TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen.
We have previously demonstrated that transforming growth factor-beta(1) (TGF-beta(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-beta-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) in the TGF-beta(1) signaling cascade. Rapid activation of endogenous TAK1 activity by TGF-beta(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-beta(1) stimulation, whereas a dominant-negative mutant of TAK1 (TAK1DN) suppressed TGF-beta(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 p38alpha MAPK activity by ectopic expression of either TAB1 or wild-type p38alpha MAPK resulted in enhanced TGF-beta(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-beta(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.
Kim
Sung Il
SI
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Kwak
Joon Hyeok
JH
Zachariah
Mareena
M
He
Yanjuan
Y
Wang
Lin
L
Choi
Mary E
ME
D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005799:Genes, Dominant; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D009154:Mutation; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D024042:Collagen Type I; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D048371:MAP Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C099510:TAB1 protein, MAPKKK activator, vertebrate; C482531:Map2k3 protein, mouse