The MAD-Related Protein Smad7 Associates with the TGFβ Receptor and Functions as an Antagonist of TGFβ Signaling

Abstract

TGFbeta signaling is initiated when the type I receptor phosphorylates the MAD-related protein, Smad2, on C-terminal serine residues. This leads to Smad2 association with Smad4, translocation to the nucleus, and regulation of transcriptional responses. Here we demonstrate that Smad7 is an inhibitor of TGFbeta signaling. Smad7 prevents TGFbeta-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2. Furthermore, mutations in Smad7 that interfere with receptor binding disrupt its inhibitory activity. These studies thus define a novel function for MAD-related proteins as intracellular antagonists of the type I kinase domain of TGFbeta family receptors.

The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

“…Smad2/Smad4 and Smad3/Smad4 complexes then translocate to the nucleus where they regulate gene transcription (Heldin et al, 1997;. Two novel members of the Smad family, Smad6 and Smad7, were cloned from vascular endothelial cells (Topper et al, 1996Hayashi et al, 1997;Imamura et al, 1997). They associate with the activated TbRI, thereby blocking access and phosphorylation of Smad2 (Hayashi et al, 1997;Imamura et al, 1997) and possibly Smad3.…”

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

“…Expression and Revised 6 March 2003;accepted 12 March 2003 activation of these intracellular effectors of the TGF-b1 pathway are critical to the execution of the apoptotic process (DeCaestecker et al, 2000). An inhibitory regulator of TGF-b1 signalling, Smad7, (Whitman, 1997) is regulated by TGF-b1 specifically via Smad3 and Smad4 indicating a negative feedback mechanism (Hayashi et al, 1997). Smad7 is induced during apoptosis of prostate epithelial cells (Brodin et al, 1999) and has recently been shown to sensitise other cell types to apoptosis Schiffer et al, 2001).…”

A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3

“…Smad4 is the unique member of the second class of Smad proteins: central ones. The third class includes Smad6 and Smad7 which have been identi®ed as inhibitors of TGFb signalling (Imamura et al, 1997;Hayashi et al, 1997;Nakao et al, 1997;Topper et al, 1997;Hata et al, 1998a). Interestingly, Smad2 and Smad4 genes are tumor suppressor gene candidates found either deleted or mutated in a number of human cancers including pancreatic and colon carcinomas, providing compelling support for a role of TGFb signalling in the development of some cancers (Hahn et al, 1996;Eppert et al, 1996;Hata et al, 1997Hata et al, , 1998bShi et al, 1997).…”