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.
Keywords:
ARHGEF39; AXL; EGFR; FARP1; Rac-GEF; Rac1; TIAM2; lung cancer; migration; ruffles.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Video-Audio Media
MeSH terms
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A549 Cells
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Adenocarcinoma of Lung / enzymology*
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Adenocarcinoma of Lung / genetics
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Adenocarcinoma of Lung / pathology
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Aged
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Axl Receptor Tyrosine Kinase
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Cell Movement
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Epithelial Cell Adhesion Molecule / metabolism
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Gene Expression Regulation, Neoplastic
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Male
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Middle Aged
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Neoplasm Invasiveness
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Rho Guanine Nucleotide Exchange Factors / genetics
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Rho Guanine Nucleotide Exchange Factors / metabolism*
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Signal Transduction
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism*
Substances
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ARHGEF39 protein, human
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EPCAM protein, human
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Epithelial Cell Adhesion Molecule
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FARP1 protein, human
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Guanine Nucleotide Exchange Factors
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Proto-Oncogene Proteins
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RAC1 protein, human
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Rho Guanine Nucleotide Exchange Factors
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TIAM2 protein, human
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EGFR protein, human
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ErbB Receptors
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MET protein, human
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Proto-Oncogene Proteins c-met
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Receptor Protein-Tyrosine Kinases
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rac1 GTP-Binding Protein
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Axl Receptor Tyrosine Kinase
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AXL protein, human