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PMID:9111321

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Citation

Wu, RY, Zhang, Y, Feng, XH and Derynck, R (1997) Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4. Mol. Cell. Biol. 17:2521-8

Abstract

Homologs of Drosophila Mad function as downstream mediators of the receptors for transforming growth factor beta (TGF-beta)-related factors. Two homologs, the receptor-associated Smad3 and the tumor suppressor Smad4/DPC4, synergize to induce ligand-independent TGF-beta activities and are essential mediators of the natural TGF-beta response. We now show that Smad3 and Smad4 associate in homomeric and heteromeric interactions, as assessed by yeast two-hybrid and coimmunoprecipitation analyses. Heteromeric interactions are mediated through the conserved C-terminal domains of Smad3 and Smad4. In Smad3, the homomeric interaction is mediated by the same domain. In contrast, the homomeric association of Smad4 requires both the N-terminal domain and the C-terminal domain, which by itself does not homomerize. Mutations that have been associated with impaired Mad activity in Drosophila or decreased tumor suppressor activity of Smad4/DPC4 in pancreas cancer, including a short C-terminal truncation and two point mutations in the conserved C-terminal domains, impair the ability of Smad3 and Smad4 to undergo homo- and heteromeric associations. Analyses of the biological activity of Smad3 and Smad4 and their mutants show that full signaling activity correlates with their ability to undergo efficient homo- and heteromeric interactions. Mutations that interfere with these interactions result in decreased signaling activity. Finally, we evaluated the ability of Smad3 or Smad4 to induce transcriptional activation in yeast. These results correlate the ability of individual Smads to homomerize with transcriptional activation and additionally with their biological activity in mammalian cells.

Links

PubMed PMC232101

Keywords

Animals; COS Cells; Chromosome Mapping; Conserved Sequence; DNA-Binding Proteins/metabolism; Genes, Tumor Suppressor; Protein Conformation; Signal Transduction; Smad3 Protein; Trans-Activators/metabolism; Transcription, Genetic; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SMAD1

enables

GO:0070410: co-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13485

F

Seeded From UniProt

complete

HUMAN:SMAD1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15797

F

Seeded From UniProt

complete

HUMAN:SMAD1

involved_in

GO:0007183: SMAD protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD2

involved_in

GO:0007183: SMAD protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD2

enables

GO:0070410: co-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13485

F

Seeded From UniProt

complete

HUMAN:SMAD3

contributes_to

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0007183: SMAD protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

enables

GO:0030618: transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

enables

GO:0070410: co-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13485

F

Seeded From UniProt

complete

HUMAN:SMAD4

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13485

F

Seeded From UniProt

complete

HUMAN:SMAD4

enables

GO:0070412: R-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P84022

F

Seeded From UniProt

complete

HUMAN:SMAD4

enables

GO:0070412: R-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15796

F

Seeded From UniProt

complete

HUMAN:SMAD4

enables

GO:0070412: R-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15797

F

Seeded From UniProt

complete


See also

References

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