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14-3-3 Proteins: Active Cofactors in Cellular Regulation by Serine/Threonine Phosphorylation

2002; Elsevier BV; Volume: 277; Issue: 5 Linguagem: Inglês

10.1074/jbc.r100059200

ISSN

1083-351X

Autores

Guri Tzivion, Joseph Avruch,

Tópico(s)

Microbial Natural Products and Biosynthesis

Resumo

protein kinase A protein kinase B protein kinase C insulin-like growth factor The 14-3-3 proteins are a family of abundant, widely expressed 28–33-kDa acidic polypeptides that spontaneously self-assemble as dimers. The 14-3-3 proteins were first detected by virtue of their relatively high abundance in brain extracts and given their unique name (an unfailing source of curiosity) based on their fraction number on DEAE-cellulose chromatography and migration position on starch gel electrophoresis (1Moore B.E. Perez V.J. Carlson F.D. Physiological and Biochemical Aspects of Nervous Integration. Prentice-Hall, Englewood Cliffs, NJ1967: 343-359Google Scholar). One or another 14-3-3 isoforms was repeatedly rediscovered in association with proteins of biologic interest; however, the functions of these polypeptides remained speculative until the demonstration by Shaw and colleagues (2Muslin A.J. Tanner J.W. Allen P.M. Shaw A.S. Cell. 1996; 84: 889-897Abstract Full Text Full Text PDF PubMed Scopus (1188) Google Scholar) that 14-3-3 proteins bind to phosphoserine-containing motifs in a sequence-specific manner. This insight enabled a systematic approach to understanding the functional roles of the 14-3-3 proteins and was followed by the demonstration that the 14-3-3 proteins participate in a wide range of biologic processes acting through a variety of regulatory mechanisms mediated mostly, and perhaps exclusively, through their binding to phosphoserine-containing sequence motifs in diverse partners (for review see Refs. 3Aitken A. Jones D. Soneji Y. Howell S. Biochem. Soc. Trans. 1995; 23: 605-611Crossref PubMed Scopus (115) Google Scholar, 4Skoulakis E.M. Davis R.L. Mol. Neurobiol. 1998; 16: 269-284Crossref PubMed Scopus (134) Google Scholar, 5Finnie C. Borch J. Collinge D.B. Plant Mol. Biol. 1999; 40: 545-554Crossref PubMed Scopus (119) Google Scholar, 6Fu H. Subramanian R.R. Masters S.C. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 617-647Crossref PubMed Scopus (1328) Google Scholar, 7Muslin A.J. Xing H. Cell. Signal. 2000; 12: 703-709Crossref PubMed Scopus (349) Google Scholar, 8Shaw A. Curr. Biol. 2000; 10: R400Abstract Full Text Full Text PDF PubMed Google Scholar, 9Tzivion G. Shen Y.H. Zhu J. Oncogene. 2001; 20: 6331-6338Crossref PubMed Scopus (258) Google Scholar). Other sequence-specific phosphoserine/phosphothreonine-binding domains have been subsequently defined with differing target specificity (TableI) such as WW domains, FHA domains, and WD40 and LRR domains of F-box proteins (reviewed in Refs. 10Yaffe M.B. Cantley L.C. Nature. 1999; 402: 30-31Crossref PubMed Scopus (70) Google Scholar, 11Yaffe M.B. Elia A.E. Curr. Opin. Cell Biol. 2001; 13: 131-138Crossref PubMed Scopus (289) Google Scholar, 12Yaffe M.B. Smerdon S.J. Structure. 2001; 9: R33-R38Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), complementing the previously defined phosphotyrosine-binding, SH2 and PTB domains. This review seeks to summarize the features of the 14-3-3 proteins critical to the phosphoserine/phosphothreonine binding function and to illustrate through specific examples several ways in which a stereotyped binding function is deployed to regulate diverse biologic functions and signal transduction pathways. The reader is referred to recent excellent reviews on 14-3-3 proteins (6Fu H. Subramanian R.R. Masters S.C. