α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3.
α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3.
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DOI：
10.1083/jcb.201502040
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发表时间：
2015-09-14
期刊：
影响因子：
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通讯作者：
Caswell PT
中科院分区：
文献类型：
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作者：
Paul NR;Allen JL;Chapman A;Morlan-Mairal M;Zindy E;Jacquemet G;Fernandez del Ama L;Ferizovic N;Green DM;Howe JD;Ehler E;Hurlstone A;Caswell PT
Rab-coupling蛋白介导的整合素运输通过RhoA-ROCK-FHOD 3促进丝状伪足形成，产生非片状伪足肌动蛋白刺突，其驱动癌细胞在3D细胞外基质和体内迁移。三维细胞外基质（ECM）中的侵入性迁移对癌症转移至关重要，但当癌细胞在体内扩散时，驱动细胞骨架重组的分子机制知之甚少。2D Rac驱动的板状伪足迁移是很好理解的，但这些特征如何应用于3D迁移尚不清楚。我们发现，在三维ECM中移动的细胞中确实观察到片状伪足样突起和逆行肌动蛋白流。然而，Rab-coupling protein（RCP）驱动的α5β1整联蛋白的内吞再循环增强了癌细胞侵入性迁移到富含纤连蛋白的3D ECM中，这是由RhoA和基于丝状伪足棘突的突起驱动的，而不是由板状伪足驱动的。此外，我们表明，肌动蛋白尖峰突起Arp 2/3-独立的。在体内外侵袭细胞中动态的肌动蛋白锋电位组装受包含3的Formin同源结构域（FHOD 3）的调控，FHOD 3被RhoA/ROCK激活，建立了RCP-α5β1途径重编程肌动蛋白细胞骨架以促进体内侵袭性迁移和局部侵袭的新机制。
Rab-coupling protein–mediated integrin trafficking promotes filopodia formation via RhoA-ROCK-FHOD3, generating non-lamellipodial actin spike protrusions that drive cancer cell migration in 3D extracellular matrix and in vivo. Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of α5β1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP–α5β1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo.