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PMID:8774881

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Citation

Zhang, Y, Feng, X, We, R and Derynck, R (1996) Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383:168-72

Abstract

Transforming growth factor-beta TGF-beta is the prototype for a family of extracellular proteins that affect cell proliferation and tissue differentiation. TGF-beta-related factors, including BMP-2/4, Dpp and activin, act through two types of serine/threonine kinase receptors which can form a heteromeric complex. However, the mechanism of signal transduction by these receptors is largely unknown. In Drosophila, Mad is required for signalling by Dpp. We have isolated complementary DNAs for four human Mad homologues, one of which, hMAD-4, is identical to DPC-4, a candidate tumour suppressor. hMAD-3 and -4 synergized to induce strong ligand-independent TGF-beta-like responses. When truncated at their carboxy termini, hMAD-3 and -4 act as dominant-negative inhibitors of the normal TGF-beta response. The activity of hMAD-3 and -4 was regulated by the TGF-beta receptors, and hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex. These results define hMAD-3 and -4 as effectors of the TGF-beta response and demonstrate a function for DPCA-4/hMAD-4 as a tumour suppressor.

Links

PubMed Online version:10.1038/383168a0

Keywords

Activin Receptors, Type I; Amino Acid Sequence; Cell Line; DNA-Binding Proteins/metabolism; Gene Expression Regulation; Genes, Reporter; Humans; Luciferases/genetics; Molecular Sequence Data; Peptide Fragments/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Receptors, Transforming Growth Factor beta/metabolism; Sequence Homology, Amino Acid; Signal Transduction; Smad Proteins; Smad2 Protein; Smad3 Protein; Smad4 Protein; Trans-Activators/metabolism; Transforming Growth Factor beta/antagonists & inhibitors; Transforming Growth Factor beta/metabolism

Significance

Annotations

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

HUMAN:TGFR1

part_of

GO:0043235: receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0017015: regulation of transforming growth factor beta receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD3

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P84022

F

Seeded From UniProt

complete

HUMAN:SMAD3

part_of

GO:0043235: receptor complex

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD3

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

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

involved_in

GO:0017015: regulation of transforming growth factor beta receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD4

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD4

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13485

F

Seeded From UniProt

complete

HUMAN:SMAD4

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD4

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:SMAD4

enables

GO:0070412: R-SMAD binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P84022

F

Seeded From UniProt

complete

HUMAN:TGFR2

part_of

GO:0043235: receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SMAD3

involved_in

GO:0007179: transforming growth factor beta receptor signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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