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 617-647Crossref PubMed Scopus (1328) Google Scholar, 7Muslin A.J. Xing H. Cell. Signal. 2000; 12: 703-709Crossref PubMed Scopus (349) Google Scholar, 8Shaw A. Curr. Biol. 2000; 10: R400Abstract Full Text Full Text PDF PubMed Google Scholar, 9Tzivion G. Shen Y.H. Zhu J. Oncogene. 2001; 20: 6331-6338Crossref PubMed Scopus (258) Google Scholar) and phosphoserine/phosphothreonine binding motifs in general (10Yaffe M.B. Cantley L.C. Nature. 1999; 402: 30-31Crossref PubMed Scopus (70) Google Scholar, 11Yaffe M.B. Elia A.E. Curr. Opin. Cell Biol. 2001; 13: 131-138Crossref PubMed Scopus (289) Google Scholar, 12Yaffe M.B. Smerdon S.J. Structure. 2001; 9: R33-R38Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar).Table IBinding preferences of phosphoserine/phosphothreonine-binding proteins and domainsPhosphoserine/phosphothreonine-binding protein/domainBinding preferenceRef.14-3-3RSX(pS/T)XP or RXXX(pS/T)XP2Muslin A.J. Tanner J.W. Allen P.M. Shaw A.S. Cell. 1996; 84: 889-897Abstract Full Text Full Text PDF PubMed Scopus (1188) Google Scholar,31Yaffe M.B. Rittinger K. Volinia S. Caron P.R. Aitken A. Leffers H. Gamblin S.J. Smerdon S.J. Cantley L.C. Cell. 1997; 91: 961-971Abstract Full Text Full Text PDF PubMed Scopus (1348) Google ScholarWW(pS/T)P9Tzivion G. Shen Y.H. Zhu J. Oncogene. 2001; 20: 6331-6338Crossref PubMed Scopus (258) Google Scholar–11Yaffe M.B. Elia A.E. Curr. Opin. Cell Biol. 2001; 13: 131-138Crossref PubMed Scopus (289) Google ScholarWD40DpSGXXpS or pSXXXpS9Tzivion G. Shen Y.H. Zhu J. Oncogene. 2001; 20: 6331-6338Crossref PubMed Scopus (258) Google Scholar–11Yaffe M.B. Elia A.E. Curr. Opin. Cell Biol. 2001; 13: 131-138Crossref PubMed Scopus (289) Google ScholarFHAPTXX(D/I)9Tzivion G. Shen Y.H. Zhu J. Oncogene. 2001; 20: 6331-6338Crossref PubMed Scopus (258) Google Scholar–11Yaffe M.B. Elia A.E. Curr. Opin. Cell Biol. 2001; 13: 131-138Crossref PubMed Scopus (289) Google Scholar Open table in a new tab 14-3-3 proteins are expressed in all eukaryotic cells and are highly conserved in amino acid sequences from yeast to mammals. Seven isoforms encoded by seven distinct genes are identified in mammals, more than 10 isoforms are identified in plants, and two isoforms are identified in yeast, Drosophila, and C. elegans. Interestingly, the yeast 14-3-3s are functionally interchangeable with the plant and mammalian isoforms, indicating the high level of functional conservation of the gene products. The 14-3-3 proteins assemble as stable homo- and heterodimers (3Aitken A. Jones D. Soneji Y. Howell S. Biochem. Soc. Trans. 1995; 23: 605-611Crossref PubMed Scopus (115) Google Scholar, 6Fu H. Subramanian R.R. Masters S.C. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 617-647Crossref PubMed Scopus (1328) Google Scholar, 13Roberts M.R. Curr. Opin. Plant Biol. 2000; 3: 400-405Crossref PubMed Scopus (61) Google Scholar, 14Jones D.H. Ley S. Aitken A. FEBS Lett. 1995; 368: 55-58Crossref PubMed Scopus (209) Google Scholar). All the 14-3-3 proteins appear to share similar tertiary structure, first defined for the τ (15Xiao B. Smerdon S.J. Jones D.H. Dodson G.G. Soneji Y. Aitken A. Gamblin S.J. Nature. 1995; 376: 188-191Crossref PubMed Scopus (400) Google Scholar) and ζ (16Liu D. Bienkowska J. Petosa C. Collier R.J. Fu H. Liddington R. Nature. 