Role of Polarity Complex Signaling on Non-muscle Myosin in Intestinal Epithelia

描述(申请人提供)：我们实验室最近报道，在炎症性肿瘤坏死因子信号下，进化上保守的信号通路“极性复合体”(非典型的PKC-PAR3-PAR6)被深度下调。在结肠炎的小鼠模型以及溃疡性结肠炎和克罗恩病患者中，它的表达也下调。 由于炎症性肠病是人类健康的一个重大问题，我想进一步分析aPKC下调调控的下游后果。我们已发表的和初步的数据表明，极性复合体对非肌肉肌球蛋白IIA的激活具有拮抗控制作用，IIA是一种被广泛接受的上皮细胞炎症信号的效应器。其他实验室已经证明nmmyosin ii参与了紧密连接。 但我们首次提出nmMyoIIA亚型中的一个亚型是控制上皮屏障的主要分子机制。因此，我在这里提出了一个假设：炎症依赖的极性复合体aPKC的下调是一种新的信号机制，它协同上调nmMyosinIIA的顶端表达，从而消除重链的直接磷酸化。本项目致力于分析aPKC-Par3-Par6拮抗MLCK介导的nmMyosin II激活的作用及其分子机制。

DESCRIPTION (provided by applicant): Our laboratory recently reported that the "polarity complex" (atypical PKC-Par3-Par6), an evolutionarily conserved signaling pathway is deeply downregulated under inflammatory TNF signaling. It is also downregulated in a mouse model of colitis as well as in ulcerative colitis and Crohn's disease patients. Because Inflammatory Bowel Disease represents a substantial problem for human health, I would like to further analyze the downstream consequences of aPKC downregulation. Our published and preliminary data show that the polarity complex exerts antagonistic control on the activation of non-muscle Myosin IIA, a broadly accepted effector of inflammatory signaling in epithelial cells. Other laboratories have shown the involvement of nmMyosin II in tight junction maintenance and downstream of inflammatory signaling, but we are the first to postulate specifically one of the isoforms nmMyoIIA as the main molecular mechanism controlling epithelial barrier. Accordingly, here I put forth the hypothesis that: Inflammation-dependent downregulation of the polarity complex aPKC is a novel signaling mechanism that synergistically upregulates the apical expression of nmMyosinIIA abrogating direct phosphorylation of the heavy chains. This project is devoted to analyze the effects and the molecular mechanisms by which aPKC-Par3-Par6 antagonizes MLCK- mediated nmMyosin II activation.