Regulation of focal adhesion kinase by a novel protein inhibitor FIP200
Regulation of focal adhesion kinase by a novel protein inhibitor FIP200
复制标题
DOI：
10.1091/mbc.e02-05-0295
复制
发表时间：
2002-09-01
影响因子：
3.3
通讯作者：
Guan, JL
中科院分区：
文献类型：
--
作者：
Abbi, S;Ueda, H;Guan, JL
局灶黏附激酶（FAK）是整合素信号通路的主要介质。调控FAK活性及其相关细胞功能的机制尚不清楚。在这里，我们提供的数据表明，一种新的蛋白FIP200可以作为FAK的抑制剂。我们发现了内源性FIP200与FAK的关联，当整合素介导的细胞粘附伴随着FAK激活时，这种关联会降低。体外和体内结合研究表明，FIP200通过多个结构域直接与FAK相互作用。FIP200结合到FAK的激酶结构域，在体外抑制FAK的激酶活性，在体内抑制FAK的自磷酸化。过表达FIP200或其变体抑制细胞扩散、细胞迁移和细胞周期进展，这与它们在体内抑制FAK活性有关。FIP200对这些细胞功能的抑制可以通过FAK的共表达来恢复。最后，我们发现内源性FIP200与FAK之间功能相互作用的破坏导致FAK磷酸化增加，并在聚l -赖氨酸细胞中部分恢复细胞周期进程，进一步支持FIP200作为FAK的负调节因子。总之，这些结果确定FIP200是一种新的FAK蛋白抑制剂。
Focal adhesion kinase (FAK) is a major mediator of integrin signaling pathways. The mechanisms of regulation of FAK activity and its associated cellular functions are not very well understood. Here, we present data suggesting that a novel protein FIP200 functions as an inhibitor for FAK. We show the association of endogenous FIP200 with FAK, which is decreased upon integrin-mediated cell adhesion concomitant with FAK activation. In vitro- and in vivo-binding studies indicate that FIP200 interacts with FAK through multiple domains directly. FIP200 bound to the kinase domain of FAK inhibited its kinase activity in vitro and its autophosphorylation in vivo. Overexpression of FIP200 or its sements inhibited cell spreading, cell migration, and cell cycle progression, which correlated with their inhibition of FAK activity in vivo. The inhibition of these cellular functions by FIP200 could be rescued by coexpression of FAK. Last, we show that disruption of the functional interaction between endogenous FIP200 with FAK leads to increased FAK phosphorylation and partial restoration of cell cycle progression in cells plated on poly-L-lysine, providing further support for FIP200 as a negative regulator of FAK. Together, these results identify FIP200 as a novel protein inhibitor for FAK.