Identification of a functional proprotein convertase cleavage site in microfibril-associated glycoprotein 2

Donovan, Lauren J.; Seung, E.; Yale, Andrew R; Dreikorn, Stephanie; Miyamoto, Alison

doi:10.1016/j.matbio.2012.11.009

Cited by 7 publications

(10 citation statements)

References 26 publications

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“…The two MAGPs share a functional C-terminal matrix-binding domain that is characterized by conserved cysteine residues (9,10). MAGP2 has a conserved proprotein convertase cleavage site within this domain that makes MAGP2 a substrate for multiple proprotein convertase family members (11). Also unique to MAGP2 is an RGD integrin-binding motif located at the N terminus.…”

Section: The Ecmmentioning

confidence: 99%

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs¹,

Knutsen²,

Broekelmann³

et al. 2013

Journal of Biological Chemistry

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Section: The Ecmmentioning

confidence: 99%

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Combs¹,

Knutsen²,

Broekelmann³

et al. 2013

Journal of Biological Chemistry

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“…Immunoblotting analysis of both T3 cell lysates and conditioned medium indicates that MAGP2 is processed as previously described (Donovan et al, 2013). Specifically, the wild-type MAGP2 protein and the cleavageresistant mutant form of MAGP2 (RR → AA) in the whole cell lysate are of similar apparent molecular mass of~23 kD (Fig.…”

Section: Microfibril Association Of Magp2 Is Promoted By Pc Processinmentioning

confidence: 64%

“…The RR → AA and ΔC20 mutations have been previously described (Donovan et al, 2013), as have the MAGP2 CT and MAGP2 NT constructs (Miyamoto et al, 2006). The RR → AA mutant is the same as construct 'M' in Donovan et al, and the MAGP2 CT and NT constructs are the same as C-mycMAGP-2 and N-MAGP-2 in Miyamoto et al, 2006, respec-tively.…”

Section: Plasmids and Cell Linesmentioning

confidence: 99%

“…T3 cells were grown in DMEM high glucose supplemented with 10% FBS (Tissue Culture Biologicals, Tulare, CA). The maintenance and transfection of 293T cells have been previously described (Donovan et al, 2013).…”

Section: Plasmids and Cell Linesmentioning

confidence: 99%

“…In this regard, a conserved proprotein convertase (PC) site in MAGP2 has been identified (Donovan et al, 2013). Proteolytic PC enzymes process many cell-surface and secreted proteins (Seidah et al, 2013), and processing can regulate secretion or activity of extracellular proteins.…”

Section: Introductionmentioning

confidence: 99%

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Binding of MAGP2 to microfibrils is regulated by proprotein convertase cleavage

et al. 2014

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MAGP2 is a small extracellular protein with both tumor angiogenesis and cell signaling activity. MAGP2 was originally isolated biochemically from microfibril-rich connective tissue. The localization of MAGP2 to microfibrils has been confirmed by both immunohistochemistry and immunogold electron microscopy. Whether MAGP2 binding to microfibrils is regulated post-translationally is still unclear, however, and a better understanding of this process would be instructive to understanding the angiogenesis and signaling functions ascribed to MAGP2. Here we show via immunofluorescence studies that the T3 cell line, derived from ovarian mouse tumor cells, produces abundant fibrillin-2 microfibrils to which MAGP2 can bind. Co-localization of MAGP2 and fibrillin-2 can be detected either when MAGP2 is overexpressed in, or exogenously introduced to, the cells. As expected, matrix association of MAGP2 required its conserved Matrix Binding Domain. Matrix association was positively regulated by proprotein convertase (PC) cleavage of MAGP2; mutation of the MAGP2 PC consensus site reduced the amount of matrix-associated MAGP2. Deletion analysis of the C-terminal 20-amino acid domain that is defined by the PC cleavage site suggests that this domain also positively modulates matrix localization of MAGP2, in a manner that requires the amino-terminal half of the protein. Together, our data indicate that matrix localization of MAGP2 by its Matrix Binding Domain is promoted by PC cleavage and the presence of its C-terminal 20 amino acids.

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MFAP5 Loss-of-Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections

Barbier

Gross

Aubart

et al. 2014

The American Journal of Human Genetics

117

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Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.

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Identification of a functional proprotein convertase cleavage site in microfibril-associated glycoprotein 2

Cited by 7 publications

References 26 publications

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Microfibril-associated Glycoprotein 2 (MAGP2) Loss of Function Has Pleiotropic Effects in Vivo

Binding of MAGP2 to microfibrils is regulated by proprotein convertase cleavage

MFAP5 Loss-of-Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections

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