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

Using a genetic complementation approach we have identified disabled-2 (Dab 2), a structural homolog of the Dab1 adaptor molecule, as a critical link b etween the transforming growth factor beta (TGF beta) receptors and the Sma d family of proteins, Expression of wildtype Dab2 in a TGF beta -signaling mutant restores TGF beta -mediated Smad2 phosphorylation, Smad translocatio n to the nucleus and Smad-dependent transcriptional responses. TGF beta sti mulation triggers a transient increase in association of Dab2 with Smad2 an d Smad3, which is mediated by a direct interaction between the N-terminal p hosphotyrosine binding domain of Dab2 and the MH2 domain of Smad2, Dab2 ass ociates with both the type I and type II TGF beta receptors in vive, sugges ting that Dab2 is part of a multiprotein signaling complex. Together, these data indicate that Dab2 is an essential component of the TGF beta signalin g pathway, aiding in transmission of TGF beta signaling from the TGF beta r eceptors to the Smad family of transcriptional activators.