Signal-crosstalk between Rho/ROCK and c-Jun NH2-terminal kinase mediates migration of vascular smooth muscle cells stimulated by angiotensin II.
BACKGROUND
Rho and its effector Rho-kinase/ROCK mediate cytoskeletal reorganization as well as smooth muscle contraction. Recent studies indicate that Rho and ROCK are critically involved in vascular remodeling. Here, we tested the hypothesis that Rho/ROCK are critically involved in angiotensin II (Ang II)-induced migration of vascular smooth muscle cells (VSMCs) by mediating a specific signal cross-talk.


RESULTS
Immunoblotting demonstrated that Ang II stimulated phosphorylation of a ROCK substrate, regulatory myosin phosphatase targeting subunit (MYPT)-1. Phosphorylation of MYPT-1 as well as migration of VSMCs induced by Ang II was inhibited by dominant-negative Rho (dnRho) or ROCK inhibitor, Y27632. Ang II-induced c-Jun NH2-terminal kinase (JNK) activation, but extracellular signal-regulated kinase (ERK) activation was not mediated through Rho/ROCK. Thus, infection of adenovirus encoding dnJNK inhibited VSMC migration by Ang II. We have further demonstrated that the Rho/ROCK activation by Ang II requires protein kinase C-delta (PKCdelta) and proline-rich tyrosine kinase 2 (PYK2) activation, but not epidermal growth factor receptor transactivation. Also, VSMCs express PDZ-Rho guanine nucleotide exchange factor (GEF) and Ang II stimulated PYK2 association with tyrosine phosphorylated PDZ-RhoGEF.


CONCLUSIONS
PKCdelta/PYK2-dependent Rho/ROCK activation through PDZ-RhoGEF mediates Ang II-induced VSMC migration via JNK activation in VSMCs, providing a novel mechanistic role of the Rho/ROCK cascade that is involved in vascular remodeling.
Ohtsu
Haruhiko
H
Cardiovascular Research Center, Temple University School of Medicine, 3420 N Broad St, Philadelphia, PA 19140, USA.
Mifune
Mizuo
M
Frank
Gerald D
GD
Saito
Shuichi
S
Inagami
Tadashi
T
Kim-Mitsuyama
Shokei
S
Takuwa
Yoh
Y
Sasaki
Terukatsu
T
Rothstein
Jeffrey D
JD
Suzuki
Hiroyuki
H
Nakashima
Hidekatsu
H
Woolfolk
Elethia A
EA
Motley
Evangeline D
ED
Eguchi
Satoru
S
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases
C577234:ARHGEF11 protein, human; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D051418:Focal Adhesion Kinase 2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins