Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, M13 9PT Manchester, England, UK.
J Cell Biol. 2013 Sep 16;202(6):917-35. doi: 10.1083/jcb.201302041. Epub 2013 Sep 9.
Inhibition of αvβ3 or expression of mutant p53 promotes invasion into fibronectin (FN)-containing extracellular matrix (ECM) by enhancing Rab-coupling protein (RCP)-dependent recycling of α5β1 integrin. RCP and α5β1 cooperatively recruit receptor tyrosine kinases, including EGFR1, to regulate their trafficking and downstream signaling via protein kinase B (PKB)/Akt, which, in turn, promotes invasive migration. In this paper, we identify a novel PKB/Akt substrate, RacGAP1, which is phosphorylated as a consequence of RCP-dependent α5β1 trafficking. Phosphorylation of RacGAP1 promotes its recruitment to IQGAP1 at the tips of invasive pseudopods, and RacGAP1 then locally suppresses the activity of the cytoskeletal regulator Rac and promotes the activity of RhoA in this subcellular region. This Rac to RhoA switch promotes the extension of pseudopodial processes and invasive migration into FN-containing matrices, in a RhoA-dependent manner. Thus, the localized endocytic trafficking of α5β1 within the tips of invasive pseudopods elicits signals that promote the reorganization of the actin cytoskeleton, protrusion, and invasion into FN-rich ECM.
αvβ3 的抑制或突变 p53 的表达通过增强 Rab 偶联蛋白 (RCP) 依赖性 α5β1 整联蛋白的再循环，促进整合素向含有纤维连接蛋白 (FN) 的细胞外基质 (ECM) 的侵袭。RCP 和 α5β1 共同募集受体酪氨酸激酶，包括 EGFR1，通过蛋白激酶 B (PKB)/Akt 调节它们的运输和下游信号，这反过来又促进了侵袭性迁移。在本文中，我们鉴定了一种新的 PKB/Akt 底物 RacGAP1，它是由于 RCP 依赖性 α5β1 运输而磷酸化的。RacGAP1 的磷酸化促进其在侵袭性伪足尖端与 IQGAP1 的募集，然后 RacGAP1 在该亚细胞区域局部抑制细胞骨架调节剂 Rac 的活性并促进 RhoA 的活性。这种 Rac 到 RhoA 的转换以 RhoA 依赖性的方式促进伪足过程的延伸和侵入 FN 富含 ECM 的迁移。因此，在侵袭性伪足尖端的 α5β1 的局部内吞运输引发了促进肌动蛋白细胞骨架重排、突起和侵入富含 FN 的 ECM 的信号。
