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2015 ; 34
(15
): 1979-90
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Vimentin regulates lung cancer cell adhesion through a VAV2-Rac1 pathway to
control focal adhesion kinase activity
#MMPMID24858039
Havel LS
; Kline ER
; Salgueiro AM
; Marcus AI
Oncogene
2015[Apr]; 34
(15
): 1979-90
PMID24858039
show ga
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.
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