Journal
JOURNAL OF CELL BIOLOGY
Volume 204, Issue 2, Pages 247-263Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201307067
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Funding
- ViCell XR cell analyzer [CM1950 cryostat, BX43 microscope, CKX31 microscope]
- National Institutes of Health [HL093156, CA102310, R37 CA50286]
- Italian Association for Cancer Research and European Research Council [268870]
- American Heart Association [12POST11760014]
- Susan G. Komen for the Cure grant [KG111237]
- Canadian Institutes of Health Research grant [200810MFE-193594-139144]
- Ruth Kirschstein National Institutes of Health [F32CA159558]
- British Heart Foundation [PG/11/62/29010] Funding Source: researchfish
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Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.
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