Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5
Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5
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DOI：
10.1074/jbc.m704873200
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发表时间：
2007-12-21
影响因子：
4.8
通讯作者：
Moens, Ugo
中科院分区：
文献类型：
--
作者：
Gerits, Nancy;Mikalsen, Theresa;Moens, Ugo
MAPK激活的蛋白激酶属于Ca ~（2+）/钙调素依赖性蛋白激酶。在该组中，MK2、MK 3和MK 5构成了三种结构相关的酶，具有不同的功能。很少有真正的基板MK 5已被确定，唯一已知的生物学作用是在ras诱导的衰老和肿瘤抑制。在这里，我们证明，cAMP依赖性蛋白激酶（PKA）的激活或异位表达的催化亚基C α在PC 12细胞的结果在MK 5的瞬时核出口，这需要的激酶活性的C α和MK 5和C α进入细胞核的能力。C α和MK 5，但不是MK2，在体内相互作用，并且C α增加MK 5的激酶活性。此外，C α增强MK 5磷酸化，但不增强MK2，而MK 5似乎不磷酸化C α。PKA的激活可以诱导肌动蛋白丝在质膜上的积累和肌动蛋白为基础的丝状伪足的形成。我们证明了小干扰RNA触发的MK 5耗竭干扰PKA诱导的F-肌动蛋白重排。此外，活化的MK 5变体的细胞质表达足以模拟PKA引起的F-肌动蛋白重塑。我们的研究结果描述了PKA通路和MAPK信号级联之间的一种新的相互作用，并表明，MK 5，而不是MK2，涉及PKA诱导的微丝重排。
The MAPK-activated protein kinases belong to the Ca2+/ calmodulin-dependent protein kinases. Within this group, MK2, MK3, and MK5 constitute three structurally related enzymes with distinct functions. Few genuine substrates for MK5 have been identified, and the only known biological role is in ras-induced senescence and in tumor suppression. Here we demonstrate that activation of cAMP-dependent protein kinase (PKA) or ectopic expression of the catalytic subunit C alpha in PC12 cells results in transient nuclear export of MK5, which requires the kinase activity of both C alpha and MK5 and the ability of C alpha to enter the nucleus. C alpha and MK5, but not MK2, interact in vivo, and C alpha increases the kinase activity of MK5. Moreover, C alpha augments MK5 phosphorylation, but not MK2, whereas MK5 does not seem to phosphorylate C alpha. Activation of PKA can induce actin filament accumulation at the plasma membrane and formation of actin-based filopodia. We demonstrate that small interfering RNA-triggered depletion of MK5 interferes with PKA-induced F-actin rearrangement. Moreover, cytoplasmic expression of an activated MK5 variant is sufficient to mimic PKA-provoked F-actin remodeling. Our results describe a novel interaction between the PKA pathway and MAPK signaling cascades and suggest that MK5, but not MK2, is implicated in PKA-induced microfilament rearrangement.