Protein Interactions that Regulate Cell Polarity

描述(申请人提供)：这项工作的长期目标是了解细胞极化的分子基础。极性是细胞的基本属性，对正常发育和成人生理都是必需的。例如，在发育过程中，细胞命运决定因素在分裂细胞时两极分化，作为产生细胞类型多样性的机制，细胞极性的丧失是包括癌症在内的许多疾病状态的标志。为了在空间和时间上精确地确定细胞的极性，必须解释细胞信号，并最终将其与相关细胞成分的分离相联系。在不同类型的细胞中，极性由进化上保守的PAR复合体控制，该复合体由Bazooka(BAZ；又名PAR-3)、PAR-6和非典型蛋白激酶C(APKC)组成。最近清楚的是，aPKC活性是PAR复合体的主要输出。在这项资助中，我们试图回答PKC的三个基本方面--它如何针对特定的细胞部位，其活性如何被调节，以及底物的磷酸化如何调节它们的定位。了解导致PAR复合体耦合招募和激活的分子事件将对细胞极性产生新的见解。

DESCRIPTION (provided by applicant): The long-term objective of this work is to understand the molecular basis by which cells are polarized. Polarity is a fundamental property of cells that is required for proper development as well as adult physiology. For example, during development cell fate determinants are polarized in dividing cells as a mechanism for generating cell type diversity and the loss of cell polarity is a hallmark of many disease states, including cancer. For spatially and temporally precise establishment of cell polarity to occur, cellular signals must be interpreted and ultimately coupled to the segregation of the relevant cellular components. In diverse cell types, polarity is controlled by the evolutionarily conserved Par complex consisting of Bazooka (Baz; aka Par-3), Par-6, and atypical Protein Kinase C (aPKC). It has recently become clear that aPKC activity is the primary output of the Par complex. In this grant we seek to answer three fundamental aspects of aPKC-how it is targeted to specific cellular sites, how its activity is regulated, and how phosphorylation of substrates regulate their localization. Understanding the molecular events that lead to the coupled recruitment and activation of the Par complex will yield new insight into cell polarity.