HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/F1471    most recent 00485.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, S. I. Articles by Choi, M. E. Search for Related Content PubMed PubMed Citation Articles by Kim, S. I. Articles by Choi, M. E.

TGF--activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-₁-induced MKK3-p38 MAPK activation and stimulation of type I collagen

Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Submitted 8 December 2006 ; accepted in final form 11 February 2007

We have previously demonstrated that transforming growth factor-₁ (TGF-₁) rapidly activates the mitogen-activated protein kinase kinase 3 (MKK3)-p38 MAPK signaling cascade, leading to the induction of type I collagen synthesis in mouse glomerular mesangial cells (Wang L, Ma R, Flavell RA, Choi ME. J Biol Chem 277: 47257–47262, 2002). In the present study, we investigated the functional role of upstream TGF--activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-₁ signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-₁ was observed in mouse mesangial cells. Transient overexpression of TAK1 with TAB1 enhanced the activation of MKK3 and p38 MAPK with or without TGF-₁ stimulation, whereas a dominant-negative mutant of TAK1 (TAK1DN) suppressed TGF-₁-induced activation of MKK3 and p38 MAPK. Moreover, constitutive expression of TAK1DN reduced steady-state protein levels of MKK3 and p38 MAPK as well as MKK3 phosphorylation. Increased p38 MAPK activity by ectopic expression of either TAB1 or wild-type p38 MAPK resulted in enhanced TGF-₁-induced type I collagen expression. In contrast, constitutive expression of TAK1DN inhibited collagen induction. Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-₁. In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK.

mouse mesangial cell; TGF- signaling; stable transfection; dominant negative mutant of TAK1