The binding of PRAS40 to 14-3-3 proteins is not required for activation of mTORC1 signalling by phorbol esters/ERK
The binding of PRAS40 to 14-3-3 proteins is not required for activation of mTORC1 signalling by phorbol esters/ERK
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DOI：
10.1042/bj20071001
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发表时间：
2008-04-01
影响因子：
4.1
通讯作者：
Proud, Christopher G.
中科院分区：
文献类型：
--
作者：
Fonseca, Bruno D.;Lee, Vivian H. -Y.;Proud, Christopher G.
PRAS 40与mT 0 RC 1（雷帕霉素复合物1的哺乳动物靶标）结合并响应于胰岛素而释放。有人认为，这种作用是由于14-3-3结合，并导致mTORC 1信号转导的激活。以与胰岛素类似的方式，佛波酯也激活mTORC 1信号传导，在这种情况下通过PKC（蛋白激酶C）和ERK（细胞外信号调节激酶）。然而，佛波醇酯不诱导PRAS 40在Thr（246）处的磷酸化、14-3-3蛋白与PRAS 40的结合或其从mTORC 1的释放。Th-246突变为丝氨酸残基允许佛波醇酯诱导磷酸化并与14-3-3蛋白结合。这种磷酸化显然由位于ERK下游的RSK（核糖体S6激酶）介导。然而，尽管PRAS 40（T246 S）突变体比野生型PRAS 40更好地与14-3-3结合，但每种突变体都以相似的程度抑制mTORC 1信号传导。我们的结果表明，佛波酯激活mTORC 1信号传导不需要PRAS 40在Thr（246）处磷酸化、与14-3-3结合或从mTORC 1释放。可以想象，佛波醇酯通过不涉及PRAS 40的独特机制激活mTORC 1。事实上，我们的研究结果表明，PRAS 40可能实际上并不参与控制mTORC 1，而是mTORC 1的下游靶点，仅对特定刺激（如胰岛素）进行调节。
PRAS40 binds to the mTORC1 (mammalian target of rapamycin complex 1) and is released in response to insulin. It has been suggested that this effect is due to 14-3-3 binding and leads to activation of mTORC1 signalling. In a similar manner to insulin, phorbol esters also activate mTORC1 signalling, in this case via PKC (protein kinase C) and ERK (extracellular-signal-regulated kinase). However, phorbol esters do not induce phosphorylation of PRAS40 at Thr(246), binding of 14-3-3 proteins to PRAS40 or its release from mTORC1. Mutation of Th-246 to a serine residue permits phorbol esters to induce phosphorylation and binding to 14-3-3 proteins. Such phosphorylation is apparently mediated by RSKs (ribosomal S6 kinases), which lie downstream of ERK. However, although the PRAS40(T246S) mutant binds to 14-3-3 better than wild-type PRAS40, each inhibits mTORC1 signalling to a similar extent. Our results show that activation of mTORC1 signalling by phorbol esters does not require PRAS40 to be phosphorylated at Thr(246), bind to 14-3-3 or be released from mTORC1. It is conceivable that phorbol esters activate mTORC1 by a distinct mechanism not involving PRAS40. Indeed, our results suggest that PRAS40 may not actually be involved in controlling mTORC1, but rather be a downstream target of mTORC1 that is regulated in response only to specific stimuli, such as insulin.