RacGAP1驱动的粘着斑形成通过介导黏着连接的解体促进黑色素瘤跨内皮迁移。
RacGAP1-driven focal adhesion formation promotes melanoma transendothelial migration through mediating adherens junction disassembly.
作者信息
Zhang Pu, Bai Huiyuan, Fu Changliang, Chen Feng, Zeng Panying, Wu Chengxiang, Ye Qichao, Dong Cheng, Song Yang, Song Erqun
机构信息
College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA.
College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
出版信息
Biochem Biophys Res Commun. 2015 Mar 27;459(1):1-9. doi: 10.1016/j.bbrc.2014.11.088. Epub 2014 Dec 2.
Melanoma cell migration across vascular endothelial cells is an essential step of tumor metastasis. Here, we provide evidence that RacGAP1, a cytokinesis-related Rho GTPase-activating protein, contributed to this process. Depletion of RacGAP1 with RacGAP1-targeting siRNA or overexpression of RacGAP1 mutant (T249A) attenuated melanoma cell transendothelial migration and concomitant changes of adherens junctions. In addition, RacGAP1 promoted the activations of RhoA, FAK, paxillin and triggered focal adhesion formation and cytoskeletal rearrangement. By overexpressing FAK-related non-kinase (FRNK) in endothelium, we showed that RacGAP1 mediated endothelial barrier function loss and melanoma transmigration in a focal adhesion-dependent manner. These results suggest that endothelial RacGAP1 may play critical roles in pathogenic processes of cancer by regulating endothelial permeability.
黑色素瘤细胞穿过血管内皮细胞的迁移是肿瘤转移的关键步骤。在此，我们提供证据表明RacGAP1，一种与胞质分裂相关的Rho GTP酶激活蛋白，参与了这一过程。用靶向RacGAP1的小干扰RNA耗尽RacGAP1或过表达RacGAP1突变体（T249A）会减弱黑色素瘤细胞的跨内皮迁移以及黏附连接的相应变化。此外，RacGAP1促进RhoA、黏着斑激酶（FAK）、桩蛋白的激活，并触发黏着斑形成和细胞骨架重排。通过在内皮细胞中过表达FAK相关非激酶（FRNK），我们发现RacGAP1以黏着斑依赖的方式介导内皮屏障功能丧失和黑色素瘤细胞迁移。这些结果表明，内皮RacGAP1可能通过调节内皮通透性在癌症致病过程中发挥关键作用。
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