Cyclic Mechanical Stretch Decreases Cell Migration by Inhibiting Phosphatidylinositol 3-Kinase-and Focal Adhesion Kinase-mediated JNK1 Activation
Cyclic Mechanical Stretch Decreases Cell Migration by Inhibiting Phosphatidylinositol 3-Kinase-and Focal Adhesion Kinase-mediated JNK1 Activation
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DOI：
10.1074/jbc.m109.084335
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发表时间：
2010-02-12
影响因子：
4.8
通讯作者：
Waters, Christopher M.
中科院分区：
文献类型：
--
作者：
Desai, Leena P.;White, Steven R.;Waters, Christopher M.
伤口愈合过程中的上皮细胞迁移需要协调的信号传导途径，这些信号传导途径指导细胞前端和后端的极化、细胞骨架组织和局部粘连的重塑。这些固有的机械过程被循环拉伸（CS）破坏，但参与这种破坏的特定信号分子还不清楚。在这项研究中，我们证明，抑制磷脂酰肌醇3-激酶（PI 3 K）或表达的显性负性形式的PI 3 K引起气道上皮细胞伤口闭合的抑制。CS引起持续的PI 3 K活化降低，抑制伤口愈合。组成型活性PI 3 K的表达刺激Tiam 1易位到细胞膜，增加Rac 1活性，并增加气道上皮细胞的伤口愈合。Rac 1活性增加导致JNK 1磷酸化增加。PI 3 K活化不受粘着斑激酶的调节。恢复有效的细胞迁移过程中CS需要的组成型活性PI 3 K，粘着斑激酶，和JIP 3的共表达。
Epithelial cell migration during wound healing requires coordinated signaling pathways that direct polarization of the leading and trailing ends of the cells, cytoskeletal organization, and remodeling of focal adhesions. These inherently mechanical processes are disrupted by cyclic stretch (CS), but the specific signaling molecules involved in this disruption are not well understood. In this study, we demonstrate that inhibition of phosphatidylinositol 3-kinase (PI3K) or expression of a dominant-negative form of PI3K caused inhibition of airway epithelial cell wound closure. CS caused a sustained decrease in activation of PI3K and inhibited wound healing. Expression of constitutively active PI3K stimulated translocation of Tiam1 to the membrane, increased Rac1 activity, and increased wound healing of airway epithelial cells. Increased Rac1 activity resulted in increased phosphorylation of JNK1. PI3K activation was not regulated by association with focal adhesion kinase. Restoration of efficient cell migration during CS required coexpression of constitutively active PI3K, focal adhesion kinase, and JIP3.