TGF-β-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-β₁-induced MKK3-p38 MAPK activation and stimulation of type I collagen

Abstract

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.

Autophagy Promotes Intracellular Degradation of Type I Collagen Induced by Transforming Growth Factor (TGF)-β1

“…The present study demonstrates that TGF-␤1 induction of autophagy in MMC involves activation of the TAK1-MKK3-p38 signaling axis (33). TAK1 can activate MKK4/7-JNK, MKK3/6-p38, NF-B, and AMPK in a cell-specific manner (8,(55)(56)(57) and, intriguingly, all of these molecules are known to be involved in either the expression of certain Atg proteins or the activation of autophagy. For instance, JNK is implicated in the expression and activation of Beclin 1 (58, 59), whereas p38 is necessary for LPS or oxidative stress-induced formation of autophagosomes in C2C12 myoblasts (60) and in HL-1 cardiomyocytes (61).…”

TGF-β signaling in the kidney: profibrotic and protective effects

“…1) including the MAPKs, mediated by Ras-Raf-activating MEK (also called MAPKK) and ERK (16,68,90), or the TGF-␤-activated kinase 1 (TAK1) pathway, the upstream MAPK kinase kinase (MKKK) activating MKK3-p38 and MKK4-JNK (c-Jun N-terminal kinase) signaling cascades (13,37,38,69). TGF-␤1 signaling also activates Rho family small GTPases Rho, Rac, and Cdc42 as well as phosphatidylinositol 3-kinase (PI3K)/AKT and integrin-linked kinase (ILK) (3,23,50,66,95,98).…”

“…Recent investigations have also demonstrated that the noncanonical, non-Smad pathways can also mediate TGF-␤1 fibrogenic responses (13,38). However, new findings show that blocking TGF-␤1 signaling in renal cells in vitro or in experimental animal models in vivo does not necessarily reduce renal fibrosis.…”

“…Data from in vitro studies indicate that TGF-␤1-stimulated collagen expression in mesangial cells is mediated via the TAK1/MKK3/p38 signaling cascade and fibronectin expression in fibroblasts (13,38,69). Moreover, investigations using pharmacological and genetic blockade in in vivo models of glomerular and tubulointerstitial injury in mice have shown that the TAK1/MKK3/p38 and JNK pathways promote renal fibrosis (13,39).…”

Transforming Growth Factor-β (TGF-β) and TGF-β–Associated Kinase 1 Are Required for R-Ras–Mediated Transformation of Mammary Epithelial Cells

“…19), and the MAPK cascade (20). The MAPK kinase kinase (MKK), TGF-h-associated kinase 1 (TAK1), plays a key role in activating its downstream kinases JNK and p38 MAPK (21,22).…”