REGULATION OF THE ARP2/3 COMPLEX BY INTEGRINS

通过整合素粘附到细胞外基质触发细胞铺展，以及丝状伪足和板状伪足的延伸。 丝状伪足和板状伪足延伸的驱动力是肌动蛋白的聚合。肌动蛋白聚合可以通过两种机制中的任一种引发：通过从头聚合，或将加帽的肌动蛋白丝脱帽以暴露丝的“倒钩”末端，额外的肌动蛋白亚基可以附着在其上.目前的证据表明，Arp 2/3复合物在成核从头聚合中起着关键作用，并且Arp 2/3复合物参与了在板状伪足和丝状伪足延伸期间发生的肌动蛋白聚合。由于整联蛋白参与促进丝状伪足和板状伪足的形成，因此整联蛋白和Arp 2/3复合物之间可能存在联系。本提案的重点是确定是否存在这样的联系和它的性质。我想确定Arp 2/3功能是否有助于整合素介导的细胞骨架事件，Arp 2/3复合物是否被整合素募集，以及Arp 2/3复合物是否响应整合素参与而酪氨酸磷酸化。我的假设是Arp 2/3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的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以引起细胞运动的新信息，并将产生允许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.