Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization.
Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization.
复制标题
RAC1-PAK1 RAB11循环的调节促进了连接处的稳定化。
DOI：
10.1083/jcb.202002114
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发表时间：
2021-06-07
期刊：
影响因子：
--
通讯作者：
Braga VMM
中科院分区：
文献类型：
--
作者：
Erasmus JC;Smolarczyk K;Brezovjakova H;Mohd-Naim NF;Lozano E;Matter K;Braga VMM
Rac 1促进恶性肿瘤。致癌Rac 1及其效应物PAK 1通过大量液体摄取使钙粘蛋白粘附受体内化而破坏连接。PAK 1磷酸化细胞内运输的关键调节因子RabGDIβ，从而调节其与特定配偶体的亲和力（即，Rab 11）重新路由钙粘蛋白远离细胞-细胞接触。Rac 1 GT3在肿瘤中过度活化并导致恶性肿瘤。Rac 1破坏连接需要其效应子PAK 1，但确切的机制尚不清楚。在这里，我们表明，E-钙粘蛋白是通过微胞饮在PAK 1依赖的方式没有连环蛋白解离和降解的内化。除了内化外，PAK 1还通过微调Rab小GT3功能来调节E-钙粘蛋白转运。PAK 1磷酸化核心Rab调节因子RabGDIβ，但不磷酸化RabGDIα。磷酸化的RabGDIβ优先与Rab 5和Rab 11结合，这被预测为促进Rab从膜的回收。与这一假设相一致，Rac 1激活Rab 11，抑制Rab 11功能部分挽救了E-钙粘蛋白的不稳定性。因此，Rac 1活化降低了表面钙粘蛋白水平，这是由于膜吸收的更高的整体流动抵消了Rab 11依赖性E-钙粘蛋白向连接处的递送（再循环和/或胞吐）。这种独特的小GTdR串扰对Rac 1和PAK 1在上皮去分化、粘附和运动过程中调节膜重塑有影响。
Rac1 promotes malignancy. Oncogenic Rac1 and its effector PAK1 disrupt junctions via internalization of cadherin adhesion receptors by bulk fluid uptake. PAK1 phosphorylates a key regulator of intracellular trafficking, RabGDIβ, thereby modulating its affinity with specific partners (i.e., Rab11) to re-route cadherin away from cell–cell contacts. Rac1 GTPase is hyperactivated in tumors and contributes to malignancy. Rac1 disruption of junctions requires its effector PAK1, but the precise mechanisms are unknown. Here, we show that E-cadherin is internalized via micropinocytosis in a PAK1–dependent manner without catenin dissociation and degradation. In addition to internalization, PAK1 regulates E-cadherin transport by fine-tuning Rab small GTPase function. PAK1 phosphorylates a core Rab regulator, RabGDIβ, but not RabGDIα. Phosphorylated RabGDIβ preferentially associates with Rab5 and Rab11, which is predicted to promote Rab retrieval from membranes. Consistent with this hypothesis, Rab11 is activated by Rac1, and inhibition of Rab11 function partially rescues E-cadherin destabilization. Thus, Rac1 activation reduces surface cadherin levels as a net result of higher bulk flow of membrane uptake that counteracts Rab11-dependent E-cadherin delivery to junctions (recycling and/or exocytosis). This unique small GTPase crosstalk has an impact on Rac1 and PAK1 regulation of membrane remodeling during epithelial dedifferentiation, adhesion, and motility.
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影响因子：
3.3
作者：
Braga, VMM;Betson, M;Lamarche-Vane, N
通讯作者：
Lamarche-Vane, N
影响因子：
4
作者：
Escobar, David J.;Desai, Ridhdhi;Gottardi, Cara J.
通讯作者：
Gottardi, Cara J.
影响因子：
5.3
作者：
Dupre-Crochet, Sophie;Figueroa, Angelica;Fujita, Yasuyuki
通讯作者：
Fujita, Yasuyuki
影响因子：
4
作者：
Bek, S;Kemler, R
通讯作者：
Kemler, R
影响因子：
4
作者：
Bryant, David M.;Kerr, Markus C.;Stow, Jennifer L.
通讯作者：
Stow, Jennifer L.