Regulation of integrin trafficking, cell adhesion, and cell migration by WASH and the Arp2/3 complex.
Regulation of integrin trafficking, cell adhesion, and cell migration by WASH and the Arp2/3 complex.
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DOI：
10.1002/cm.21069
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发表时间：
2012-12
期刊：
影响因子：
2.9
通讯作者：
Welch, Matthew D.
中科院分区：
文献类型：
--
作者：
Duleh, Steve N.;Welch, Matthew D.
WASH是Arp2/3复合体的成核促进因子，参与多种内吞转运途径，包括受体循环、货物降解和逆转录介导的受体恢复。我们试图研究WASH是否在整合素等特殊货物分子的贩运中发挥重要作用，对于整合素来说，细胞迁移过程中的贩运受到高度调控。我们观察到，与动态洗涤和丝状肌动蛋白以及α5-整合素相关的早期/分选内容体的亚域通过该内容体群体进行交易。WASH的耗尽导致α5-整合素在细胞内的积聚，α5-整合素在局灶性粘连的定位减少，以及局灶性粘附数的减少。当洗涤耗尽或α/3复合体被抑制时，ARP5-整合素从内部内吞细胞结构到局部粘连的运输被破坏。此外，洗涤耗尽的细胞对包括纤维连接蛋白在内的特定ECM蛋白的亲和力大大降低，并损害了细胞的扩散能力。有趣的是，在伤口愈合试验中，洗涤耗尽细胞的黏附能力降低导致它们的迁移速度比对照细胞更快。我们的结果定义了在整合素的专门运输中对WASH、Arp2/3复合体和肌动蛋白的要求。这些发现强调了肌动蛋白动力学通过整合素的胞内转运影响细胞黏附和迁移的作用，以及肌动蛋白在质膜动力学和收缩中的作用。
WASH is a nucleation-promoting factor for the Arp2/3 complex that is implicated in multiple endocytic trafficking pathways including receptor recycling, cargo degradation, and retromer-mediated receptor retrieval. We sought to examine whether WASH plays an important role in trafficking of specialized cargo molecules such as integrins, for which trafficking is highly regulated during cell migration. We observed that subdomains of early/sorting endosomes associated with dynamic WASH and filamentous actin, and α5-integrins trafficked through this population of endosomes. Depletion of WASH caused accumulation of α5-integrins in intracellular compartments, reduction of α5-integrin localization at focal adhesions, and reduction in focal adhesion number. Transport of α5-integrins from internal endocytic structures to focal adhesions was disrupted upon WASH depletion or Arp2/3 complex inhibition. Furthermore, WASH-depleted cells displayed greatly reduced affinity for specific ECM proteins including fibronectin, and impaired cell spreading ability. Interestingly, the reduced adhesion capacity of WASH-depleted cells resulted in their migrating more rapidly than control cells in wound healing assays. Our results define a requirement for WASH, Arp2/3 complex, and actin in specialized trafficking of integrins. These findings highlight a role for actin dynamics in influencing cell adhesion and migration via endocytic trafficking of integrins, in addition to the well-established role of actin in plasma membrane dynamics and contractility.
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DOI：
10.1038/nrm2867
发表时间：
2010-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
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DOI：
10.1083/jcb.201009119
发表时间：
2011-05-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Carnell M;Zech T;Calaminus SD;Ura S;Hagedorn M;Johnston SA;May RC;Soldati T;Machesky LM;Insall RH
通讯作者：
Insall RH
影响因子：
4
作者：
Humphries JD;Byron A;Humphries MJ
通讯作者：
Humphries MJ
影响因子：
11.8
作者：
Lobert, Viola Helene;Brech, Andreas;Stenmark, Harald
通讯作者：
Stenmark, Harald