1995; 376: 191-194Crossref PubMed Scopus (440) Google Scholar) isoforms (Fig.1). Each polypeptide is organized into nine α-helices (A–I) in an antiparallel array, each separated by a short loop. The four N-terminal helices (A–D) lie in a planar array and create an extensive dimer surface with a central hole in the interface that is lined by polar and charged residues. The dimer contact residues are primarily hydrophobic with some uncharged polar residues and are highly conserved among all 14-3-3 isoforms, pointing to the likely basis for facile heterodimerization. Specifically, the 14-3-3ζ dimerization interface is formed by interaction of helix A (amino acids 3–17) of one 14-3-3 polypeptide with helices C (amino acids 39–68) and D (amino acids 75–107) of the opposite 14-3-3 and vice versa (6Fu H. Subramanian R.R. Masters S.C. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 617-647Crossref PubMed Scopus (1328) Google Scholar, 15Xiao B. Smerdon S.J. Jones D.H. Dodson G.G. Soneji Y. Aitken A. Gamblin S.J. Nature. 1995; 376: 188-191Crossref PubMed Scopus (400) Google Scholar, 16Liu D. Bienkowska J. Petosa C. Collier R.J. Fu H. Liddington R. Nature. 1995; 376: 191-194Crossref PubMed Scopus (440) Google Scholar). Indeed, N-terminal deletions or substitution of critical amino acids in the predicted dimerization interface completely abolishes 14-3-3 dimerization, producing monomeric 14-3-3 forms (17Luo Z.J. Zhang X.F. Rapp U. Avruch J. J. Biol. Chem. 1995; 270: 23681-23687Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 18Gu M. Du X. J. Biol. Chem. 1998; 273: 33465-33471Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 19Tzivion G. Luo Z. Avruch J. Nature. 1998; 394: 88-92Crossref PubMed Scopus (388) Google Scholar). The five C-terminal helices (E–I) hang down in a palisade at nearly 90° from the extended planar surface created by the N-terminal four helices, so that the dimer, viewed from the side, looks like a symmetrical claw, whose inner concave channel is lined by highly invariant residues. Co-crystallization of 14-3-3 with a synthetic phosphopeptide of optimized sequence (see below) combined with mutational analysis demonstrates that the 14-3-3 phosphopeptide binding pocket is composed of residues from both the N-terminal and the C-terminal parts of the protein (15Xiao B. Smerdon S.J. Jones D.H. Dodson G.G. Soneji Y. Aitken A. Gamblin S.J. Nature. 1995; 376: 188-191Crossref PubMed Scopus (400) Google Scholar, 16Liu D. Bienkowska J. Petosa C. Collier R.J. Fu H. Liddington R. Nature. 1995; 376: 191-194Crossref PubMed Scopus (440) Google Scholar, 17Luo Z.J. Zhang X.F. Rapp U. Avruch J. J. Biol. Chem. 1995; 270: 23681-23687Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 20Ichimura T. Uchiyama J. Kunihiro O. Ito M. Horigome T. Omata S. Shinkai F. Kaji H. Isobe T. J. Biol. Chem. 1995; 270: 28515-28518Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 21Zhang L. Wang H. Liu D. Liddington R. Fu H. J. Biol. Chem. 1997; 272: 13717-13724Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 22Wang H. Zhang L. Liddington R. Fu H. J. Biol. Chem. 1998; 273: 16297-16304Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 23Rittinger K. Budman J. Xu J. Volinia S. Cantley L.C. Smerdon S.J. Gamblin S.J. Yaffe M.B. Mol. Cell. 1999; 4: 153-166Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). The phosphopeptide binds along a groove on the inner surface of the half-dimer formed by the C-terminal five helices with the phosphate group directed into a pocket formed by the N-terminal helices. Thus 14-3-3ζ mutations that abrogate phosphopeptide binding include Lys-49, Arg-56, and Arg-60 in the N-terminal region (21Zhang L. Wang H. Liu D. Liddington R. Fu H. J. Biol. Chem. 1997; 272: 13717-13724Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar) and Val-176 and Leu at positions 216, 220, and 227 near the C terminus (22Wang H. Zhang L. Liddington R. Fu H. J. Biol. Chem. 1998; 273: 16297-16304Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). In addition to these residues, 14-3-3-phosphopeptide co-crystal structures point