Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase α
Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase α
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DOI：
10.1074/jbc.c100196200
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发表时间：
2001-06-22
影响因子：
4.8
通讯作者：
Nakamura, T
中科院分区：
文献类型：
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作者：
Sumi, T;Matsumoto, K;Nakamura, T
LIM 激酶（LIMK1 和 LIMK2）通过不同 Rho 家族 GTPases 下游的肌动蛋白丝切蛋白磷酸化来调节肌动蛋白细胞骨架重组。 Pak1和ROCK分别激活Rac和Rho下游的LIMK1和LIMK2；然而，Cdc42 下游 LIMK 的效应蛋白激酶仍有待定义。我们现在报道的证据表明，细胞中强直性肌营养不良激酶相关的 Cdc42 结合激酶 α (MRCK α)（Cdc42 的一种效应蛋白激酶）的共表达可刺激细胞中 LIMK1 和 LIMK2 对丝切蛋白磷酸化的活性。在体外，MRCK α 磷酸化 LIM 激酶的蛋白激酶结构域，并且 LIMK2 中被 MRCK α 磷酸化的位点被证明是激活片段内的苏氨酸 505。 MRCK α 的表达诱导细胞中肌动蛋白解聚因子 (ADF)/cofilin 的磷酸化，而 MRCK α 诱导的 ADF/cofilin 磷酸化受到与蛋白激酶缺陷形式的 LIM 激酶共表达的抑制。这些结果表明，MRCK α 磷酸化并激活 Cdc42 下游的 LIM 激酶，进而通过 ADF/cofilin 的磷酸化和失活来调节肌动蛋白细胞骨架重组。
LIM kinases (LIMK1 and LIMK2) regulate actin cytoskeletal reorganization through cofilin phosphorylation downstream of distinct Rho family GTPases. Pak1 and ROCK, respectively, activate LIMK1 and LIMK2 downstream of Rac and Rho; however, an effector protein kinase for LIMKs downstream of Cdc42 remains to be defined. We now report evidence that LIMK1 and LIMK2 activities toward cofilin phosphorylation are stimulated in cells by the co-expression of myotonic dystrophy kinase-related Cdc42-binding kinase alpha (MRCK alpha), an effector protein kinase of Cdc42. In vitro, MRCK alpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCK alpha proved to be threonine 505 within the activation segment. Expression of MRCK alpha induced phosphorylation of actin depolymerizing factor (ADF)/cofilin in cells, whereas MRCK alpha -induced ADF/cofilin phosphorylation was inhibited by the co expression with the protein kinase-deficient form of LIM kinases. These results indicate that MRCK alpha phosphorylates and activates LIM kinases downstream of Cdc42, which in turn regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of ADF/cofilin.