Matrix-associated signaling events directly influence cell differentiation, proliferation and migration, thereby impacting embryogenesis, tissue repair, and a wide range of diseases such as cancer, vascular disease, and lung development. In recent years, there has been the suggestion that some ECM proteins can act both extracellularly and intracellularly. MAGP1 (microfibril associated glycoprotein-1) is one such protein. In addition to its extracellular role as a component of microfibrils, an alternatively spliced form of MAGP1 can be found as a stable, intracellular protein that exerts a regulatory function on the cell. The experimentation described in this application will focus on delineating the intracellular and extracellular functions of MAGP1, particularly as they relate to development and regulation of elastin-rich tissues. We will investigate the hypothesis that MAGP plays a major role in both elastic fiber assembly and in influencing expression of differentiation-specific genes. We will also assess the possibility of using a unique domain of MAGP1 (the matrix-binding domain) to target biologically active molecules to the extracellular matrix.
Our specific aims are: 1) To better define the functional role of MAGP as a microfibrillar protein and characterize its interactions with fibrillin, 2) To ascertain the second & tertiary structure of MAGP1, focusing on the matrix-binding domain, 3) To understand how MAGP1 and its intracellular alternatively spliced isoforms influence cell adhesion, cell phenotypes, and tissue development, and 4) To characterize the promoter sequences of the MAGP1 gene and to identify the critical regions for tissue expression and regulation during cell differentiation.
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| Craft, Clarissa S; Zou, Wei; Watkins, Marcus et al. (2010) Microfibril-associated glycoprotein-1, an extracellular matrix regulator of bone remodeling. J Biol Chem 285:23858-67 |
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| Werneck, Claudio C; Vicente, Cristina P; Weinberg, Justin S et al. (2008) Mice lacking the extracellular matrix protein MAGP1 display delayed thrombotic occlusion following vessel injury. Blood 111:4137-44 |
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| Broekelmann, Thomas J; Ciliberto, Christopher H; Shifren, Adrian et al. (2008) Modification and functional inactivation of the tropoelastin carboxy-terminal domain in cross-linked elastin. Matrix Biol 27:631-9 |
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| Wagenseil, Jessica E; Mecham, Robert P (2007) New insights into elastic fiber assembly. Birth Defects Res C Embryo Today 81:229-40 |
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