Activation of MAPKs by angiotensin II in vascular smooth muscle cells - Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK
S. Eguchi et al., Activation of MAPKs by angiotensin II in vascular smooth muscle cells - Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK, J BIOL CHEM, 276(11), 2001, pp. 7957-7962
In cultured vascular smooth muscle cells (VSMC), the vasculotrophic factor,
angiotensin II (AngII) activates three major MAPKs via the G(q)-coupled AT
(1) receptor. Extracellular signal-regulated kinase (ERK) activation by Ang
II requires Ca2+-dependent "transactivation" of the EGF receptor that may i
nvolve a metalloprotease to stimulate processing of an EGF receptor ligand
from its precursor. Whether EGF receptor transactivation also contributes t
o activation of other members of MAPKs such as p38MAPK and c-Jun N-terminal
kinase (JNK) by AngII remains unclear. In the present study, we have exami
ned the effects of a synthetic metalloprotease inhibitor BB2116, and the EG
F receptor kinase inhibitor AG1478 on AngII-induced activation of MAPKs in
cultured VSMC, BB2116 markedly inhibited ERK activation induced by AngII or
the Ca2+ ionophore A23187 without affecting the activation by EGF or PDGF,
BB2116 as well as HB-EGF neutralizing antibody inhibited the EGF receptor
transactivation by AngII, suggesting a critical role of HB-EGF in the metal
loprotease-dependent EGF receptor transactivation. In addition to the ERK a
ctivation, activation of p38MAPK and JNK by AngII was inhibited by an AT(1)
receptor antagonist, RNH6270. A23187 and EGF markedly activate p38MAPK, wh
ereas A23187 but not EGF markedly activates JNK, indicating the possible co
ntribution of the EGF receptor transactivation to the p38MAPK activation, T
he findings that both BB2116 and AG1478 specifically inhibited activation o
f p38MAPK but not JNK by AngII support this hypothesis. From these data, we
conclude that ERK and p38MAPK activation by AngII requires the metalloprot
ease-dependent EGF receptor transactivation, whereas the JNK activation is
regulated without involvement of EGF receptor transactivation.