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J. Biol. Chem., Vol. 277, Issue 49, 47257-47262, December 6, 2002
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From the § Section of Immunobiology, Yale University
School of Medicine and Howard Hughes Medical Institute, New Haven,
Connecticut 06520 and the Transforming growth factor-
Requirement of Mitogen-activated Protein Kinase Kinase 3 (MKK3) for Activation of p38
and p38
MAPK Isoforms by
TGF-
1 in Murine Mesangial Cells*
,,¶
Renal-Electrolyte Division,
Department of Medicine, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15213
1 (TGF-1)
is a potent inducer of extracellular matrix (ECM) synthesis that leads
to renal fibrosis. Intracellular signaling mechanisms involved
in this process remain incompletely understood. Mitogen-activated
protein kinase (MAPK) is a major stress signal-transducing pathway, and
we have previously reported activation of p38 MAPK by TGF-1 in rat
mesangial cells and its role in the stimulation of pro-
1(I)
collagen. In this study, we further investigated the mechanism
of p38 MAPK activation by TGF-1 and the role of MKK3, an upstream
MAPK kinase of p38 MAPK, by examining the effect of targeted disruption
of the Mkk3 gene. We first isolated glomerular mesangial
cells from MKK3-null (Mkk3
/) and wild-type
(Mkk3+/+) control mice. Treatment with TGF-1 induced
rapid phosphorylation of MKK3 as well as p38 MAPK within 15 min in
cultured wild-type (Mkk3+/+) mouse mesangial cells. In
contrast, TGF-1 failed to induce phosphorylation of either MKK3 or
p38 MAPK in MKK3-deficient (Mkk3/) mouse mesangial cells, indicating that MKK3 is required for TGF-1-induced p38 MAPK
activation. TGF-1 selectively activated the p38 MAPK isoforms p38
and p38
in wild-type (Mkk3+/+) mesangial cells, but not in MKK3-deficient (Mkk3/) mesangial cells. Thus,
activation of p38 and p38 is dependent on the activation of
upstream MKK3 by TGF-1. Furthermore, MKK3 deficiency resulted
in a selective disruption of TGF-1-stimulated up-regulation of
pro-1(I) collagen expression but not TGF-1 induction of
fibronectin and PAI-1. These data demonstrate that the MKK3 is a
critical component of the TGF-1 signaling pathway, and its
activation is required for subsequent p38 and p38 MAPK activation
and collagen stimulation by TGF-1.
*
This work was supported in part by NIDDK, National
Institutes of Health Grant R01 DK57661, Grant-in-Aid 0051319T from the American Heart Association (AHA), and a Veterans Affairs Career Development Award (to M. E. C.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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