title: RacGAP1-driven focal adhesion formation promotes melanoma transendothelial migration through mediating adherens junction disassembly.
abstract: 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.
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA. Electronic address: pxz122@swu.edu.cn.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA.
authors.forename: Changliang
authors.initials: C
authors.lastname: Fu
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Panying
authors.initials: P
authors.lastname: Zeng
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Chengxiang
authors.initials: C
authors.lastname: Wu
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Bioengineering, Pennsylvania State University, University Park, PA 16801, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Dong
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Erqun
authors.initials: E
authors.lastname: Song
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C496061:PXN protein, human; D051419:Paxillin; C115995:mgcRacGAP; C066737:RHOA protein, human; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020742:rhoA GTP-Binding Protein
keywords: Actin; Endothelial junction; FAK; Paxillin; RacGAP1; RhoA