HOMER2 AS A SUPPRESSOR OF CELL INVASION AND PODOSOME FORMATION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 足体是细胞膜上富含肌动蛋白的突起，与癌细胞的迁移和转移有关。它们的形成需要肌动蛋白细胞骨架的重排，这是通过一系列肌动蛋白结合蛋白的相互作用来调节的。促进肿瘤的佛波酯引起肌动蛋白细胞骨架重排，导致多种细胞类型的足小体形成；包括血管平滑肌细胞、破骨细胞、巨噬细胞、内皮细胞、神经细胞、成肌细胞和转化的成纤维细胞。促进肿瘤的佛波酯通过激活一个或多个PKC亚型来发挥作用，导致肌动蛋白细胞骨架的重组和src激活AFAP-110，AFAP-110是一种连接肌动蛋白细丝的接头蛋白，在PKC-a的磷酸化反应中激活src，并参与足体的形成。在A7r5肿瘤细胞和前列腺癌中，AFAP-110水平的增加与足体寿命的延长相关。尽管AFAP-110作为src激活剂的作用已经得到很好的证实，但激活的AFAP-110本身被调控的机制仍然不完全确定。支架蛋白，如Tks5，招募AFAP-110和其他信号蛋白到足体。Hmer 2是VESL/Hmer家族的一种支架蛋白，它与小鼠小脑细胞中的肌动蛋白细丝和激活的Rho GTP酶相互作用，并能阻止Cdc42激活的HeLa细胞中足体的形成。在两项独立的酵母双杂交研究中，Hmer 2已被确定为AFAP-110的结合伙伴。我们假设Hmer 2是AFAP-110的结合伙伴和调节因子。在这项提案中，我们将讨论Hmer 2废除足体形成的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Podosomes are actin-rich projections of the cell membrane that are associated with cancer cell migration and metastases. Their formation requires rearrangements of the actin cytoskeleton, which are mediated through the interaction of a host of actin-binding proteins. Tumor-promoting phorbol esters cause actin cytoskeletal rearrangements that result in podosome formation in a variety of cell types; including vascular smooth muscle cells, osteoclasts, macrophages, endothelial cells, neural cells myoblasts and transformed fibroblasts. Tumor-promoting phorbol esters function by activating one or more PKC isoforms, resulting in the reorganization of the actin cytoskeleton and src activation AFAP-110, an adaptor protein that cross-links actin filaments, activates src in response to phosphorylation by PKC-a and is involved in podosome formation. Increased levels of AFAP-110 are correlated with increases in podosome lifetime in A7r5 tumor cells and prostate cancer. Although the role of AFAP-110 as a src activator is well established, the mechanism by which activated AFAP-110 is itself regulated remains incompletely characterized. Scaffolding proteins, such as Tks5, recruit AFAP-110 and other signaling proteins to podosomes. Homer2 is a scaffolding protein of the Vesl/Homer family that interacts with both actin filaments and activated Rho GTPases in mouse cerebellar cells and can prevent podosome formation in cdc42-activated HeLa cells. Homer2 has been identified as a binding partner for AFAP-110 in two independent yeast two-hybrid studies. We hypothesize that Homer2 is a binding partner and regulator for AFAP-110. In this proposal we will address the mechanism by which Homer2 abrogates podosome formation.