Using a genetic complementation approach we have identified disabled-2 (Dab2), a structural homolog of the Dab1 adaptor molecule, as a critical link between the transforming growth factor beta (TGFbeta) receptors and the Smad family of proteins. Expression of wild-type Dab2 in a TGFbeta-signaling mutant restores TGFbeta-mediated Smad2 phosphorylation, Smad translocation to the nucleus and Smad-dependent transcriptional responses. TGFbeta 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 TGFbeta 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 TGFbeta signaling pathway, aiding in transmission of TGFbeta signaling from the TGFbeta receptors to the Smad family of transcriptional activators.
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