ATF-2 Is a Common Nuclear Target of Smad and TAK1 Pathways in Transforming Growth Factor-β Signaling

Abstract

Upon transforming growth factor-␤ (TGF-␤) binding to its cognate receptor, Smad3 and Smad4 form heterodimers and transduce the TGF-␤ signal to the nucleus. In addition to the Smad pathway, another pathway involving a member of the mitogen-activated protein kinase kinase kinase family of kinases, TGF-␤-activated kinase-1 (TAK1), is required for TGF-␤ signaling. However, it is unknown how these pathways function together to synergistically amplify TGF-␤ signaling. Here we report that the transcription factor ATF-2 (also called CRE-BP1) is bound by a hetero-oligomer of Smad3 and Smad4 upon TGF-␤ stimulation. ATF-2 is one member of the ATF/CREB family that binds to the cAMP response element, and its activity is enhanced after phosphorylation by stress-activated protein kinases such as c-Jun N-terminal kinase and p38. The binding between ATF-2 and Smad3/4 is mediated via the MH1 region of the Smad proteins and the basic leucine zipper region of ATF-2. TGF-␤ signaling also induces the phosphorylation of ATF-2 via TAK1 and p38. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. These results indicate that ATF-2 plays a central role in TGF-␤ signaling by acting as a common nuclear target of both Smad and TAK1 pathways.

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.…”

Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells

“…For example, TGF-b-activated kinase (TAK1) has been shown to be an upstream activator of MKK6 and activation of this pathway results in phosphorylation of activating transcription factor 2 (ATF2) and enhancement of complex formation between Smad4 and ATF2. 41,42 However, another report shows that Smad and p38MAPK independently regulate collagen I a1 mRNA in hepatic stellate cells 41 and thus further study will be needed to uncover gene expression regulation by TGF-b. Regardless, attenuation of TGF-b2-dependent effects on migration and production of ECM by ARPE-19 cells by Inhibition of p38MAP kinase and PVR S Saika et al addition of a p38MAPK inhibitor suggests that such an inhibitor might be efficacious in the prevention/ treatment of PVR.…”

Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesis

“…Its expression is induced by TGF-b and transcriptionally regulated by both Smad-and TAK1-dependent mechanisms (Hanafusa et al, 1999;Sano et al, 1999). Furthermore, it is also possible that AFT-2 participates in transcription complexes in association with Smad proteins (Sano et al, 1999).…”