Thrombin is a potent mitogen for vascular smooth muscle cells. However, the
signaling pathways by which thrombin mediates its mitogenic response are n
ot fully understood. The ERK (extracellular signal-regulated protein kinase
) and JNK (c-Jun N-terminal kinase) members of the mitogen-activated protei
n kinase (MAPK) family are reported to be activated by thrombin. We have in
vestigated the response to thrombin of another member of the MAPK family, p
38 MAPK, which has been suggested to be activated by both stress and inflam
matory stimuli in vascular smooth muscle cells. We found that thrombin indu
ced time- and dose-dependent activation of p38 MAPK. Maximal stimulation of
p38 MAPK was observed after a 10-min incubation with 1 unit ml(-1) thrombi
n. GF109203X, a protein kinase C inhibitor, and prolonged treatment with ph
orbol 12-myristate 13-acetate partially inhibited p38 MAPK activation. A ty
rosine kinase inhibitor, genistein, also inhibited p38 MAPK activation in a
dose-dependent manner. p38 MAPK activation was inhibited by overexpression
of beta ARK1ct (beta -adrenergic receptor kinase 1 C-terminal peptide). p3
8 MAPK activation was also inhibited by expression of dominant-negative Ras
, not by dominant-negative Rac. We next examined the effect of a p38 MAPK i
nhibitor, SB203580, on thrombin-induced proliferation. SB203580 inhibited t
hrombin-induced DNA synthesis in a dose-dependent manner. These results sug
gest that thrombin activates p38 MAPK in a manner dependent on G beta gamma
, protein kinase C, a tyrosine kinase, and Ras, that p38 MAPK has a role in
thrombin-induced mitogenic response in the cells. (C) 2001 Elsevier Scienc
e Inc. All rights reserved.