P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces.
P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces.
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DOI：
10.1083/jcb.201505105
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发表时间：
2016-01-18
期刊：
影响因子：
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通讯作者：
Gauthier-Rouvière C
中科院分区：
文献类型：
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作者：
Plutoni C;Bazellieres E;Le Borgne-Rochet M;Comunale F;Brugues A;Séveno M;Planchon D;Thuault S;Morin N;Bodin S;Trepat X;Gauthier-Rouvière C
P-cadherin通过增加机械力的强度和各向异性诱导极化和集体细胞迁移，这是由P-cadherin/β-PIX/Cdc42轴介导的。集体细胞迁移（CCM）对生物体发育、伤口愈合和转移转移（癌症相关死亡的主要原因）至关重要，它涉及钙粘蛋白家族的细胞-细胞粘附分子。P-cadherin表达水平升高与肿瘤侵袭性相关；然而，p -钙粘蛋白如何促进肿瘤恶性仍不清楚。在这里，我们利用细胞生物学和生物物理学的综合方法，确定了P-cadherin通过增加机械力的强度和各向异性特异性地诱导极化和CCM。我们发现这种机械调节是由P-cadherin/β-PIX/Cdc42轴介导的；P-cadherin通过β-PIX特异性激活Cdc42， β-PIX在CCM细胞间接触时特异性募集。这种细胞极化和迁移机制在表达E-或r -钙粘蛋白的细胞中是不存在的。因此，我们通过β- pix介导的Cdc42激活，确定了P-cadherin在调节细胞极性和驱动CCM的力各向异性中的特定作用。
P-cadherin induces polarization and collective cell migration through an increase in the strength and anisotropy of mechanical forces, which is mediated by the P-cadherin/β-PIX/Cdc42 axis. Collective cell migration (CCM) is essential for organism development, wound healing, and metastatic transition, the primary cause of cancer-related death, and it involves cell–cell adhesion molecules of the cadherin family. Increased P-cadherin expression levels are correlated with tumor aggressiveness in carcinoma and aggressive sarcoma; however, how P-cadherin promotes tumor malignancy remains unknown. Here, using integrated cell biology and biophysical approaches, we determined that P-cadherin specifically induces polarization and CCM through an increase in the strength and anisotropy of mechanical forces. We show that this mechanical regulation is mediated by the P-cadherin/β-PIX/Cdc42 axis; P-cadherin specifically activates Cdc42 through β-PIX, which is specifically recruited at cell–cell contacts upon CCM. This mechanism of cell polarization and migration is absent in cells expressing E- or R-cadherin. Thus, we identify a specific role of P-cadherin through β-PIX–mediated Cdc42 activation in the regulation of cell polarity and force anisotropy that drives CCM.