Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation
Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation
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DOI：
10.1007/s11373-005-9060-8
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发表时间：
2006-03-01
影响因子：
11
通讯作者：
Wang, CLA
中科院分区：
文献类型：
--
作者：
Kordowska, J;Huang, RJ;Wang, CLA
肌动蛋白结合蛋白钙调素（CaD）存在于平滑肌（重异构体，h-CaD）和非肌肉细胞（轻异构体，l-CaD）。在平滑肌中，h-CaD同时与肌球蛋白和肌动蛋白结合并调节肌动球蛋白相互作用。在非肌肉细胞中，L-CaD与肌动蛋白结合并稳定肌动蛋白应力纤维;它也可以介导肌动蛋白和非肌肉肌球蛋白之间的相互作用。h-和l-CaD在体内刺激后都被磷酸化。当被佛波醇酯激活时，h-CaD的主要磷酸化位点是ERK特异性位点，其修饰被MEK抑制剂PD 98059减弱。当细胞被刺激迁移时，L-CaD中的相同位点也被磷酸化，而在分裂细胞中，L-CaD被更广泛地磷酸化，推测是通过cdc 2激酶。Erk和cdc 2都是MAPK家族的成员。因此，CaD似乎是Ras信号通路的下游效应物。值得注意的是，两种钙调素亚型所共有的磷酸化丝氨酸残基位于C-末端区域，该区域也含有肌动蛋白结合位点。生化和结构的研究表明，磷酸化的钙调素在Erk网站是伴随着构象的变化，部分解离钙调素肌动蛋白。这样的结构变化在h-CaD暴露肌动蛋白表面上的肌球蛋白结合位点，并允许肌动球蛋白在平滑肌中的相互作用。在非肌肉细胞的情况下，l-CaD的变化削弱了肌动蛋白丝的稳定性，并促进其解体。事实上，L-CaD修饰的水平与肌动蛋白应力纤维的水平以相互的方式非常好地相关。由于细胞迁移和细胞分裂都需要肌动蛋白细胞骨架的动态重塑，导致细胞形状的变化，因此CaD的磷酸化可能是一种合理的手段来调节这些过程。因此，CaD不仅将平滑肌收缩和非肌肉运动联系起来，而且还为细胞迁移和细胞增殖的调节提供了共同的机制。
The actin-binding protein caldesmon (CaD) exists both in smooth muscle (the heavy isoform, h-CaD) and non-muscle cells (the light isoform, l-CaD). In smooth muscles h-CaD binds to myosin and actin simultaneously and modulates the actomyosin interaction. In non-muscle cells l-CaD binds to actin and stabilizes the actin stress fibers; it may also mediate the interaction between actin and non-muscle myosins. Both h- and l-CaD are phosphorylated in vivo upon stimulation. The major phosphorylation sites of h-CaD when activated by phorbol ester are the Erk-specific sites, modification of which is attenuated by the MEK inhibitor PD98059. The same sites in l-CaD are also phosphorylated when cells are stimulated to migrate, whereas in dividing cells l-CaD is phosphorylated more extensively, presumably by cdc2 kinase. Both Erk and cdc2 are members of the MAPK family. Thus it appears that CaD is a downstream effector of the Ras signaling pathways. Significantly, the phosphorylatable serine residues shared by both CaD isoforms are in the C-terminal region that also contains the actin-binding sites. Biochemical and structural studies indicated that phosphorylation of CaD at the Erk sites is accompanied by a conformational change that partially dissociates CaD from actin. Such a structural change in h-CaD exposes the myosin-binding sites on the actin surface and allows actomyosin interactions in smooth muscles. In the case of non-muscle cells, the change in l-CaD weakens the stability of the actin filament and facilitates its disassembly. Indeed, the level of l-CaD modification correlates very well in a reciprocal manner with the level of actin stress fibers. Since both cell migration and cell division require dynamic remodeling of actin cytoskeleton that leads to cell shape changes, phosphorylation of CaD may therefore serve as a plausible means to regulate these processes. Thus CaD not only links the smooth muscle contractility and non-muscle motility, but also provides a common mechanism for the regulation of cell migration and cell proliferation.