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首页> 外文期刊>Oncogene >The p85 regulatory subunit of PI3K mediates TSH|[ndash]|cAMP|[ndash]|PKA growth and survival signals
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The p85 regulatory subunit of PI3K mediates TSH|[ndash]|cAMP|[ndash]|PKA growth and survival signals

机译：PI3K的p85调节亚基介导TSH | n | cAMP | n || PKA生长和存活信号

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Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85PI3K phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells (FRTL-5). The aspartic version of the p85PI3K (p85D) inhibited apoptosis following TSH withdrawal. The p85PI3K wild type not the p85A bound PKA regulatory subunit RII in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85PI3K to RII was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wild-type p85PI3K but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factor-stimulated PI3K activity. We suggest that (1) TSH–cAMP-induced PKA phosphorylates p85PI3K at serine 83, (2) phosphorylated p85PI3K binds RII-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH–cAMP growth signals.
机译：磷脂酰肌醇3-激酶（PI3K）对于甲状腺刺激激素（TSH）诱导的细胞周期进程是必需的。为了确定将PI3K连接到TSH的分子机制，我们已经在体外和体内鉴定了p85PI3K中被蛋白激酶A（PKA）磷酸化的丝氨酸残基。丙氨酸突变体（p85A）的表达消除了环AMP / TSH诱导的细胞周期进程，并且在甲状腺细胞（FRTL-5）中具有致死性。在TSH撤药后，p85PI3K（p85D）的天冬氨酸抑制细胞凋亡。在由cAMP或TSH刺激的细胞中，p85PI3K野生型不是p85A结合的PKA调节亚基RII。 p85PI3K的天冬氨酸形式与RII的结合与cAMP或TSH刺激无关。同样，在表达p85A突变体的细胞中，PI3K与p21Ras的结合以及下游PI3K靶标AKT的激活受到严重损害。最后，我们发现在表达野生型p85PI3K的细胞中，TSH刺激了PI3K的催化活性，但在表达p85A的细胞中却没有。后一种突变体不影响表皮生长因子刺激的PI3K活性。我们建议（1）TSH–cAMP诱导的PKA磷酸化丝氨酸83上的p85PI3K，（2）磷酸化的p85PI3K结合RII-PKA并将PKAII靶向膜，（3）PI3K活性和p21Ras与PI3K的结合增加并激活下游的PI3K目标。该途径对于TSH-cAMP生长信号的传递至关重要。

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