FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
Mariana Cooke,
Gabriel Kreider-Letterman,
Martin J. Baker,
Suli Zhang,
Neil T. Sullivan,
Evgeniy Eruslanov,
Martin C. Abba,
Silvia M. Goicoechea,
Rafael García-Mata,
Marcelo G. Kazanietz
Affiliations
Mariana Cooke
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA 19141, USA
Gabriel Kreider-Letterman
Department of Biological Sciences, University of Toledo, Ohio, OH 43606, USA
Martin J. Baker
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Suli Zhang
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Neil T. Sullivan
Division of Thoracic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Evgeniy Eruslanov
Division of Thoracic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Martin C. Abba
Centro de Investigaciones Inmunológicas Básicas y Aplicadas, Universidad Nacional de La Plata, CP1900 La Plata, Argentina
Silvia M. Goicoechea
Department of Biological Sciences, University of Toledo, Ohio, OH 43606, USA
Rafael García-Mata
Department of Biological Sciences, University of Toledo, Ohio, OH 43606, USA; Corresponding author
Marcelo G. Kazanietz
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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.
