Smith Stephen D, Jaffer Zahara M, Chernoff Jonathan, Ridley Anne J
Ludwig Institute for Cancer Research, University College London, 91 Riding House Street, London W1W 7BS, UK.
J Cell Sci. 2008 Nov 15;121(Pt 22):3729-36. doi: 10.1242/jcs.027680. Epub 2008 Oct 21.
PAK1 is a member of the p21-activated kinase (PAK) family of serine/threonine kinases that are activated by the Rho GTPases Rac and Cdc42, and are implicated in regulating morphological polarity, cell migration and adhesion. Here we investigate the function of PAK1 in cell motility using macrophages derived from PAK1-null mice. We show that CSF1, a macrophage chemoattractant, transiently stimulates PAK1 and MAPK activation, and that MAPK activation is reduced in PAK1-/- macrophages. PAK1 regulates the dynamics of lamellipodium extension as cells spread in response to adhesion but is not essential for macrophage migration or chemotaxis towards CSF1. Following adhesion, PAK1-/- macrophages spread more rapidly and have more lamellipodia than wild-type cells; however, these lamellipodia were less stable than those in wild-type macrophages. ERK1/2 activity was reduced in PAK1-/- macrophages during adhesion, and inhibition of ERK1/2 activation in wild-type macrophages was sufficient to increase the spread area and mimic the lamellipodial dynamics of PAK1-/- macrophages. Together, these data indicate that PAK1 signals via ERK1/2 to regulate lamellipodial stability.
PAK1是丝氨酸/苏氨酸激酶的p21激活激酶（PAK）家族的成员，该家族由Rho GTPases Rac和Cdc42激活，并参与调节形态极性、细胞迁移和黏附。在这里，我们使用源自PAK1基因敲除小鼠的巨噬细胞来研究PAK1在细胞运动中的功能。我们发现，巨噬细胞趋化因子CSF1可短暂刺激PAK1和MAPK的激活，并且在PAK1基因敲除的巨噬细胞中MAPK的激活会减弱。当细胞因黏附而铺展时，PAK1调节片状伪足延伸的动力学，但对于巨噬细胞向CSF1的迁移或趋化性并非必不可少。黏附后，与野生型细胞相比，PAK1基因敲除的巨噬细胞铺展得更快且有更多的片状伪足；然而，这些片状伪足比野生型巨噬细胞中的片状伪足更不稳定。在黏附过程中，PAK1基因敲除的巨噬细胞中ERK1/2的活性降低，并且在野生型巨噬细胞中抑制ERK1/2的激活足以增加铺展面积并模拟PAK1基因敲除的巨噬细胞的片状伪足动力学。总之，这些数据表明PAK1通过ERK1/2发出信号来调节片状伪足的稳定性。
