The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway

Abstract

Using a genetic complementation approach we have identi®ed disabled-2 (Dab2), a structural homolog of the Dab1 adaptor molecule, as a critical link between the transforming growth factor b (TGFb) receptors and the Smad family of proteins. Expression of wildtype Dab2 in a TGFb-signaling mutant restores TGFb-mediated Smad2 phosphorylation, Smad translocation to the nucleus and Smad-dependent transcriptional responses. TGFb stimulation triggers a transient increase in association of Dab2 with Smad2 and Smad3, which is mediated by a direct interaction between the N-terminal phosphotyrosine binding domain of Dab2 and the MH2 domain of Smad2. Dab2 associates with both the type I and type II TGFb receptors in vivo, suggesting that Dab2 is part of a multiprotein signaling complex. Together, these data indicate that Dab2 is an essential component of the TGFb signaling pathway, aiding in transmission of TGFb signaling from the TGFb receptors to the Smad family of transcriptional activators.

Regulation of cell proliferation by Smad proteins

“…Similar as found for SARA, Dab-2 can directly interact with Smad2 and Smad3 and the TGF-b receptor complex. However, in contrast with SARA, the interaction of Dab-2 with the TGF-b receptor complex is constitutive, and the interaction between Dab-2 and Smads is ligand dependent (Hocevar et al, 2001).…”

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

“…The cyclin D1 promoter luciferase construct has been described previously (Herber et al, 1994). Expression constructs for Myc-Axin (Furuhashi et al, 2001), Flag-tagged Dab2 (Hocevar et al, 2001) and Flag-tagged LRP5 (kindly provided by Dr Dianqing Wu, University of Connecticut) have been previously described. The monoclonal antibody to Dab2/p96 was purchased from Transduction Laboratories (San Jose, CA, USA).…”

“…Disabled-2 (Dab2) is a widely expressed adaptor protein shown to be involved in several receptor-mediated signaling pathways (Xu et al, 1995;Hocevar et al, 2001;Prunier et al, 2004). Like other adaptors, Dab2 has no catalytic activity but elicits its function through interaction and modulation of other proteins.…”

A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

“…In addition to the Ras/Mapk and Smad pathways, several proteins have been identified based upon their interaction with the TGF␤ receptors (Yue and Mulder, 2001). Furthermore, various Smad-interacting proteins have also been identified, including SARA and Dab2, which interact with both Smads and the TGF␤ receptors (Tsukazaki et al, 1998;Hocevar et al, 2001;Yue and Mulder, 2001).…”

“…In addition to the Ras/Mapk and Smad pathways, several proteins have been identified based upon their interaction with the TGF␤ receptors (Yue and Mulder, 2001). Furthermore, various Smad-interacting proteins have also been identified, including SARA and Dab2, which interact with both Smads and the TGF␤ receptors (Tsukazaki et al, 1998;Hocevar et al, 2001;Yue and Mulder, 2001).Despite advances in our understanding of the mechanisms by which the Smad and Ras/Mapk cascades mediate some TGF␤ effects, these pathways seem to regulate primarily transcriptional events (Hocevar et al, 1999;Hu et al, 1999;Sporn and Vilcek, 2000; Mulder, 2000a, 2001). However, TGF␤ is multifunctional and its biological responses are diverse.…”