Structure and function of extracellular microfibril proteins
Microfibril-associated glycoprotein 2 (MAGP2) is a secreted protein that was originally discovered due to its co-purification with extracellular elastic fibers that provide mechanical resilience in skin, large vessels, lung, and cartilage, among others. More recently, it has been discovered that MAGP2 is more than a structural protein; it can regulate cell signaling and induce cell activities such as blood vessel formation. Moreover, overexpression or mutation of MAGP2 has been associated with human disease, suggesting these functions are important to maintain homeostasis. For example, MAGP2 is highly expressed in ovarian cancer cell lines and patient samples; this expression correlates with poor patient prognosis. Loss-of-function mutations of MAGP2 have been genetically linked to an aortic aneurysm and dissection disorder.
In order to better understand the MAGP2 protein, the Miyamoto laboratory is studying the normal function of MAGP2 using biochemical and cell biological tools. We believe that a better understanding of the normal structure and function of MAGP2 will provide insight into its role(s) in human disease. We were the first to identify an enzymatic cleavage site within the MAGP2 protein that can regulate the proper localization of the protein to extracellular microfibrils. We are now extending these studies, using genome editing techniques such as CRISPR/Cas9, to ask questions about endogenous MAGP2 and the role proteolytic cleavage plays in fibroblast and endothelial cell microfibril assembly. These studies are designed to reveal the role of enzymatic cleavage and/or microfibril localization of MAGP2 at tumor sites and in blood vessels.
A. Miyamoto, L. Donovan, E. Perez, B. Connett, R. Cervantes, K. Lai, G. withers, and G. Hogrebe. Binding of MAGP2 to microfibrils is regulated by proprotein convertase cleavage. Matrix Biology 2014 40 27-33
L. Donovan, S. Cha, A. Yale, S. Dreikorn, and A. Miyamoto. Identification of a functional proprotein convertase cleavage site in MAGP2. Matrix Biology 2013 32 117-122
J. Nichols, A. Miyamoto, S. Olsen, B. D'Souza, C. Yao, and G. Weinmaster. mwr DSL-ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. Journal of Cell Biology 2007 176 445-458