The Extracellular Matrix Protein MAGP-2 Interacts with Jagged1 and Induces Its Shedding from the Cell Surface

Leslie C. Nehring, Alison Miyamoto, Patrick W. Hein, Gerry Weinmaster, J. Michael Shipley
2005 Journal of Biological Chemistry  
Elastic fibers are composed of the protein elastin and a network of 10 -12-nm microfibrils, which are composed of several glycoproteins, including fibrillin-1, fibrillin-2, and MAGP1/2 (microfibril-associated glycoproteins-1 and -2). Although fibrillins and MAGPs covalently associate, we find that the DSL (Delta/Serrate/LAG2) protein Jagged1, an activating ligand for Notch receptor signaling, also interacts with MAGP-2 in both yeast two-hybrid and coimmunoprecipitation studies. Interaction
more » ... en Jagged1 and MAGP-2 requires the epidermal growth factor-like repeats of Jagged1. MAGP-2 was found complexed with the Jagged1 extracellular domain shed from 293T cells and COS-7 cells coexpressing fulllength Jagged1 and MAGP-2. MAGP-2 shedding of the Jagged1 extracellular domain was decreased by the metalloproteinase hydroxamate inhibitor BB3103 implicating proteolysis in its release. Although MAGP-2 also interacted with the other DSL ligands, Jagged2 and Del-ta1, they were not found associated with MAGP-2 in the conditioned media, identifying differential effects of MAGP-2 on DSL ligand shedding. The related microfibrillar protein MAGP-1 was also found to interact with DSL ligands but, unlike MAGP-2, was unable to facilitate the shedding of Jagged1. Our findings suggest that in addition to its role in microfibrils, MAGP-2 may also affect cellular differentiation through modulating the Notch signaling pathway either by binding to cell surface DSL ligands or by facilitating release and/or stabilization of a soluble extracellular form of Jagged1. Structural integrity and elastic resilience of tissues that undergo repeated stretch and recoil, including the lung, skin, and large blood vessels in vertebrates, are imparted by extracellular matrix-associated elastic fibers. It is thought that there are two structural components of elastic fibers. The first is an amorphous component entirely made up of the protein elastin. Elastin is deposited on a bed of 10 -12-nm microfibrils, which make up the second component. Microfibrils are in turn composed of a number of glycoproteins including MAGP (microfibril-associated glycoproteins)-1 (1), MAGP-2 (2), MP70/78
doi:10.1074/jbc.m500273200 pmid:15788413 fatcat:ny62sbzej5fa7ft52vn3ly5vdu