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Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells

Department of Life Sciences, 600 Chestnut St., Indiana State University, Terre Haute, IN 47809, USA.
Microvascular Research (Impact Factor: 2.43). 06/2008; 76(1):7-14. DOI: 10.1016/j.mvr.2008.01.001
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ABSTRACT Angiogenesis is highly sensitive to the composition of the vascular microenvironment, however, our understanding of the structural and matricellular components of the vascular microenvironment that regulate angiogenesis and the molecular mechanisms by which these molecules function remains incomplete. Our previous results described a novel pro-angiogenic activity for Microfibril-Associated Glycoprotein-2 (MAGP-2), but did not address the molecular mechanism(s) by which this is accomplished. We now demonstrate that MAGP-2 promotes angiogenic cell sprouting by antagonizing Notch signaling pathways in endothelial cells. MAGP-2 decreased basal and Jagged1 induced expression from the Notch sensitive Hes-1 promoter in ECs, and blocked Jagged1 stimulated Notch1 receptor processing in transiently transfected 293T cells. Interestingly, inhibition of Notch signaling by MAGP-2 seems to be restricted to ECs since MAGP-2 increased Hes-1 promoter activity and Notch1 receptor processing in heterologous cell types. Importantly, constitutive activation of the Notch signaling pathway blocked the ability of MAGP-2 to promote angiogenic cell sprouting, as well as morphological changes associated with angiogenesis. Collectively, these observations indicate that MAGP-2 promotes angiogenic cell spouting in vitro by antagonizing Notch signaling pathways in ECs.

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Available from: Allan R Albig, Aug 12, 2015
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    • "Both cell-associated and matrix-associated functions have been ascribed to microfibril-associated glycoprotein 2 (MAGP2, official nomenclature MFAP5), a small secreted protein originally identified biochemically from microfibril-rich cartilage tissue (Gibson et al., 1996). In vitro, MAGP2 has been implicated in binding and activation of αvβ3 integrins (Gibson et al., 1999; Mok et al., 2009) and modulation of Notch signaling (Miyamoto et al., 2006; Albig et al., 2008). Although loss of MAGP2 does not grossly affect mammalian lifespan or health (Combs et al., 2013), MAGP2 overexpression has been correlated with poor prognosis in a study of human papillary serous ovarian carcinomas (Mok et al., 2009). "
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    • "As true for other secreted matrix proteins, MAGP proteins have been shown to regulate Notch in a context dependent fashion, since MAGP inhibits Notch in endothelial cells (Albig et al., 2008). The biochemical mechanisms that underlying the diversity of its functions remain to be elucidated. "
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    ABSTRACT: Originally discovered nearly a century ago, the Notch signaling pathway is critical for virtually all developmental programs and modulates an astounding variety of pathogenic processes. The DSL (Delta, Serrate, LAG-2 family) proteins have long been considered canonical activators of the core Notch pathway. More recently, a wide and expanding network of non-canonical extracellular factors has also been shown to modulate Notch signaling, conferring newly appreciated complexity to this evolutionarily conserved signal transduction system. Here, I review current concepts in Notch signaling, with a focus on work from the last decade elucidating novel extracellular proteins that up- or down-regulate signal potency.
    The international journal of biochemistry & cell biology 08/2011; 43(11):1550-62. DOI:10.1016/j.biocel.2011.08.005 · 4.24 Impact Factor
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    • "Although the biological relevance of MAGP-2-induced Notch signaling is unclear, endogenous Notch1 and MAGP-2 can interact in co-immunoprecipitation studies. Additionally, it now appears that depending on the cell type MAGP-2 can also have inhibitory effects on Notch signaling although the molecular basis for these cell-type differences are not understood (Albig et al., 2008). "
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    ABSTRACT: The Notch signaling pathway regulates a diverse array of cell types and cellular processes and is tightly regulated by ligand binding. Both canonical and noncanonical Notch ligands have been identified that may account for some of the pleiotropic nature associated with Notch signaling. This review focuses on the molecular mechanisms by which Notch ligands function as signaling agonists and antagonists, and discusses different modes of activating ligands as well as findings that support intrinsic ligand signaling activity independent of Notch. Post-translational modification, proteolytic processing, endocytosis and membrane trafficking, as well as interactions with the actin cytoskeleton may contribute to the recently appreciated multifunctionality of Notch ligands. The regulation of Notch ligand expression by other signaling pathways provides a mechanism to coordinate Notch signaling with multiple cellular and developmental cues. The association of Notch ligands with inherited human disorders and cancer highlights the importance of understanding the molecular nature and activities intrinsic to Notch ligands. Oncogene (2008) 27, 5148-5167; doi:10.1038/onc.2008.229.
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