The JNK Signalsome and its Functions

描述(申请人提供)：c-jun氨基末端蛋白激酶(JNK；也称为应激激活蛋白激酶，SAPK)在细胞增殖、分化、程序性死亡和转化中发挥核心作用。大量证据表明，JNK在包括炎症、免疫反应、糖尿病、肥胖、心脏肥大和肿瘤发生在内的许多病理生理事件中是一个关键的调节因子。然而，JNK活性受不同的细胞外刺激调控的分子机制仍不完全清楚。在这个提案中，我们将研究不同的细胞外刺激对JNK的激活是否由JNK信号体介导，JNK信号体是一个动态的蛋白质复合体，包括JNK相关的刺激特异性调节器或调节器(SMOR)。使用遗传和生化方法，我们最近发现JNK形成一种蛋白质复合体，其活性可以由刺激特异性调节因子调节。此外，我们发现两种普遍表达的JNK亚型JNK1和JNK2受到不同细胞外刺激的差异调节。因此，我们假设刺激特异的JNK信号体通过环境刺激和/或胚胎发育线索决定JNK的激活。这一建议是新颖的，因为它将确定JNK信号体是JNK激活的动态和功能蛋白质复合体，并确定JNK1和JNK2在不同发育阶段差异调控的分子机制。这项研究将提出一种新的范式，以了解细胞外刺激调节JNK丝裂原活化蛋白激酶亚家族的分子机制，以及以JNK为靶点预防和治疗人类疾病和癌症的原理。与公共健康相关：细胞信号网络由许多重要的信号通路组成，包括应激激活蛋白激酶JNK通路，该通路在许多病理生理事件中发挥核心作用，并与许多人类疾病和某些类型的癌症有关。然而，在不影响人类正常生理功能的情况下，将JNK作为靶点用于治疗是困难的。这项建议研究了刺激特异性调节剂或调节剂通过特定的细胞外刺激控制JNK激活的分子机制，从而提供了一种新的策略，靶向JNK的独特调节器或调节器，而不是JNK本身，以预防和治疗人类疾病和癌症。

DESCRIPTION (provided by applicant): c-Jun N-terminal protein kinase (JNK; also known as stress-activated protein kinase, SAPK) plays a central role in proliferation, differentiation, programmed cell death and transformation. Overwhelming evidence implicates that JNK is a key regulator in many pathophysiological events including inflammation, immune responses, diabetes, obesity, heart hypertrophy, and oncogenesis. However, the molecular mechanism by which JNK activity is regulated by distinct extracellular stimuli is still incompletely understood. In this proposal, we will investigate whether JNK activation by distinct extracellular stimuli is mediated by a JNK signalsome, which is a dynamic protein complex that includes JNK-associated, stimulus-specific modulators or regulators (SMOR). Using both genetic and biochemical approaches, we recently found that JNK forms a protein complex and its activity can be regulated by stimulus-specific regulators. Furthermore, we found that two ubiquitously expressed JNK isoforms, JNK1 and JNK2, are differentially regulated by various extracellular stimuli. Thus, we hypothesize that the stimulus-specific JNK signalsome determines JNK activation by environmental stimuli and/or embryonic development cues. This proposal is novel, as it will identify the JNK signalsome } a dynamic and functional protein complex for JNK activation, and determine the molecular mechanisms by which JNK1 and JNK2 are differentially regulated at different developmental stages. This study will put forward a novel paradigm regarding the molecular mechanism underlying the regulation of the JNK mitogen-activated protein kinase subfamily by extracellular stimuli and the rationale in targeting JNK for prevention and treatment of human diseases and cancer. PUBLIC HEALTH RELEVANCE: The cell signaling network is composed of many important signaling pathways, including the stress activated protein kinase JNK pathway, which plays a central role in many pathophysiological events and has been implicated in numerous human diseases and certain types of cancer. However, it is difficult to target JNK for therapeutic purposes without affecting normal physiological functions in human. This proposal studies the molecular mechanism by which stimulus-specific modulators or regulators control JNK activation by specific extracellular stimuli, thereby providing a novel strategy to target the unique modulators or regulators of JNK, rather than JNK itself, for prevention and treatment of human diseases and cancer.