"A signaling integrator plays a critical role in regulating cell migration"

描述(申请人提供)：调控细胞迁移的信号机制还不是很清楚，尽管它在许多生物和病理过程中很重要，包括胚胎发生、炎症反应、组织修复和再生、癌症、关节炎、动脉粥样硬化、骨质疏松症和先天性发育脑缺陷。一个新兴的概念是，整合信号成分以协调调节潜在迁移过程的分子，如肌动蛋白重组、黏附组装和拆解(翻转)，以及极性的建立，对这一过程至关重要。我们假设，包含多结构域的蛋白质ASEF2通过整合这些过程的关键信号成分来调节细胞迁移，从而发挥这一功能。我们的初步工作已经产生了可行的假说，这项提议的目标是严格检验具体目标中概述的这些假说。具体目的I将通过整合分子信号的能力来检验Asf2是迁移的关键调节因子的假设，分子信号对这一过程非常重要。我们将确定调节ASEF2这一功能的结构域，以深入了解它调节细胞迁移的分子机制。在特定的目标II中，我们将检验这样的假设，即Asef2将Akt等激酶和Rho家族GTPase信号结合在一起来调节细胞迁移。在这个目标中，我们将使用表达结构、基于突变的策略、药理抑制剂和siRNA研究来验证这一假设。我们的工作模型是Asf2信号协调调节激酶和Rho GTP酶的活性，以刺激前沿粘连的快速周转，从而导致细胞迁移的增强。特定的AIM III将确定Asef2信号组件，如Akt和其他激酶效应器是否调节前沿粘连的周转。在这个目标中，我们将使用我们开发的新的定量分析方法来检验我们的假设，这些方法是为了研究粘附性周转。这项提案中概述的研究将使我们更好地理解ASEF2调节细胞迁移的信号机制。 公共卫生相关性：细胞迁移是许多生物和病理过程的核心，如癌症、关节炎、动脉粥样硬化和先天性脑缺陷。了解调节迁移的分子将导致治疗这些疾病的新的治疗方法。这项提议的目标是确定对细胞迁移起关键调节作用的分子。

DESCRIPTION (provided by applicant): The signaling mechanisms that regulate cell migration are not well understood despite its importance in numerous biological and pathological processes, including embryogenesis, the inflammatory response, tissue repair and regeneration, cancer, arthritis, atherosclerosis, osteoporosis, and congenital developmental brain defects. An emerging concept is that molecules, which integrate signaling components to coordinately regulate processes underlying migration, such as actin reorganization, adhesion assembly and disassembly (turnover), and the establishment of polarity, are critical for this process. We hypothesize that the multi-domain containing protein, Asef2, functions in this capacity by integrating critical signaling components of these processes to regulate cell migration. Our preliminary work has lead to working hypotheses and the objective of this proposal is to rigorously test these hypotheses as outlined in the specific aims. Specific Aim I will test the hypothesis that Asef2 is a critical regulator of migration through its ability to integrate molecular signals, which are important to this process. We will determine the domains that mediate this function of Asef2 to gain insight into the molecular mechanisms by which it regulates cell migration. In Specific Aim II, we will test the hypothesis that Asef2 brings together kinases, such as Akt, and Rho family GTPase signaling to modulate cell migration. In this aim, we will use expression constructs, mutant based strategies, pharmacological inhibitors, and siRNA studies to test this hypothesis. Our working model is that Asef2 signaling coordinately regulates the activities of kinases and Rho GTPases to stimulate the rapid turnover of leading edge adhesions, which leads to enhanced cell migration. Specific Aim III will determine if Asef2 signaling components, such as Akt and other kinase effectors, regulate the turnover of leading edge adhesions. In this aim, we will test our hypothesis by using new quantitative assays that we developed to study adhesion turnover. The studies outlined in this proposal will lead to a greater understanding of the signaling mechanisms by which Asef2 regulates cell migration. PUBLIC HEALTH RELEVANCE: Cell migration is central to many biological and pathological processes, such as cancer, arthritis, atherosclerosis, and congenital brain defects. Understanding the molecules that regulate migration will lead to new therapeutic approaches to treating these disorders. The goal of this proposal is to identify molecules that are critical regulators of cell migration.