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J. Biol. Chem., Vol. 280, Issue 25, 23475-23483, June 24, 2005

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Cooperation of the Metalloprotease, Disintegrin, and Cysteine-rich Domains of ADAM12 during Inhibition of Myogenic Differentiation^*

Haiqing Yi, Joanna Gruszczynska-Biegala, Denise Wood, Zhefeng Zhao, and Anna Zolkiewska

From the Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506

The extracellular domain of the mature form of ADAM12 consists of the metalloprotease, disintegrin, cysteine-rich, and epidermal growth factor (EGF)-like domains. The disintegrin, cysteine-rich, and EGF-like fragments have been shown previously to support cell adhesion via activated integrins or proteoglycans. In this study, we report that the entire extracellular domain of mouse ADAM12 produced in Drosophila S2 cells supported efficient adhesion and spreading of C2C12 myoblasts even in the absence of exogenous integrin activators. This adhesion was not mediated by ₁ integrins or proteoglycans, was myoblast-specific, and required the presence of both the metalloprotease and disintegrin/cysteine-rich domains of ADAM12. Analysis of the recombinant proteins by far-UV circular dichroism suggested that the secondary structures of the autonomously expressed metalloprotease domain and the disintegrin/cysteine-rich/EGF-like domains differ from the structures present in the intact extracellular domain. Furthermore, the intact extracellular domain (but not the metalloprotease domain or the disintegrin/cysteine-rich/EGF-like fragment alone) decreased the expression of the cell cycle inhibitor p21 and myogenin, two markers of differentiation, and inhibited C2C12 myoblast fusion. Thus, the novel protein-protein interaction reported here involving the extracellular domain of ADAM12 may have important biological consequences during myoblast differentiation.

Received for publication, December 2, 2004 , and in revised form, April 20, 2005.

^* This work was supported by National Institutes of Health Grant GM065528 and Centers of Biomedical Research Excellence Award P20 RR17708 and by matching funds from the State of Kansas. This is Contribution 05-158-J from the Kansas Agricultural Experiment Station. 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.

To whom correspondence should be addressed: Dept. of Biochemistry, Kansas State University, 104 Willard Hall, Manhattan, KS 66506. Tel.: 785-532-3082; Fax: 785-532-7278; E-mail: zolkiea{at}ksu.edu.

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