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Molecular and Cellular Biology, October 2003, p. 7230-7242, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7230-7242.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Myostatin Signals through a Transforming Growth Factor ß-Like Signaling Pathway To Block Adipogenesis

A. Rebbapragada,1 H. Benchabane,2,3 J. L. Wrana,2,3 A. J. Celeste,4 and L. Attisano1*

Department of Biochemistry,1 Department of Medical Genetics and Microbiology, University of Toronto, Toronto M5S 1A8,2 Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada,3 Wyeth Research, Cambridge, Massachusetts 021404

Received 21 October 2002/ Returned for modification 14 May 2003/ Accepted 14 July 2003

Myostatin, a transforming growth factor ß (TGF-ß) 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 (TßRI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-ß-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.

* Corresponding author. Mailing address: Department of Biochemistry, Medical Sciences Bldg. Rm. 6336, University of Toronto, Toronto, ON M5S 1A8, Canada. Phone: (416) 946-3129. Fax: (416) 978-3954. E-mail: liliana.attisano{at}utoronto.ca.

Molecular and Cellular Biology, October 2003, p. 7230-7242, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7230-7242.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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