The bi-directional translocation of MARCKS between membrane and cytosol regulates integrin-mediated muscle cell spreading
The bi-directional translocation of MARCKS between membrane and cytosol regulates integrin-mediated muscle cell spreading
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DOI：
10.1242/jcs.01309
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发表时间：
2004-09-01
影响因子：
4
通讯作者：
Rando, TA
中科院分区：
文献类型：
--
作者：
Disatnik, MH;Boutet, SC;Rando, TA
细胞骨架的调节对于组织形态发生过程中的正常细胞功能至关重要。整合素介导的细胞-基质相互作用调节细胞骨架动力学，但控制这些过程的信号级联仍然很大程度上未知。在这里，我们表明，肉豆蔻酰化富含丙氨酸的 C 激酶底物 (MARCKS) 是蛋白激酶 C (PKC) 的特定底物，受 α5β1 整合素介导的 PKC 激活的调节，并且对于肌肉细胞扩散过程中肌动蛋白应力纤维形成的调节至关重要。使用膜关联或对 PKC 依赖性磷酸化反应有缺陷的 MARCKS 突变体，我们证明 MARCKS 以 PKC 依赖性方式从膜易位到胞质溶胶允许细胞粘附的初始阶段。 MARCKS 的去磷酸化及其易位回膜允许细胞在肌动蛋白聚合和交联以及细胞骨架成熟过程中进行后期扩散。所有这些过程都直接依赖于 α5β1 整合素与其细胞外基质受体纤连蛋白的结合。这些结果证明了将 α5β1 整联蛋白信号传导与细胞骨架动力学联系起来的直接生化途径，并涉及细胞迁移和组织形态发生过程中发生的细胞形态急剧变化期间 MARCKS 的双向易位。
The regulation of the cytoskeleton is critical to normal cell function during tissue morphogenesis. Cell-matrix interactions mediated by integrins regulate cytoskeletal dynamics, but the signaling cascades that control these processes remain largely unknown. Here we show that myristoylated alanine-rich C-kinase substrate (MARCKS) a specific substrate of protein kinase C (PKC), is regulated by alpha5beta1 integrin-mediated activation of PKC and is critical to the regulation of actin stress fiber formation during muscle cell spreading. Using MARCKS mutants that are defective in membrane association or responsiveness to PKC-dependent phosphorylation, we demonstrate that the translocation of MARCKS from the membrane to the cytosol in a PKC-dependent manner permits the initial phases of cell adhesion. The dephosphorylation of MARCKS and its translocation back to the membrane permits the later stages of cell spreading during the polymerization and cross-linking of actin and the maturation of the cytoskeleton. All of these processes are directly dependent on the binding of alpha5beta1 integrin to its extracellular matrix receptor, fibronectin. These results demonstrate a direct biochemical pathway linking alpha5beta1 integrin signaling to cytoskeletal dynamics and involving bi-directional translocation of MARCKS during the dramatic changes in cellular morphology that occur during cell migration and tissue morphogenesis.