.J. Chou M.M. Panettieri Jr., R.A. Krymskaya V.P. J. Biol. Chem. 2002; 277: 30958-30967Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar) and that defects in phosphoinositide 3-kinase/Akt signaling are for least of the lesions associated with TSC. Tuberin is by Akt (14Manning 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 (1286) Google and in either tuberin or hamartin, S6, of the of phosphoinositide 3-kinase/Akt is (16Kwiatkowski D.J. Zhang H. Bandura J.L. Heiberger K.M. Glogauer M. el-Hashemite N. Onda H. Hum. Mol. Genet. 2002; 11: 525-534Crossref PubMed Scopus (540) Google Scholar, 17Goncharova E.A. Goncharov D.A. Eszterhas A. Hunter D.S. Glassberg M.K. Yeung R.S. Walker C.L. Noonan D. Kwiatkowski D.J. Chou M.M. Panettieri Jr., R.A. Krymskaya V.P. J. Biol. Chem. 2002; 277: 30958-30967Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). has been suggested that the tuberin-hamartin complex may different p70 S6 kinase activity and the between the phosphoinositide 3-kinase/Akt signal and regulation of the p70 S6 kinase (14Manning 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 (1286) Google Scholar). However, it is not clear how the tuberin-hamartin complex One is that phosphorylation of p70 S6 kinase (14Manning 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 (1286) Google Scholar). To obtain additional insight into tuberin and hamartin function, the yeast two-hybrid was to identify proteins that interact with tuberin and thereby regulate the functions of tuberin, hamartin, and the tuberin-hamartin complex. One of the proteins identified was 14-3-3ζ, a member of the 14-3-3 protein family. 14-3-3 proteins the functions of many different proteins and an in multiple cell involved in signal 14-3-3 proteins regulate protein control protein target proteins for or and to different proteins (19Tzivion G. Avruch J. J. Biol. Chem. 2002; 277: 3061-3064Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, M.B. FEBS Lett. 2002; 513: 53-57Crossref PubMed Scopus (557) Google Scholar). Therefore, 14-3-3ζ was a candidate for a of tuberin in the phosphoinositide 3-kinase/Akt signaling The interaction between 14-3-3ζ and tuberin identified in the yeast two-hybrid was confirmed by in vitro binding experiments and by The binding experiments indicated that tuberin is to interact with multiple 14-3-3 isoforms and that tuberin multiple with of in the tuberin amino acid The of multiple sites in tuberin is with the that the tuberin-hamartin complex may different (14Manning 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 (1286) Google Scholar). In many target protein phosphorylation the binding between 14-3-3 proteins and (19Tzivion G. Avruch J. J. Biol. Chem. 2002; 277: 3061-3064Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, M.B. FEBS Lett. 2002; 513: 53-57Crossref PubMed Scopus (557) Google Scholar). of evidence that 14-3-3ζ interacts with isoforms of tuberin. Tuberin is to be multiple amino acid (4Aicher L.D. Campbell J.S. Yeung R.S. J. Biol. Chem. 2001; 276: 21017-21021Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 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 (1286) Google and in this a tuberin that is not not interact with In the and tuberin/14-3-3ζ whereas a of Akt tuberin/14-3-3ζ The interaction between tuberin and 14-3-3ζ phosphorylation of tuberin may the of p70 S6 kinase The Akt is to the RSXpSXP and Indeed, putative Akt in tuberin and that are also At least of these sites has been shown to be a for phosphorylation of tuberin (14Manning 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 (1286) Google Scholar). Therefore, phosphorylation of tuberin by for 14-3-3ζ may to and the of p70 S6 14-3-3ζ may this of in of 14-3-3ζ binding may tuberin or target tuberin for (19Tzivion G. Avruch J. J. Biol. Chem. 2002; 277: 3061-3064Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). 14-3-3ζ may the interactions between tuberin and other binding or of tuberin to tuberin and p70 S6 Indeed, phosphorylation-dependent of tuberin to the has been D. N. Noonan D.J. Mol. Cell. Biol. 2001; 4: PubMed Scopus Google Scholar). the binding and the experiments indicated that the interaction between tuberin and 14-3-3ζ was with However, a interaction between hamartin and 14-3-3ζ not be by either the binding or the of the hamartin amino acid identified two acids and acids However, with hamartin by the of the tuberin-hamartin complex, interaction between hamartin and 14-3-3ζ was in the yeast two-hybrid In to the interaction between tuberin and 14-3-3ζ, of the tuberin-hamartin complex was not by the of and that the of tuberin/14-3-3ζ binding is that of of tuberin and hamartin was by the of either protein, that the tuberin-hamartin complex. The may binding by with PubMed Scopus Google that the interaction may be by the phosphorylation of or both proteins, with C.J. Pedraza L.G. Xu T. Nat. Cell. Biol. 2002; 4: 658-665Crossref PubMed Scopus (781) Google Scholar). 14-3-3ζ not interact with a pathogenic tuberin containing a in either the yeast two-hybrid or the binding The also inhibits formation of the tuberin-hamartin complex and tuberin phosphorylation M. Verhaaf B. Goedbloed M.A. Reuser A.J.J. van den Ouweland A.M.W. Halley D.J.J. Hum. Mol. Genet. 2001; 10: 2889-2898Crossref PubMed Scopus (88) Google Scholar). Therefore, the tuberin/14-3-3ζ and interactions to be a amino acid is to both is that the may cause a that both tuberin/14-3-3ζ and binding the interactions with Akt and possibly other phosphorylation of the may both the tuberin/14-3-3ζ and more of the mutations on tuberin is in In an interaction between tuberin and 14-3-3ζ was the yeast two-hybrid and confirmed in vitro and by The interaction between 14-3-3ζ and tuberin was by the of activity and by Akt-mediated phosphorylation of tuberin, providing a between tuberin/14-3-3ζ binding and a for tuberin in the phosphoinositide 3-kinase/Akt signaling N. for and J. J. M. van F. and E. van for providing in this
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