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J. Biol. Chem., Vol. 283, Issue 7, 3782-3790, February 15, 2008

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Activin A/Bone Morphogenetic Protein (BMP) Chimeras Exhibit BMP-like Activity and Antagonize Activin and Myostatin^*

From the Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla California 92037

Activins and bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β family of growth and differentiation factors that induce signaling in target cells by assembling type II and type I receptors at the cell surface. Ligand residues involved in type II binding are located predominantly in the C-terminal region that forms an extended β-sheet, whereas residues involved in type I binding are located in the -helical and preceding loop central portion of the molecule. To test whether the central residues are sufficient to determine specificity toward type I receptors, activin A/BMP chimeras were constructed in which the central residues (45–79) of activin A were replaced with corresponding residues of BMP2 and BMP7. The chimeras were assessed for activin type II receptor (Act RII) binding, activin-like bioactivity, and BMP-like activity as well as antagonistic properties toward activin A and myostatin. ActA/BMP7 chimera retained Act RII binding affinity comparable with wild type activin A, whereas ActA/BMP2 chimera showed a slightly reduced affinity toward Act RII. Both the chimeras were devoid of significant activin bioactivity in 293T cells in the A3 Lux reporter assay up to concentrations 10-fold higher than the minimal effective activin A concentration (4 nM). In contrast, these chimeras showed BMP-like activity in a BRE-Luc assay in HepG2 cells as well as induced osteoblast-like phenotype in C2C12 cells expressing alkaline phosphatase. Furthermore, both the chimeras activated Smad1 but not Smad2 in C2C12 cells. Also, both the chimeras antagonized ligands that signal via activin type II receptor, such as activin A and myostatin. These data indicate that activin residues in the central region determine its specificity toward type I receptors. ActA/BMP chimeras can be useful in the study of receptor specificities and modulation of transforming growth factor-β members, activins, and BMPs.

Received for publication, June 1, 2006 , and in revised form, November 30, 2007.

^* This work was supported by the National Institutes of Health Grant HD-13527. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 10010 North Torrey Pines Rd., La Jolla, CA 92037. Fax: 858-552-1546; E-mail: fischer{at}salk.edu.

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