文章基本信息

标题：Inside-out signaling through FAK–integrin axis may regulate circulating cancer cell metastatic adhesion
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作者：April Gunawan ; Rilla Sovitriana ; Agus Djoko Santosa 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：40
页码：19795-19796
DOI：10.1073/pnas.1904767116
出版社：The National Academy of Sciences of the United States of America
摘要：In PNAS, Chang et al. (1) call attention to the function of focal adhesion kinase (FAK) in mediating inside-out signaling regulating immune cell adhesion to the endothelium by elegantly studying the FAK–RAP1–RIAM–talin pathway for feedforward inside-out signaling through integrin described by Lagarrigue (2). Chang et al. solve the crystal structure of the RIAM inhibitory segment (IN), RAS association (RA), and Pleckstrin homology (PH) domains, showing that IN/RA-PH domain interaction autoinhibits RIAM, hampering RIAM–RAP1 association. This abrogates RAP1-dependent translocation of RIAM to the plasma membrane. Upon T cell receptor activation, FAK phosphorylates Tyr45 on the RIAM IN domain, abolishing the RIAM autoinhibitory loop and facilitating RIAM membrane translocation (1). However, FAK-driven inside-out signaling also regulates epithelial cell adhesion (3). In particular, Akt1–FAK interaction also mediates adhesion of epithelial cancer cells to matrix proteins (4⇓–6) and endothelial cells (7) exposed to forces like pressure (4, 7) and shear (8). Activation of this pathway impairs survival in animal models of direct surgical tumor implantation.