Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12–rapamycinassociated protein
AUTOR(ES)
Peterson, Randall T.
FONTE
The National Academy of Sciences
RESUMO
The FKBP12–rapamycin-associated protein (FRAP; also called RAFT1/mTOR) regulates translation initiation and entry into the cell cycle. Depriving cells of amino acids or treating them with the small molecule rapamycin inhibits FRAP and results in rapid dephosphorylation and inactivation of the translational regulators 4E-BP1(eukaryotic initiation factor 4E-binding protein 1) and p70s6k (the 70-kDa S6 kinase). Data published recently have led to the view that FRAP acts as a traditional mitogen-activated kinase, directly phosphorylating 4E-BP1 and p70s6k in response to mitogenic stimuli. We present evidence that FRAP controls 4E-BP1 and p70s6k phosphorylation indirectly by restraining a phosphatase. A calyculin A-sensitive phosphatase is required for the rapamycin- or amino acid deprivation-induced dephosphorylation of p70s6k, and treatment of Jurkat I cells with rapamycin increases the activity of the protein phosphatase 2A (PP2A) toward 4E-BP1. PP2A is shown to associate with p70s6k but not with a mutated p70s6k that is resistant to rapamycin- and amino acid deprivation-mediated dephosphorylation. FRAP also is shown to phosphorylate PP2A in vitro, consistent with a model in which phosphorylation of PP2A by FRAP prevents the dephosphorylation of 4E-BP1 and p70s6k, whereas amino acid deprivation or rapamycin treatment inhibits FRAP’s ability to restrain the phosphatase.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=16350Documentos Relacionados
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