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PMID:14517293

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Citation

Rebbapragada, A, Benchabane, H, Wrana, JL, Celeste, AJ and Attisano, L (2003) Myostatin signals through a transforming growth factor beta-like signaling pathway to block adipogenesis. Mol. Cell. Biol. 23:7230-42

Abstract

Myostatin, a transforming growth factor beta (TGF-beta) family member, is a potent negative regulator of skeletal muscle growth. In this study we characterized the myostatin signal transduction pathway and examined its effect on bone morphogenetic protein (BMP)-induced adipogenesis. While both BMP7 and BMP2 activated transcription from the BMP-responsive I-BRE-Lux reporter and induced adipogenic differentiation, myostatin inhibited BMP7- but not BMP2-mediated responses. To dissect the molecular mechanism of this antagonism, we characterized the myostatin signal transduction pathway. We showed that myostatin binds the type II Ser/Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (TbetaRI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-beta-like signaling pathway. We demonstrated that myostatin prevents BMP7 but not BMP2 binding to its receptors and that BMP7-induced heteromeric receptor complex formation is blocked by competition for the common type II receptor, ActRIIB. Thus, our results reveal a strikingly specific antagonism of BMP7-mediated processes by myostatin and suggest that myostatin is an important regulator of adipogenesis.

Links

PubMed PMC230332

Keywords

Adipocytes/metabolism; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins/metabolism; COS Cells; Cell Differentiation; Cell Line; DNA-Binding Proteins/metabolism; Genes, Reporter; Homeostasis; Humans; Mice; Mice, Inbred C3H; Models, Biological; Myostatin; NIH 3T3 Cells; Phosphorylation; Polymerase Chain Reaction; Protein Binding; RNA/metabolism; RNA Interference; Signal Transduction; Smad2 Protein; Time Factors; Trans-Activators/metabolism; Transcription, Genetic; Transcriptional Activation; Transfection; Transforming Growth Factor beta/metabolism

Significance

Annotations

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

HUMAN:ACV1B

contributes_to

GO:0019838: growth factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14793

F

Seeded From UniProt

complete

HUMAN:ACV1B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14793

F

Seeded From UniProt

complete

HUMAN:ACV1B

part_of

GO:0043235: receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TGFR1

contributes_to

GO:0019838: growth factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14793

F

Seeded From UniProt

complete

HUMAN:TGFR1

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TGFR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14793

F

Seeded From UniProt

complete

HUMAN:TGFR1

part_of

GO:0043235: receptor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:AVR2B

enables

GO:0019838: growth factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14793

F

Seeded From UniProt

complete

HUMAN:GDF8

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:GDF8

enables

GO:0005102: signaling receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P36896

F

Seeded From UniProt

complete

HUMAN:GDF8

enables

GO:0005102: signaling receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P36897

F

Seeded From UniProt

complete

HUMAN:GDF8

enables

GO:0005102: signaling receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13705

F

Seeded From UniProt

complete

HUMAN:TGFB1

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:BMP7

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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