Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycin-associated protein
Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycin-associated protein
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DOI：
10.1073/pnas.96.8.4438
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发表时间：
1999-04-13
影响因子：
11.1
通讯作者：
Schreiber, SL
中科院分区：
文献类型：
--
作者：
Peterson, RT;Desai, BN;Schreiber, SL
FKBP 12-雷帕霉素相关蛋白（FRAP;也称为RAFT 1/mTOR）调节翻译起始和进入细胞周期。剥夺细胞的氨基酸或用小分子雷帕霉素处理它们抑制FRAP并导致翻译调节因子4 E-BP 1的快速去磷酸化和失活（真核起始因子4 E结合蛋白1）和p70（s6 k）（70-kDa S6激酶），最近发表的数据导致了FRAP作为传统的促分裂原活化激酶的观点，FRAP直接磷酸化4 E-BP 1和p70（s6 k），我们提供的证据表明，FRAP通过抑制磷酸酶间接控制4 E-BP 1和p70（s6 k）的磷酸化。雷帕霉素或氨基酸剥夺诱导的p70（s6 k）去磷酸化需要calyculin A敏感性磷酸酶，并且用雷帕霉素处理Jurkat I细胞增加了蛋白磷酸酶2A（PP 2A）对4 E-BP 1的活性，PP 2A被证明与p70（s6 k）相关，但不与突变的p70（s6 k）相关，突变的p70（s6 k）对雷帕霉素和氨基酸剥夺具有抗性。除了FRAP介导的去磷酸化之外，FRAP还显示出在体外磷酸化PP 2A，这与其中FRAP对PP 2A的磷酸化阻止4 E-BP 1和p70（s6 k）的去磷酸化的模型一致，而氨基酸剥夺或雷帕霉素处理抑制FRAP抑制磷酸酶的能力。
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 p70(s6k) (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 p70(s6k) in response to mitogenic stimuli, We present evidence that FRAP controls 4E-BP1 and p70(s6k) phosphorylation indirectly by restraining a phosphatase. A calyculin A-sensitive phosphatase is required for the rapamycin- or amino acid deprivation-induced dephosphorylation of p70(s6k), 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 p70(s6k) hut not with a mutated p70(s6k) 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 p70(s6k), whereas amino acid deprivation or rapamycin treatment inhibits FRAP's ability to restrain the phosphatase.