REGULATION OF THE ARP2/3 COMPLEX BY INTEGRINS

通过整合素与细胞外基质的粘附触发细胞扩散，并延长丝状足和板足。丝状足和板足延伸的驱动力是肌动蛋白的聚合。动作聚合可以通过两种机制中的任何一种启动：通过重新聚合，或者通过打开有盖的肌动蛋白丝的盖子，露出丝的“倒钩”端，从而使其他肌动蛋白亚基可以在其上聚合。目前的证据表明，Arp2/3复合物在成核新生聚合中起着关键作用，并且Arp2/3复合物参与了板状足和丝状足延伸过程中发生的肌动蛋白聚合。由于整合素参与促进丝状足和板足的形成，因此整合素与Arp2/3复合体之间似乎存在联系。本建议的重点是确定这种联系是否存在及其性质。我想确定Arp2/3的功能是否有助于整合素介导的细胞骨架事件，Arp2/3复合物是否被整合素招募，以及Arp2/3复合物是否因整合素参与而酪氨酸磷酸化。我的假设是，Arp2/3复合物与整合素和酪氨酸磷酸化的关联是细胞经历细胞运动和肿瘤细胞侵袭所必需的事件能力的重要决定因素。因此，这些研究将提供关于细胞粘附和肌动蛋白聚合如何协调产生细胞运动的新信息，并将提供有助于更好地理解肿瘤细胞侵袭和转移的发生和进展的信息。

Adhesion to the extracellular matrix via integrins triggers cell spreading, and extension of filopodia and lamellipodia. A driving force for the extension of filopodia and lamellipodia is the polymerization of actin. Act- in polymerization can be initiated by either of two mechanisms: by de novo polymerization, or the uncapping of capped actin filaments to expose the "barbed" end of the filaments, onto which additional actin subunits can polymerize. Current evidence indicates that the Arp2/3 complex plays a critical role in nucleating de novo polymerization, and that the Arp2/3 complex is involved in the actin polymerization that occurs during extension of lamellipodia and filopodia. Since integrin engagement promotes the formation of filopodia and lamellipodia, it seems likely therefore that there is a link between integrins and the Arp2/3 complex. The focus of this proposal is to determine if such a link exists and the nature of it. I would like to determine if Arp2/3 function contributes to the integrin- mediated cytoskeletal events, whether the Arp2/3 complex is recruited to the integrins, and if the Arp2/3 complex is tyrosine phosphorylated in response to integrin engagement. My hypothesis is that association of the Arp2/3 complex with integrins and tyrosine phosphorylation is an important determinant of the ability of cells to undergo events that are essential for cell movement and tumor cell invasion. Hence, these studies will provide novel information regarding how cell adhesion and actin polymerization are coordinated to give rise to cell motility and will yield information that will allow for a better understanding of the genesis and progression of tumor cell invasion and metastasis.