Urotensin II-induced activation of extracellular signal-regulated kinase in cultured vascular smooth muscle cells: involvement of cell adhesion-mediated integrin signaling.
Urotensin II (UII), a cyclic dodecapeptide, is a potent mammalian vasoconstrictive substance recently shown to induce proliferation of vascular smooth muscle cells (VSMCs). However, little is known about mechanisms involved in UII-induced mitogenic response such as cell proliferation. To investigate the intracellular signaling pathways involved in this process, we examined the effects of UII on activation of extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK) in VSMCs. UII stimulated in time- and dose-dependent manners the phosphorylation level of ERK. In contrast, UII failed to alter the phosphorylation level of FAK. Although angiotensin II-induced ERK phosphorylation was noted even in suspended cells, UII failed to induce an increase in ERK phosphorylation in such cells. On the other hand, UII induced an increase in the phosphorylation level of ERK, but not FAK, in cells adherent to fibronectin. Furthermore, UII-induced proliferation of VSMCs was inhibited by ERK kinase inhibitor PD98059. Our results suggested that activation of integrin-mediated signaling pathways play a critical role in UII-induced phosphorylation of ERK, leading to proliferation of VSMCs, which does not involved increased phosphorylation of FAK.
Tamura
Kazuhiko
K
The Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Okazaki
Masahiro
M
Tamura
Masahito
M
Isozumi
Kazuhiko
K
Tasaki
Hiromi
H
Nakashima
Yasuhide
Y
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014579:Urotensins / Q000494:pharmacology*
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D005419:Flavonoids; D014579:Urotensins; D000804:Angiotensin II; C029677:urotensin II; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one