Zihni Ceniz, Mitsopoulos Costas, Tavares Ignatius A, Ridley Anne J, Morris Jonathan D H
KCL School of Medicine and Dentistry, Rayne Institute, Kings College London, 123 Coldharbour Lane, London SE5 9NU, UK.
J Biol Chem. 2006 Mar 17;281(11):7317-23. doi: 10.1074/jbc.M513769200. Epub 2006 Jan 2.
We have reported previously that human prostate-derived sterile 20-like kinase (PSK) 1 alters actin cytoskeletal organization and binds to microtubules, regulating their organization and stability. We have shown a structurally related protein kinase PSK2, which lacks a microtubule-binding site, activated c-Jun N-terminal kinase (JNK), and induced apoptotic morphological changes that include cell contraction, membrane blebbing, and apoptotic body formation. Apoptotic stimuli increased the catalytic activity of endogenous PSK2 and JNK, and dominant negative JNK or a physiological inhibitor of JNK blocked these apoptotic morphological responses to PSK2, demonstrating a requirement for JNK. PSK2 also stimulated the cleavage of Rho kinase-1 (ROCK-I), and the activity of ROCK-I was required for PSK2 to induce cell contraction and membrane blebbing. The activation of caspases was also needed for the induction of membrane blebbing by PSK2, which was itself a substrate for caspase 3. PSK2 therefore regulates apoptotic morphology associated with the execution phase of apoptosis, which involves dynamic reorganization of the actin cytoskeleton, via downstream targets that include JNK and ROCK-I. Our findings suggest that PSKs form a subgroup of sterile 20 (STE20)-like kinases that regulate different cytoskeletal processes.
我们之前报道过，人前列腺源无菌20样激酶（PSK）1会改变肌动蛋白细胞骨架的组织，并与微管结合，调节其组织和稳定性。我们还展示了一种结构相关的蛋白激酶PSK2，它缺乏微管结合位点，可激活c-Jun氨基末端激酶（JNK），并诱导凋亡形态变化，包括细胞收缩、膜泡形成和凋亡小体形成。凋亡刺激会增加内源性PSK2和JNK的催化活性，而显性负性JNK或JNK的生理抑制剂会阻断这些对PSK2的凋亡形态反应，表明需要JNK。PSK2还会刺激Rho激酶-1（ROCK-I）的裂解，而PSK2诱导细胞收缩和膜泡形成需要ROCK-I的活性。PSK2诱导膜泡形成还需要半胱天冬酶的激活，而PSK2本身就是半胱天冬酶3的底物。因此，PSK2通过包括JNK和ROCK-I在内的下游靶点，调节与凋亡执行阶段相关的凋亡形态，这涉及肌动蛋白细胞骨架的动态重组。我们的研究结果表明，PSK形成了一个调节不同细胞骨架过程的无菌20（STE20）样激酶亚组。
