REGULATION OF THE ARP2/3 COMPLEX BY INTEGRINS

通过整合素与细胞外基质黏附，触发细胞扩散，丝状足细胞和片状脂肪细胞伸展。丝状伪足和片状伪足的延伸的驱动力是肌动蛋白的聚合。ACT-in聚合可以通过两种机制中的任何一种来启动：从头聚合，或者去封顶的肌动蛋白细丝，以暴露细丝的“带刺”末端，在其上可以聚合额外的肌动蛋白亚单位。目前的证据表明，Arp2/3复合体在从头聚合成核过程中起着关键作用，Arp2/3复合体参与了肌动蛋白的聚合，而肌动蛋白聚合发生在片状脂壁和丝状足的伸展过程中。由于整合素的参与促进丝足和片脂的形成，因此整合素和Arp2/3复合体之间似乎有联系。这项提案的重点是确定是否存在这种联系以及这种联系的性质。我想确定Arp2/3功能是否参与了整合素介导的细胞骨架事件，Arp2/3复合体是否被招募到整合素，以及Arp2/3复合体是否因整合素的参与而被酪氨酸磷酸化。我的假设是，Arp2/3复合体与整合素和酪氨酸磷酸化的关联是细胞经历对细胞运动和肿瘤细胞侵袭至关重要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黏附和肌动蛋白聚合如何协调以引起细胞运动的新信息，并将产生有助于更好地理解肿瘤细胞侵袭和转移的发生和发展的信息。

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.