RT Journal Article
SR Electronic
T1 Src and Cas Are Essentially but Differentially Involved in Angiotensin II-Stimulated Migration of Vascular Smooth Muscle Cells via Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH<sub>2</sub>-Terminal Kinase Activation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 832
OP 841
DO 10.1124/mol.65.4.832
VO 65
IS 4
A1 Moe Kyaw
A1 Masanori Yoshizumi
A1 Koichiro Tsuchiya
A1 Shoji Kagami
A1 Yuki Izawa
A1 Yoshiko Fujita
A1 Nermin Ali
A1 Yasuhisa Kanematsu
A1 Kazunori Toida
A1 Kazunori Ishimura
A1 Toshiaki Tamaki
YR 2004
UL http://molpharm.aspetjournals.org/content/65/4/832.abstract
AB Angiotensin II (Ang II) plays an important role in several cardiovascular diseases associated with vascular smooth muscle cell (VSMC) growth and migration. Src activity is known to be required for the migration of a number of cell types. p130Cas was reported to be essential for cell migration and actin filament reorganization. Mitogen-activated protein (MAP) kinases were also reported to be critical regulatory factors for growth and migration of VSMC. However, precise intracellular mechanisms involving c-Src, p130Cas, and MAP kinases in Ang II-stimulated migration of VSMC have not been well elucidated. Here we demonstrated that Ang II rapidly and significantly stimulated tyrosine phosphorylation of Src and Cas and their association in rat aortic smooth muscle cells (RASMC). Ang II-stimulated tyrosine phosphorylation of Src and Cas and activation of ERK1/2 and JNK, but not p38, were potently inhibited by Src family tyrosine kinase inhibitors, herbimycin A (HA) and PP2. Ang II-stimulated Src and Cas association, tyrosine phosphorylation of Cas, and activation of ERK1/2 and JNK were suppressed in kinase-inactive Src (KI Src)-overexpressed RASMC. Ang II-stimulated JNK activation but not ERK1/2 activation was blocked in substrate domain-deleted Cas (ΔSD Cas)-overexpressed RASMC. In addition, HA, PP2, ERK1/2 inhibitor, 2′-amino-3′-methoxyflavone (PD98059) and JNK inhibitor, and anthra[1,9-cd]pyrazol-6(2H)-one (SP600125) significantly inhibited Ang II-stimulated migration of RASMC. Ang II-induced colocalization of Src and Cas and migration were inhibited in both KI Src- and ΔSD Cas-overexpressed RASMC. These findings suggest that Src and Cas are essentially but differentially involved in Ang II-stimulated migration of VSMC through the activation of ERK1/2 and JNK.