ADAMs, a family of cell surface proteins containing A Disintegrin And Metalloprotease domains, play important roles in cell surface proteolysis, cell-cell, or cell-matrix interactions. Our long-term goal is to understand the function of ADAM proteins and to dissect their roles in transmembrane signaling. Currently, we focus our studies on ADAM12, an ADAM family member that is involved in differentiation of mesenchymal cells such as skeletal myoblasts and osteoblasts. Based on our preliminary results, we hypothesize that ADAM12 constitutes a functional, muscle specific receptor ifor integrin alpha7betal in vivo and its DC domain mediates critical cell-cell interactions that induce cell differentiation. To test this hypothesis, we will perform a series of studies that will pursue the following Specific Aims: 1. Examine whether ADAM12 and integrin alpha7betal interact in vivo. 2. Identify the residues in the DC domain of ADAM12 that are critical for interaction with integrin alpha7betal. 3. Initiate the studies on the structure determination of the DC domain of ADAM12. The results of our studies will provide important information on the structure and function of ADAM12 and will shed more light on the function of other ADAMs. Our findings will also advance the knowledge of myogenic differentiation, an issue that is critical for planning strategies to enhance muscle repair or optimizing muscle-directed gene therapies, and may help understand the role of cell contact-mediated signaling in the regulation of cell proliferation, death, and differentiation.
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