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Molecular and Cellular Biology, July 2005, p. 5846-5858, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.5846-5858.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

GDF11 Forms a Bone Morphogenetic Protein 1-Activated Latent Complex That Can Modulate Nerve Growth Factor-Induced Differentiation of PC12 Cells

Gaoxiang Ge,1 Delana R. Hopkins,1,2 Wen-Bin Ho,3 and Daniel S. Greenspan1,2,4*

Department of Pathology and Laboratory Medicine,1 Program in Molecular and Cellular Pharmacology,2 The Waisman Center, University of Wisconsin, Madison, Wisconsin 53706,4 FibroGen, Inc., South San Francisco, California 940803

Received 15 February 2005/ Returned for modification 23 March 2005/ Accepted 16 April 2005

All transforming growth factor ß (TGF-ß) superfamily members are synthesized as precursors with prodomain sequences that are proteolytically removed by subtilisin-like proprotein convertases (SPCs). For most superfamily members, this is believed sufficient for activation. Exceptions are TGF-ßs 1 to 3 and growth differentiation factor 8 (GDF8), also known as myostatin, which form noncovalent, latent complexes with their SPC-cleaved prodomains. Sequence similarities between TGF-ßs 1 to 3, myostatin, and superfamily member GDF11, also known as bone morphogenetic protein 11 (BMP11), prompted us to examine whether GDF11 might be capable of forming a latent complex with its cleaved prodomain. Here we demonstrate that GDF11 forms a noncovalent latent complex with its SPC-cleaved prodomain and that this latent complex is activated via cleavage at a single specific site by members of the developmentally important BMP1/Tolloid family of metalloproteinases. Evidence is provided for a molecular model whereby formation and activation of this complex may play a general role in modulating neural differentiation. In particular, mutant GDF11 prodomains impervious to cleavage by BMP1/Tolloid proteinases are shown to be potent stimulators of neurodifferentiation, with potential for therapeutic applications.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, WI 53706. Phone: (608) 262-4676. Fax: (608) 262-6691. E-mail: dsgreens{at}wisc.edu.

Molecular and Cellular Biology, July 2005, p. 5846-5858, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.5846-5858.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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