title: Vimentin regulates lung cancer cell adhesion through a VAV2-Rac1 pathway to control focal adhesion kinase activity.
abstract: Vimentin is an intermediate filament protein whose expression correlates with increased metastatic disease, reduced patient survival and poor prognosis across multiple tumor types. Despite these well-characterized correlations, the molecular role of vimentin in cancer cell motility remains undefined. To approach this, we used an unbiased phosphoproteomics screen in lung cancer cell lines to discover cell motility proteins that show significant changes in phosphorylation upon vimentin depletion. We identified the guanine nucleotide exchange factor (GEF), VAV2, as having the greatest loss of phosphorylation owing to vimentin depletion. Since VAV2 serves as a GEF for the small Rho GTPase Rac1, a key player in cell motility and adhesion, we explored the vimentin-VAV2 pathway as a potential novel regulator of lung cancer cell motility. We show that VAV2 localizes to vimentin-positive focal adhesions (FAs) in lung cancer cells and complexes with vimentin and FA kinase (FAK). Vimentin loss impairs both pY142-VAV2 and downstream pY397-FAK activity showing that vimentin is critical for maintaining VAV2 and FAK activity. Importantly, vimentin depletion reduces the activity of the VAV2 target, Rac1, and a constitutively active Rac1 rescues defects in FAK and cell adhesion when vimentin or VAV2 is compromised. Based upon this data, we propose a model whereby vimentin promotes FAK stabilization through VAV2-mediated Rac1 activation. This model may explain why vimentin expressing metastatic lung cancer cells are more motile and invasive.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Havel
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Kline
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Salgueiro
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Marcus
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014746:Vimentin / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051567:Proto-Oncogene Proteins c-vav; C107953:RAC1 protein, human; C093651:VAV2 protein, human; D014746:Vimentin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020830:rac1 GTP-Binding Protein