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PMID: 11387212 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 20 ·No. 11 ·2001-06-01 ·Pages 2789-801

Hocevar BA, Smine A, Xu XX, Howe PH

Abstract

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.

MeSH Terms
Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Animals Apoptosis Regulatory Proteins Binding Sites Cell Line DNA-Binding Proteins/metabolism Genes, Reporter Genes, Tumor Suppressor Glutathione Transferase/analysis Humans Liver/physiology Luciferases/analysis Phosphotyrosine/metabolism Proteins/chemistry,genetics,metabolism Receptors, Transforming Growth Factor beta/physiology Recombinant Fusion Proteins/metabolism Signal Transduction Smad2 Protein Smad3 Protein Trans-Activators/metabolism Transfection Transforming Growth Factor beta/pharmacology,physiology Tumor Suppressor Proteins src Homology Domains
Chemicals
Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Apoptosis Regulatory Proteins DAB2 protein, human DNA-Binding Proteins Proteins Receptors, Transforming Growth Factor beta Recombinant Fusion Proteins SMAD2 protein, human SMAD3 protein, human Smad2 Protein Smad3 Protein Trans-Activators Transforming Growth Factor beta Tumor Suppressor Proteins Phosphotyrosine Luciferases Glutathione Transferase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Hocevar B A
Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Smine A
Xu X X
Howe P H
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/20.11.2789
Published
2001-06-01
Pages
2789-801
Language
English
Region
England
NLM ID
8208664
PMCID
PMC125498
Subset
IM
Grants
NCI NIH HHS · R01 CA055536 · United States
NCI NIH HHS · CA55536 · United States
External Links
PubMed source DOI: 10.1093/emboj/20.11.2789 PMC Full Text View journal details
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