Edwards D C, Sanders L C, Bokoch G M, Gill G N
Department of Chemistry, University of California at San Diego, La Jolla 92093-0650, USA.
Nat Cell Biol. 1999 Sep;1(5):253-9. doi: 10.1038/12963.
Extracellular signals regulate actin dynamics through small GTPases of the Rho/Rac/Cdc42 (p21) family. Here we show that p21-activated kinase (Pak1) phosphorylates LIM-kinase at threonine residue 508 within LIM-kinase's activation loop, and increases LIM-kinase-mediated phosphorylation of the actin-regulatory protein cofilin tenfold in vitro. In vivo, activated Rac or Cdc42 increases association of Pak1 with LIM-kinase; this association requires structural determinants in both the amino-terminal regulatory and the carboxy-terminal catalytic domains of Pak1. A catalytically inactive LIM-kinase interferes with Rac-, Cdc42- and Pak1-dependent cytoskeletal changes. A Pak1-specific inhibitor, corresponding to the Pak1 autoinhibitory domain, blocks LIM-kinase-induced cytoskeletal changes. Activated GTPases can thus regulate actin depolymerization through Pak1 and LIM-kinase.
细胞外信号通过Rho/Rac/Cdc42（p21）家族的小GTP酶调节肌动蛋白动力学。我们在此表明，p21激活激酶（Pak1）在LIM激酶激活环内的苏氨酸残基508处使LIM激酶磷酸化，并在体外将LIM激酶介导的肌动蛋白调节蛋白丝切蛋白的磷酸化增加了十倍。在体内，活化的Rac或Cdc42增加了Pak1与LIM激酶的结合；这种结合需要Pak1氨基末端调节域和羧基末端催化域中的结构决定因素。催化无活性的LIM激酶会干扰Rac、Cdc42和Pak1依赖性的细胞骨架变化。一种对应于Pak1自身抑制域的Pak1特异性抑制剂可阻断LIM激酶诱导的细胞骨架变化。因此，活化的GTP酶可通过Pak1和LIM激酶调节肌动蛋白解聚。
