title: Suppression of mitogen-activated protein kinase phosphatase-1 (MKP-1) by heparin in vascular smooth muscle cells.
abstract: Heparin inhibits vascular smooth muscle cell (VSMC) proliferation, but mechanisms remain elusive. Because heparin inhibits signaling through multiple kinase cascades, we investigated the possibility that phosphatases could be involved. Mitogen-activated protein kinase phosphatase-1 (MKP-1) was the predominant MKP detected in VSMC lines. MKP-1 protein was increased by serum stimulation of quiescent cells, and this increase was diminished by heparin (1 microg/mL). Increased MKP-1 expression was dependent on the mitogen-activated protein kinase, Erk. Decreased Erk activity in the presence of heparin preceded, and may account for, decreased MKP-1. The antimitogenic effects of heparin are therefore unlikely to act through a shift in the kinase/phosphatase balance, but rather through direct kinase suppression. However, because MKP-1 is known to cause an increase in activity of kinases upstream of Erk, that may signal through additional pathways, the decrease in MKP-1 activity may paradoxically enhance heparin's antiproliferative effects. VSMC selected to grow in the presence of heparin express decreased levels of MKP-1 that are unresponsive to heparin, and Erk activity becomes unresponsive to heparin in one cell line. We conclude that phosphatase activation is not a direct mechanism of suppression of multiple kinase cascades by heparin.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Building, Rm. 6302, 1 King's College Circle, Toronto, Ont., Canada M5S 1A8.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Weiqun
authors.initials: W
authors.lastname: Xiao
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Templeton
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D051381:Rats
chemical_list: D000925:Anticoagulants; D006493:Heparin; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases