© 1999 American Heart Association, Inc.
Original Contribution |
A Dual Inhibitor of Platelet-Derived Growth Factor ß-Receptor and Src Kinase Activity Potently Interferes With Motogenic and Mitogenic Responses to PDGF in Vascular Smooth Muscle Cells
A Novel Candidate for Prevention of Vascular Remodeling
From the Department of Internal Medicine II (J.W., J.K., H.F., U.M., V.H.), Ulm University Medical Center, Ulm, Germany; Research Unit "Molecular Cell Biology" (A.U., F-D.B.), Medical Faculty, Friedrich Schiller University, Jena, Germany; Cancer Biology Research Group (J.D.B., D.F.), University of Calgary Medical Centre, Calgary, Alberta, Canada; and Department of Biological Chemistry (A.G., A.L.), Institute of Life Sciences, and Department of Organic Chemistry (A.G.), Institute of Chemistry, The Hebrew University, Jerusalem, Israel.
Correspondence regarding biochemical aspects of this study to Frank-D. Böhmer, Research Unit "Molecular Cell Biology," Medical Faculty, Friedrich Schiller University, Drackendorfer Str 1, D-07747 Jena, Germany. E-mail i5frbo{at}rz.uni-jena.de
Abstract—PP1 has previously been
described as an inhibitor of the Src-family
kinases p56Lck and FynT. We have therefore decided to use
PP1 to determine the functional role of Src in
platelet-derived growth factor (PDGF)–induced proliferation and
migration of human coronary artery smooth muscle cells
(HCASMCs). A synthetic protocol for PP1/AGL1872 has been developed, and
the inhibitory activity of PP1/AGL1872 against
Src was examined. PP1/AGL1872 potently inhibited
recombinant p60c-src in vitro and
Src-dependent tyrosine phosphorylation
in p60c-srcF572-transformed NIH3T3 cells. PP1/AGL1872 also
potently inhibited PDGF-stimulated migration of HCASMCs, as determined
in the modified Boyden chamber, as well as PDGF-stimulated
proliferation of HCASMCs. Surprisingly, in addition to inhibition of
Src kinase, PP1/AGL1872 was found to inhibit PDGF
receptor kinase in cell-free assays and in various types of intact
cells, including HCASMCs. PP1/AGL1872 did not inhibit
phosphorylation of the vascular
endothelial growth factor receptor KDR (VEGF
receptor-2; kinase-insert domain containing receptor) in
cell-free assays as well as in intact human coronary artery
endothelial cells. In line with the insensitivity of
KDR, PP1/AGL1872 had only a weak effect on vascular
endothelial growth factor–stimulated migration of
human coronary artery endothelial cells. On
treatment of cells expressing different receptor tyrosine kinases, the
activities of the epidermal growth factor receptor, fibroblast growth
factor receptor-1, and insulin-like growth factor-1 receptor were
resistant to PP1/AGL1872, whereas PDGF 
-receptor was
susceptible, albeit to a lesser extent than PDGF ß-receptor. These
data suggest that the previously described tyrosine kinase
inhibitor PP1/AGL1872 is not selective for the
Src family of tyrosine kinases. It is also a potent
inhibitor of the PDGF ß-receptor kinase but is not a
ubiquitous tyrosine kinase inhibitor. PP1/AGL1872 inhibits
migration and proliferation of HCASMCs probably by interference with 2
distinct tyrosine phosphorylation events, creating a
novel and potent inhibitory principle with possible
relevance for the treatment of pathological HCASMC activity, such as
vascular remodeling and restenosis.
Key Words: platelet-derived growth factor ß-receptor • coronary artery smooth muscle cell • atherosclerosis • restenosis • tyrphostins • PP1/AGL1872
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