Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments.
Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments.
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DOI：
10.1083/jcb.200804140
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发表时间：
2008-10-06
影响因子：
7.8
通讯作者：
Norman, Jim C.
中科院分区：
文献类型：
--
作者：
Caswell, Patrick T.;Chan, May;Lindsay, Andrew J.;McCaffrey, Mary W.;Boettiger, David;Norman, Jim C.
我们发现，阻断αvβ3整合素与可溶性RGD配体(如骨桥蛋白或Cilengide)的黏附功能，可促进RAB偶联蛋白与α5β1整合素的结合，并推动α5β1依赖于Rcp循环到质膜上，并动员到细胞前沿的动态褶皱突起。这些RCP驱动的α5β1运输的变化导致了二维基质上的快速/随机移动，并显著增加了肿瘤细胞向三维基质中依赖纤维连接蛋白的迁移。α5β1整合素的再循环不影响其调节或与底物纤维连接蛋白形成粘连的能力。相反，α5β1控制了EGFR 1与RCP的结合，促进了这两个受体的协调循环。这改变了EGFR1下游的信号转导途径，以增加其自身磷酸化和侵袭性蛋白激酶原PKB/Akt的激活。我们的结论是，RCP提供了一种支架，促进了α-5、β-1和EGFR-1的物理结合和协调运输，并推动了肿瘤细胞向三维基质的迁移。
Here we show that blocking the adhesive function of αvβ3 integrin with soluble RGD ligands, such as osteopontin or cilengitide, promoted association of Rab-coupling protein (RCP) with α5β1 integrin and drove RCP-dependent recycling of α5β1 to the plasma membrane and its mobilization to dynamic ruffling protrusions at the cell front. These RCP-driven changes in α5β1 trafficking led to acquisition of rapid/random movement on two-dimensional substrates and to a marked increase in fibronectin-dependent migration of tumor cells into three-dimensional matrices. Recycling of α5β1 integrin did not affect its regulation or ability to form adhesive bonds with substrate fibronectin. Instead, α5β1 controlled the association of EGFR1 with RCP to promote the coordinate recycling of these two receptors. This modified signaling downstream of EGFR1 to increase its autophosphorylation and activation of the proinvasive kinase PKB/Akt. We conclude that RCP provides a scaffold that promotes the physical association and coordinate trafficking of α5β1 and EGFR1 and that this drives migration of tumor cells into three-dimensional matrices.
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