From the Department of Medicine II, Endocrine Hypertension, Metabolism,
and Renal Division, Kansai Medical University, Osaka (S.M., Y. Mori, H.
Masaki, K.M., Y. Tsutsumi, Y. Moriguchi, Y.S., Y. Tanaka, T.I., M.I., H.
Matsubara); and the Pharmacological Laboratory, Taiho Pharmaceutical Co, Ltd,
Kawanai, Tokushima (Y.N.), Japan.
Correspondence to Hiroaki Matsubara, MD, Department of Medicine II, Endocrine Hypertension, Metabolism, and Renal Division, Kansai Medical University, Fumizonocho 10-15, Moriguchi, Osaka 570-8507, Japan. E-mail matsubah{at}takii.kmu.ac.jp
Abstract—In cardiac fibroblasts, angiotensin II
(Ang II) induced a rapid increase in extracellular signal–regulated
kinase (ERK) activity in a pertussis toxin–insensitive manner. This
ERK activation was abolished by the Gq-associated
phospholipase C inhibitor U73122 but was insensitive to
protein kinase C (PKC) inhibitors or PKC downregulation by
phorbol ester. Intracellular Ca2+ chelation by BAPTA-AM or
TMB-8 abolished Ang II–induced ERK activation, whereas treatment with
EGTA or nifedipine did not affect it. Ca2+
ionophore A23187 also induced a rapid increase in ERK activity to an
extent similar to that of Ang II stimulation. Calmodulin
inhibitors (W7 and calmidazolium) and
tyrosine kinase inhibitors (genistein and ST638) completely
blocked ERK activation by Ang II and A23187. Both Ang II and A23187
caused a rapid increase in the binding of GTP to p21Ras,
which was nearly abolished by genistein and
calmidazolium. Transfection with the dominant
negative mutant of Ras and the Ras inhibitor manumycin
completely inhibited Ang II–induced ERK activation. It was also found
for the first time that cardiac fibroblasts abundantly expressed
Ca2+-sensitive tyrosine kinase Pyk2/CAKß/RAFTK and that
Ang II markedly induced its activation in a
Ca2+/calmodulin-sensitive manner.
Overexpression of the dominant negative mutant of Pyk2 significantly
attenuated Ang II– or A23187-induced ERK activities (36% and 38%
inhibition compared with that in mock-transfected cells, respectively)
and ERK tyrosine phosphorylation levels, as well as an
increase in the binding of GTP to p21Ras. These findings
demonstrate that in cardiac fibroblasts, Ang II–induced Ras/ERK
activation is dominantly regulated by Gq-coupled
Ca2+/calmodulin signaling and that Pyk2 plays
an important role in the signal transmission for efficient activation
of the Ang II–induced Ras/ERK pathway.
© 1998 American Heart Association, Inc.
Scientific Contributions
Role of Calcium-Sensitive Tyrosine Kinase Pyk2/CAKß/RAFTK in Angiotensin II–Induced Ras/ERK Signaling
Key Words: angiotensin II • receptors, angiotensin • tyrosine kinase, calcium-sensitive • Pyk2
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