to a role for Leu-120, Arg-127, Leu-172, Asn-173, Glu-180, Asn-224, and Trp-228 in formation of the phosphopeptide-binding groove (23Rittinger K. Budman J. Xu J. Volinia S. Cantley L.C. Smerdon S.J. Gamblin S.J. Yaffe M.B. Mol. Cell. 1999; 4: 153-166Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). This work demonstrates directly that, as expected, each 14-3-3 half-dimer is capable of independently binding a phosphopeptide. Moreover, the phosphopeptide-binding grooves in each 14-3-3 half-dimer lie in antiparallel relationship within the dimer, as illustrated by the structure of a 14-3-3-serotonin N-acetyltransferase co-crystal, where the 14-3-3 dimer binds to a single polypeptide that is phosphorylated at two sites (24Obsil T. Ghirlando R. Klein D.C. Ganguly S. Dyda F. Cell. 2001; 105: 257-267Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar). A number of early studies indicated that the binding of 14-3-3 required target protein phosphorylation, e.g. as in the binding of 14-3-3 to tryptophan and tyrosine hydroxylases (25Ichimura T. Isobe T. Okuyama T. Takahashi N. Araki K. Kuwano R. Takahashi Y. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 7084-7088Crossref PubMed Scopus (295) Google Scholar, 26Furukawa Y. Ikuta N. Omata S. Yamauchi T. Isobe T. Ichimura T. Biochem. Biophys. Res. Commun. 1993; 194: 144-149Crossref PubMed Scopus (87) Google Scholar), Raf and Bcr (27Michaud N.R. Fabian J.R. Mathes K.D. Morrison D.K. Mol. Cell. Biol. 1995; 15: 3390-3397Crossref PubMed Scopus (190) Google Scholar), BAD (28Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2255) Google Scholar), keratin K18 (29Liao J. Omary M.B. J. Cell Biol. 1996; 133: 345-357Crossref PubMed Scopus (179) Google Scholar), and plant nitrate reductase (30Moorhead G. Douglas P. Morrice N. Scarabel M. Aitken A. MacKintosh C. Curr. Biol. 1996; 6: 1104-1113Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Building on these observations, Muslin et al. (2Muslin A.J. Tanner J.W. Allen P.M. Shaw A.S. Cell. 1996; 84: 889-897Abstract Full Text Full Text PDF PubMed Scopus (1188) Google Scholar) used synthetic phosphopeptides based on the amino acid surrounding Ser-259 on c-Raf-1, a site of 14-3-3 binding, to define a specific sequence motif optimal for association with 14-3-3 proteins: RSXpSXP, where pSrepresents phosphoserine and X any amino acid. Substitution of amino acids surrounding the central phosphoserine (position 0) demonstrated that Arg at position −4 or −3, Ser at position −2, and Pro at position +2 were critical for high affinity association. Within this motif, phosphorylation of the serine at position −2 alone does not support 14-3-3 binding, and when the Ser at −2 is phosphorylated in addition to the Ser at position 0, phosphopeptide binding is completely abrogated. These studies did not identify a preference for specific amino acids −5, −1, +1, or +3; however, subsequent work by Yaffe et al. (31Yaffe M.B. Rittinger K. Volinia S. Caron P.R. Aitken A. Leffers H. Gamblin S.J. Smerdon S.J. Cantley L.C. Cell. 1997; 91: 961-971Abstract Full Text Full Text PDF PubMed Scopus (1348) Google Scholar) and Rittinger et al. (23Rittinger K. Budman J. Xu J. Volinia S. Cantley L.C. Smerdon S.J. Gamblin S.J. Yaffe M.B. Mol. Cell. 1999; 4: 153-166Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar) using oriented phosphopeptide libraries provided evidence for two distinct 14-3-3 binding motifs: RSXpSXP (mode 1) and RXXXpSXP (mode 2). The binding of 14-3-3 to the mode1 motif is favored by aromatic or positively charged amino acid at position −1, whereas 14-3-3 binding to the mode 2 motif exhibits a preference for aromatic residues at position −2, positive residues at position −1, and Leu, Glu, Ala, or Met at position +1. The phosphorylation of such motifs is specified largely by the Arg at −3 or −4 and is catalyzed predominantly by members of the AGC subfamilies of protein kinases, e.g.PKA,1 PKB, PKC, etc. These motifs define the requirements for optimal binding of a single phosphoserine motif to a 14-3-3 protein, and many of the 14-3-3 partners identified thus far do contain either a mode 1 or mode 2 motif. Nevertheless, several well characterized proteins that interact with 14-3-3 in a phosphorylation-dependent manner do not contain either of these motifs, including e.g. the IGF-I receptor (32Furlanetto R.W. Dey B.R. Lopaczynski W. Nissley S.P. Biochem. J. 1997; 327: 765-771Crossref PubMed Scopus (77) Google Scholar), IRS-1 (33Craparo A. Freund R. Gustafson T.A. J. Biol. Chem. 1997; 272: 11663-11669Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 34Ogihara T. Isobe T. Ichimura T. Taoka M. Funaki M. Sakoda H. Onishi Y. Inukai K. Anai M. Fukushima Y. Kikuchi M. Yazaki Y. Oka Y. Asano T. J. Biol. Chem. 1997; 272: 25267-25274Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar), vimentin (35Tzivion G. Luo Z.J. Avruch J. J. Biol. Chem. 2000; 275: 29772-29778Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar), and Wee1 (36Honda R. Ohba Y. Yasuda H. Biochem. Biophys. Res. Commun. 1997; 230: 262-265Crossref PubMed Scopus (45) Google Scholar, 37Wang Y. Jacobs C. Hook K.E. Duan H. Booher R.N. Sun Y. Cell Growth Differ. 2000; 11: 211-219PubMed Google Scholar); thus it is evident that some variation on the optimal motifs is tolerable for 14-3-3 binding. In fact, it may turn out that such “optimal” motifs defined through the use of short synthetic phosphopeptides occur in the minority of 14-3-3 partners. This possibility is raised by the finding that the majority of cellular35S-labeled Met polypeptides that were recovered in association with recombinant, wild-type 14-3-3 expressed in COS cells failed to associate with a recombinant mutant, monomeric 14-3-3 polypeptide. Thus, stable association of most cellular partners with 14-3-3 requires a 14-3-3 dimer (35Tzivion G. Luo Z.J. Avruch J. J. Biol. Chem. 2000; 275: 29772-29778Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Some 14-3-3 partners have been shown to bind monomeric and dimeric forms of 14-3-3 with similar efficiency (17Luo Z.J. Zhang X.F. Rapp U. Avruch J. J. Biol. Chem. 1995; 270: 23681-23687Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 18Gu M. Du X. J. Biol. Chem. 1998; 273: 33465-33471Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 19Tzivion G. Luo Z. Avruch J. Nature. 1998; 394: 88-92Crossref PubMed Scopus (388) Google Scholar, 20Ichimura T. Uchiyama J. Kunihiro O. Ito M. Horigome T. Omata S. Shinkai F. Kaji H. Isobe T. J. Biol. Chem. 1995; 270: 28515-28518Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 38Ichimura T. Ito M. Itagaki C. Takahashi M. Horigome T. Omata S. Ohno S. Isobe T. FEBS Lett. 1997; 413: 273-276Crossref PubMed Scopus (38) Google Scholar); however, the overall target protein binding profiles of monomeric and dimeric 14-3-3 forms differ greatly (35Tzivion G. Luo Z.J. Avruch J. J. Biol. Chem. 2000; 275: 29772-29778Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 39Cahill C.M. Tzivion G. Nasrin N. Ogg S. Dore J. Ruvkun G. Alexander-Bridges M. J. Biol. Chem. 2001; 276: 13402-13410Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Thus, proteins such as c-Raf-1 that contain a high affinity 14-3-3 binding site, e.g. matching the mode 1/2 motifs, can bind monomeric 14-3-3 in a stable manner, whereas proteins that contain only low affinity 14-3-3 binding sites bind monomeric 14-3-3 weakly and achieve stable binding only with dimeric 14-3-3. The putative 14-3-3 partners such as Wee1 (36Honda R. Ohba Y. Yasuda H. Biochem. Biophys. Res. Commun. 