Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta

Abstract

Transforming growth factor‐β (TGF‐β), when bound to its specific receptor, activates the transcription factor Smad by phosphorylation. TGF‐β also activates the p38 MAPK pathway, but there seem to be disparate mechanisms for the early p38 activation and delayed p38 activation. In this report, we demonstrate that Smad‐dependent expression of GADD45β is responsible for the delayed activation of p38 by TGF‐β. The GADD45β protein binds and activates MTK1 (= MEKK4), which is a member of the MAPKKK family kinases and an upstream activator of the p38 MAPK cascade. Both TGF‐β‐induced GADD45β expression and the delayed p38 activation require functional Smad proteins. Antisense inhibition of GADD45β expression suppresses the TGF‐β‐induced delayed p38 activation, whereas overexpression of GADD45β activates the p38 MAPK via MTK1. Expression of the angiogenesis inhibitor thrombospondin‐1 (TSP‐1) is induced by TGF‐β via Smad‐dependent p38 activation. Thus TGF‐β‐induced p38 activation, mediated by GADD45β expression, may play an important role in the biological effects of TGF‐β.

Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells

“…This basal phosphorylation of Smad3 was not dependent on p38 MAPK activity, since inhibition of p38 activity by a chemical inhibitor, SB203580, had no effect on the basal levels of phosphorylated Smad3. Interestingly, phosphorylation of p38 MAPK was dependent on Smad signaling, which is supported by reports showing that TGF-b activates p38 through both Smad-independent pathway via TGF-b-activated kinase 1 (Yamaguchi et al, 1995;Hanafusa et al, 1999;Sano et al, 1999) and through Smad-dependent pathways (Takekawa et al, 2002;Ungefroren et al, 2003). Most SCC cell lines examined produced and activated TGF-b, which could be responsible for autocrine activation of TGF-b-receptor signaling.…”

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

“…These data suggest that a pathway or pathways other than PI3K-AKT regulate TSP-1 expression. Delayed activation of p38 mitogen-activated protein kinases (MAPK) has been reported to regulate TSP-1 expression in other cancer cell types (Takekawa et al, 2002;Naito et al, 2004). Early activation of p38 kinase by the anti-HER2 antibody ID5 was reported previously (Le et al, 2000).…”

“…In other cell systems, delayed activation of the p38 MAP kinase pathway also has a negative impact on cell proliferation by inducing apoptosis (Daly et al, 1999;Takekawa et al, 2002;Bulavin and Fornace, 2004;Naito et al, 2004). Treatment of BT474 and SKBr3 cells with anti-HER2 antibodies for 72 h does not induce significant apoptosis (Le et al, 2003(Le et al, , 2005a.…”

“…The signaling pathways that regulate TSP-1 expression also remain controversial. MAP kinase signaling, including the activation of p38 and JNK, has been shown to regulate TSP-1 expression (Takekawa et al, 2002;Naito et al, 2004), as has the PI3K pathway (Watnick et al, 2003). HER2 signaling can affect TSP-1 expression in breast cancer.…”

BMP7 dose-dependently stimulates proliferation and cadherin-11 expression via ERK and p38 in a murine metanephric mesenchymal cell line

“…Delayed activation of p38 via Smad‐dependent pathway by TGF‐β has been reported in pancreatic carcinoma cells (Takekawa et al. 2002). Similar mechanism may be operative for the BMP7‐induced late activation of p38 or ERK in metanephric mesenchymal cells.…”