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Publication Detail

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

Authors: Cooke, Mariana; Kreider-Letterman, Gabriel; Baker, Martin J; Zhang, Suli; Sullivan, Neil T; Eruslanov, Evgeniy; Abba, Martin C; Goicoechea, Silvia M; García-Mata, Rafael; Kazanietz, Marcelo G

Published In Cell Rep, (2021 11 02)

Abstract: 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.

PubMed ID: 34731623 Exiting the NIEHS site

MeSH Terms: A549 Cells; Adenocarcinoma of Lung/enzymology*; Adenocarcinoma of Lung/genetics; Adenocarcinoma of Lung/pathology; Aged; Cell Movement; Epithelial Cell Adhesion Molecule/metabolism; ErbB Receptors/genetics; ErbB Receptors/metabolism; Female; Gene Expression Regulation, Neoplastic; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism*; Humans; Lung Neoplasms/enzymology*; Lung Neoplasms/genetics; Lung Neoplasms/pathology; Male; Middle Aged; Neoplasm Invasiveness; Proto-Oncogene Proteins c-met/genetics; Proto-Oncogene Proteins c-met/metabolism; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Receptor Protein-Tyrosine Kinases/genetics; Receptor Protein-Tyrosine Kinases/metabolism*; Rho Guanine Nucleotide Exchange Factors/genetics; Rho Guanine Nucleotide Exchange Factors/metabolism*; Signal Transduction; rac1 GTP-Binding Protein/genetics; rac1 GTP-Binding Protein/metabolism*

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