1997; 230: 262-265Crossref PubMed Scopus (45) Google Scholar, 37Wang Y. Jacobs C. Hook K.E. Duan H. Booher R.N. Sun Y. Cell Growth Differ. 2000; 11: 211-219PubMed Google Scholar), keratin K18 (40Ku N.O. Liao J. Omary M.B. EMBO J. 1998; 17: 1892-1906Crossref PubMed Scopus (194) Google Scholar), Cbl (41Liu Y.C. Liu Y. Elly C. Yoshida H. Lipkowitz S. Altman A. J. Biol. Chem. 1997; 272: 9979-9985Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) IGF-I receptor (33Craparo A. Freund R. Gustafson T.A. J. Biol. Chem. 1997; 272: 11663-11669Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), IRS-1 (34Ogihara T. Isobe T. Ichimura T. Taoka M. Funaki M. Sakoda H. Onishi Y. Inukai K. Anai M. Fukushima Y. Kikuchi M. Yazaki Y. Oka Y. Asano T. J. Biol. Chem. 1997; 272: 25267-25274Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar), vimentin (35Tzivion G. Luo Z.J. Avruch J. J. Biol. Chem. 2000; 275: 29772-29778Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar), and DAF-16 (39Cahill C.M. Tzivion G. Nasrin N. Ogg S. Dore J. Ruvkun G. Alexander-Bridges M. J. Biol. Chem. 2001; 276: 13402-13410Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar) have been shown to require more than one phosphorylation site for stable 14-3-3 binding, implying that a 14-3-3 dimer may be required to bind at two sites on these proteins to achieve a stable association; consistent with this view, these proteins all lack canonical high affinity 14-3-3 binding motifs. A plausible explanation for the dependence of target binding on the state of 14-3-3 dimerization is the demonstration that the creation of two identical 14-3-3 binding sites on a single synthetic phosphopeptide increases binding affinity for native 14-3-3 more than 30-fold over that of a phosphopeptide bearing a single motif (31Yaffe M.B. Rittinger K. Volinia S. Caron P.R. Aitken A. Leffers H. Gamblin S.J. Smerdon S.J. Cantley L.C. Cell. 1997; 91: 961-971Abstract Full Text Full Text PDF PubMed Scopus (1348) Google Scholar). The significance of 14-3-3 dimerization for target protein regulation has as yet been established in only a few instances. By example, although monomeric and dimeric 14-3-3 polypeptides bind Raf equally well during co-expression in COS7 cells, only the dimeric form supports Raf kinase activity in vivo or enables the reactivation of Raf kinase after displacement of 14-3-3 from c-Raf-1 in vitro (19Tzivion G. Luo Z. Avruch J. Nature. 1998; 394: 88-92Crossref PubMed Scopus (388) Google Scholar, 35Tzivion G. Luo Z.J. Avruch J. J. Biol. Chem. 2000; 275: 29772-29778Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Moreover, analysis of the structure of co-crystallized 14-3-3 and the enzyme serotoninN-acetyltransferase indicates that simultaneous binding of a dimeric 14-3-3 to two sites on the enzyme is required to create the conformation that results in enhanced catalytic activity (24Obsil T. Ghirlando R. Klein D.C. Ganguly S. Dyda F. Cell. 2001; 105: 257-267Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar). Indirect evidence for the importance of dimerization to 14-3-3 function derives from studies that demonstrate the ability of 14-3-3 mutations that disrupt target protein binding to function as dominant negative forms, presumably by sequestering endogenous 14-3-3 into dimer forms in which only one monomer is capable of target binding (42Zhang S. Xing H. Muslin A.J. J. Biol. Chem. 1999; 274: 24865-24872Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 43Xing H. Zhang S. Weinheimer C. Kovacs A. Muslin A.J. EMBO J. 2000; 19: 349-358Crossref PubMed Scopus (248) Google Scholar). Finally, it should be noted that 14-3-3 can bind well to a variety of nonphosphorylated proteins such as exoenzyme S (44Masters S.C. Pederson K.J. Zhang L. Barbieri J.T. Fu H. Biochemistry. 