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首页> 外文期刊>Molecular biology of the cell >Activation of TORC1 Transcriptional Coactivator through MEKK1-induced Phosphorylation
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Activation of TORC1 Transcriptional Coactivator through MEKK1-induced Phosphorylation

机译：通过MEKK1诱导的磷酸化激活TORC1转录共激活因子。

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摘要

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431-650 of TORC1. As a physiological activator of CREB, interleukin 1 alpha triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling.
机译：CREB是原型bZIP转录因子，是葡萄糖代谢，突触可塑性，细胞生长，细胞凋亡和肿瘤发生的主要调控因子。调节的CREB活性（TORC）的换能器是CREB的重要转录共激活因子，也是各种信号在其上汇合的重要调节点。在这项研究中，我们报告通过MEKK1介导的磷酸化激活TORC1。 MEKK1有效激活TORC1，并且此激活独立于下游效应器MEK1 / MEK2，ERK2，JNK，p38，蛋白激酶A和钙调神经磷酸酶。 MEKK1在体内和体外均可诱导TORC1磷酸化。在培养的哺乳动物细胞中单独表达MEKK1的催化结构域足以引起磷酸化并随后激活TORC1。 MEKK1与TORC1发生物理相互作用并刺激其核易位。响应MEKK1刺激的激活域被映射到TORC1的氨基酸431-650。作为CREB的生理激活剂，白介素1α触发了TORC1的MEKK1依赖性磷酸化，并随后募集到白介素8启动子中的cAMP反应元件。综上所述，我们的发现提出了一种新的机制，用于调节TORC1转录共激活因子和CREB信号传导的激活。

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