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Vascular Endothelial Growth Factor
Receptor-3 and Focal Adhesion Kinase Bind and Suppress Apoptosis in
Breast Cancer
Cells
Christopher A. Garces, Elena
V. Kurenova, Vita M. Golubovskaya and William
G. Cance
Departments of Surgery,
Biochemistry, and Molecular Biology, University of Florida,
Gainesville, Florida. Requests for reprints: William G. Cance,
Department of Surgery, University of Florida, P.O. Box 100286, 1600
Southwest Archer Road, Gainesville, FL 32610. Phone: 352-265-0622;
Fax: 352-338-9809; E-mail: cance@surgery.ufl.edu.
Received 5/13/05; revised 11/23/05; accepted 12/ 6/05.
Focal adhesion kinase (FAK) and
vascular endothelial growth factor receptor-3 (VEGFR-3) are
protein tyrosine kinases that are overexpressed in human cancer
and play an important role in survival signaling.
In addition to its involvement with
cell survival, VEGFR-3 is a primary factor in lymphatic
angiogenesis.
Because FAK function is regulated
by its COOH terminus (FAK-CD), we used FAK-CD as a target
to identify binding partners.
We isolated a peptide
from a phage library that bound to FAK-CD, specifically the
focal adhesion targeting domain of FAK and was homologous
to VEGFR-3, suggesting these two tyrosine kinases physically
interact.
We have also shown that VEGFR-3 is
overexpressed in human breast tumors and cancer
cell lines.
For the first time, we
have shown the physical association of FAK and VEGFR-3.
The association between the NH2
terminus of VEGFR-3, containing the peptide identified by
phage display, and the COOH terminus of FAK was detected by
in vitro and in vivo binding studies.
We then coupled a 12-amino-acid
VEGFR-3 peptide, AV3, to a TAT cellular penetration
sequence and showed that AV3 and not control-scrambled peptide
caused specific displacement of FAK from the focal adhesions and
affected colocalization of FAK and VEGFR-3.
In addition, AV3 peptide
decreased proliferation and caused cell detachment and
apoptosis in breast cancer
cell lines but not in normal breast cells.
Thus, the FAK/VEGFR-3 interaction
may have a potential use to develop novel molecular
therapeutics to target the signaling between FAK and
VEGFR-3 in human tumors.
(Cancer
Res 2006; 66(3): 1446-54)
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