FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma

作者：Mariana Cooke, Gabriel Kreider-Letterman, Martin J. Baker, Suli Zhang, Neil T. Sullivan, Evgeniy B. Eruslanov, Martı́n C. Abba, Silvia M. Goicoechea, Rafael García‐Mata, Marcelo G. Kazanietz · 发表于：Cell Reports · 年份：2021 · DOI：10.1016/j.celrep.2021.109905 · 被引用次数：40 · 研究领域：Microtubule and mitosis dynamics、Protein Kinase Regulation and GTPase Signaling、Hippo pathway signaling and YAP/TAZ

Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam + cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.