Pak4, a Novel Gab1 Binding Partner, Modulates Cell Migration and Invasion by the Met Receptor
Pak4, a Novel Gab1 Binding Partner, Modulates Cell Migration and Invasion by the Met Receptor
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DOI：
10.1128/mcb.01286-08
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发表时间：
2009-06-01
影响因子：
5.3
通讯作者：
Park, Morag
中科院分区：
文献类型：
--
作者：
Paliouras, Grigorios N.;Naujokas, Monica A.;Park, Morag
肝细胞生长因子 (HGF) 是 Met 受体酪氨酸激酶的配体，可诱导上皮细胞扩散、侵袭和形态发生，这些事件需要肌动蛋白细胞骨架的重塑。支架蛋白 Gab1 对于 Met 下游的这些生物反应至关重要。我们已将 p21 激活激酶 4 (Pak4) 鉴定为一种新型 Gab1 相互作用蛋白。我们发现，响应 HGF，Gab1 和 Pak4 在板状伪足内的细胞外围联合并共定位。 Pak4 和 Gab1 之间的关联依赖于 Gab1 磷酸化，但与 Pak4 激酶活性无关。这种相互作用是通过 Gab1 中的一个区域介导的，该区域与已知的 Gab1 相互作用基序没有同源性，并且通过 Pak4 的鸟嘌呤交换因子相互作用结构域介导。响应 HGF，Gab1 和 Pak4 协同增强上皮细胞的分散、迁移和侵袭，而 Pak4 的敲低会减弱这些反应。无法募集 Pak4 的 Gab1 突变体无法促进上皮细胞分散和响应 HGF 的侵入性形态发生程序，这证明了 Gab1-Pak4 关联的生理需求。这些数据证明了 Gab1 和 Pak4 之间的新关联，并确定 Pak4 是 Met 受体下游细胞迁移和侵袭性生长的关键整合因子。
Hepatocyte growth factor (HGF), the ligand for the Met receptor tyrosine kinase, induces epithelial cell dispersal, invasion, and morphogenesis, events that require remodeling of the actin cytoskeleton. The scaffold protein Gab1 is essential for these biological responses downstream from Met. We have identified p21-activated kinase 4 (Pak4) as a novel Gab1-interacting protein. We show that in response to HGF, Gab1 and Pak4 associate and colocalize at the cell periphery within lamellipodia. The association between Pak4 and Gab1 is dependent on Gab1 phosphorylation but independent of Pak4 kinase activity. The interaction is mediated through a region in Gab1, which displays no homology to known Gab1 interaction motifs and through the guanine exchange factor-interacting domain of Pak4. In response to HGF, Gab1 and Pak4 synergize to enhance epithelial cell dispersal, migration, and invasion, whereas knockdown of Pak4 attenuates these responses. A Gab1 mutant unable to recruit Pak4 fails to promote epithelial cell dispersal and an invasive morphogenic program in response to HGF, demonstrating a physiological requirement for Gab1-Pak4 association. These data demonstrate a novel association between Gab1 and Pak4 and identify Pak4 as a key integrator of cell migration and invasive growth downstream from the Met receptor.