1999; 38: 5216-5221Crossref PubMed Scopus (125) Google Scholar) and Cdc25B (45Mils V. Baldin V. Goubin F. Pinta I. Papin C. Waye M. Eychene A. Ducommun B. Oncogene. 2000; 19: 1257-1265Crossref PubMed Scopus (91) Google Scholar) as well as to nonphosphorylated synthetic or recombinant peptides (46Wang B. Yang H. Liu Y.C. Jelinek T. Zhang L. Ruoslahti E. Fu H. Biochemistry. 1999; 38: 12499-12504Crossref PubMed Scopus (253) Google Scholar). Interestingly, the residues in the 14-3-3 N-terminal segment that mediate phosphopeptide binding also mediate the binding to the nonphosphorylated peptides, and these moieties compete with each other for binding to 14-3-3 (46Wang B. Yang H. Liu Y.C. Jelinek T. Zhang L. Ruoslahti E. Fu H. Biochemistry. 1999; 38: 12499-12504Crossref PubMed Scopus (253) Google Scholar). Selection of 14-3-3 partners by phage display yielded sequences related to mode 1 and mode 2 save for the presence of multiple acidic amino acids, e.g.RSX(1–4)E. A similar sequence (RSESEE) is present in the candidate 14-3-3 partner, inositol 5-phosphatase (47Campbell J.K. Gurung R. Romero S. Speed C.J. Andrews R.K. Berndt M.C. Mitchell C.A. Biochemistry. 1997; 36: 15363-15370Crossref PubMed Scopus (40) Google Scholar). In addition, 14-3-3 proteins have been observed to interact with the nonphosphorylated Cys-His-rich (zinc finger) domain of Raf (48Petosa C. Masters S.C. Bankston L.A. Pohl J. Wang B. Fu H. Liddington R.C. J. Biol. Chem. 1998; 273: 16305-16310Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar) and with a leucine zipper structure situated upstream of the Cys-His-rich (PHD) domain of several plant homeodomain proteins (49Halbach T. Scheer N. Werr W. Nucleic Acids Res. 2000; 28: 3542-3550Crossref PubMed Scopus (42) Google Scholar). The latter interaction appears to involve a potential leucine zipper motif in 14-3-3 helix D and is thus distinct from the phosphopeptide-binding groove. Whether nonphosphorylated polypeptides are among the physiologic partners of 14-3-3 in vivo remains to be established. The mechanisms by which 14-3-3 binding participates in the regulation of target protein function can be assembled into five general categories (Fig. 2). In Fig.2A, binding of 14-3-3 can alter the ability of the target protein to interact with other partners. A well studied example is the binding of 14-3-3 to BAD. In response to ligands such as IGF-1, interleukin-3, insulin, and others, a variety of kinases,e.g. AKT, PAK, RSK1, and PKA, are activated and catalyze the phosphorylation of BAD on Ser-112, -136, and/or -155 (28Zha J. Harada H. Yang E. Jockel J. Korsmeyer S.J. Cell. 1996; 87: 619-628Abstract Full Text Full Text PDF PubMed Scopus (2255) Google Scholar, 50Datta S.R. Katsov A. Hu L. Petros A. Fesik S.W. Yaffe M.B. Greenberg M.E. Mol. Cell. 2000; 6: 41-51Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 51Lizcano J.M. Morrice N. Cohen P. Biochem. J. 2000; 349: 547-557Crossref PubMed Scopus (256) Google Scholar, 52Tan Y. Ruan H. Demeter M.R. Comb M.J. J. Biol. 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In Fig. 2C, the binding of 14-3-3 can either inhibit or augment the intrinsic catalytic activity of the target protein. Phosphorylation of tryptophan and tyrosine hydroxylases by calmodulin kinase II does not alter the catalytic activity of these enzymes, but the subsequent binding of 14-3-3 increases their activity severalfold (25Ichimura T. Isobe T. Okuyama T. Takahashi N. Araki K. Kuwa

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