Clark Kristopher, Langeslag Michiel, van Leeuwen Bart, Ran Leonie, Ryazanov Alexey G, Figdor Carl G, Moolenaar Wouter H, Jalink Kees, van Leeuwen Frank N
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
EMBO J. 2006 Jan 25;25(2):290-301. doi: 10.1038/sj.emboj.7600931. Epub 2006 Jan 12.
Actomyosin contractility regulates various cell biological processes including cytokinesis, adhesion and migration. While in lower eukaryotes, alpha-kinases control actomyosin relaxation, a similar role for mammalian alpha-kinases has yet to be established. Here, we examined whether TRPM7, a cation channel fused to an alpha-kinase, can affect actomyosin function. We demonstrate that activation of TRPM7 by bradykinin leads to a Ca(2+)- and kinase-dependent interaction with the actomyosin cytoskeleton. Moreover, TRPM7 phosphorylates the myosin IIA heavy chain. Accordingly, low overexpression of TRPM7 increases intracellular Ca2+ levels accompanied by cell spreading, adhesion and the formation of focal adhesions. Activation of TRPM7 induces the transformation of these focal adhesions into podosomes by a kinase-dependent mechanism, an effect that can be mimicked by pharmacological inhibition of myosin II. Collectively, our results demonstrate that regulation of cell adhesion by TRPM7 is the combined effect of kinase-dependent and -independent pathways on actomyosin contractility.
肌动球蛋白收缩性调控包括胞质分裂、黏附及迁移在内的多种细胞生物学过程。在低等真核生物中，α激酶控制肌动球蛋白舒张，但哺乳动物α激酶的类似作用尚未明确。在此，我们研究了与α激酶融合的阳离子通道TRPM7是否会影响肌动球蛋白功能。我们证明缓激肽激活TRPM7会导致与肌动球蛋白细胞骨架发生钙和激酶依赖性相互作用。此外，TRPM7使肌球蛋白IIA重链磷酸化。相应地，TRPM7低水平过表达会增加细胞内钙离子水平，并伴有细胞铺展、黏附及黏着斑形成。TRPM7激活通过激酶依赖性机制诱导这些黏着斑转变为侵袭足，该效应可通过肌球蛋白II的药理学抑制来模拟。总体而言，我们的结果表明TRPM7对细胞黏附的调控是激酶依赖性和非依赖性途径对肌动球蛋白收缩性的综合作用。
