Integrin-mediated cell attachment induces a PAK4-dependent feedback loop regulating cell adhesion through modified integrin alpha v beta 5 clustering and turnover.
Integrin-mediated cell attachment induces a PAK4-dependent feedback loop regulating cell adhesion through modified integrin alpha v beta 5 clustering and turnover.
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DOI：
10.1091/mbc.e10-03-0245
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发表时间：
2010-10-01
影响因子：
3.3
通讯作者：
Strömblad S
中科院分区：
文献类型：
--
作者：
Li Z;Lock JG;Olofsson H;Kowalewski JM;Teller S;Liu Y;Zhang H;Strömblad S
本文提出了细胞通过整合素粘附的自抑制调节（涉及 PAK4 的激活）来调节细胞粘附水平的新机制。细胞与细胞外基质的粘附受到核心细胞-基质粘附机制远端启动的多种途径的调节，例如通过生长因子信号传导。与这些外源途径相反，我们现在确定了核心粘附机制固有的调节途径，提供内部调节反馈回路来微调粘附水平。这种自抑制负反馈环路是由细胞与玻连蛋白的粘附启动的，导致 PAK4 激活，进而限制细胞与玻连蛋白的总粘附强度。具体来说，我们表明，PAK4 通过细胞附着到玻连蛋白（由 PAK4 结合配偶体整合素 αvβ5 介导）而被激活，并且活性 PAK4 诱导粘附复合物内整合素 αvβ5 加速周转。整合素周转加速与 PAK4 介导的其他效应相关，包括抑制整合素 αvβ5 聚类、减少整合素与 F-肌动蛋白的连接以及扰乱粘附复合物的成熟。这些特定的结果最终与细胞粘附强度的降低和细胞运动性的增加有关。因此，我们证明了细胞通过整合素粘附的自抑制调节来调节细胞粘附水平的新机制。
This article presents a novel mechanism deployed by cells to tune cell adhesion levels through the autoinhibitory regulation of integrin adhesion involving the activation of PAK4. Cell-to-extracellular matrix adhesion is regulated by a multitude of pathways initiated distally to the core cell–matrix adhesion machinery, such as via growth factor signaling. In contrast to these extrinsically sourced pathways, we now identify a regulatory pathway that is intrinsic to the core adhesion machinery, providing an internal regulatory feedback loop to fine tune adhesion levels. This autoinhibitory negative feedback loop is initiated by cell adhesion to vitronectin, leading to PAK4 activation, which in turn limits total cell–vitronectin adhesion strength. Specifically, we show that PAK4 is activated by cell attachment to vitronectin as mediated by PAK4 binding partner integrin αvβ5, and that active PAK4 induces accelerated integrin αvβ5 turnover within adhesion complexes. Accelerated integrin turnover is associated with additional PAK4-mediated effects, including inhibited integrin αvβ5 clustering, reduced integrin to F-actin connectivity and perturbed adhesion complex maturation. These specific outcomes are ultimately associated with reduced cell adhesion strength and increased cell motility. We thus demonstrate a novel mechanism deployed by cells to tune cell adhesion levels through the autoinhibitory regulation of integrin adhesion.