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

Matrix Biol. 2013 Mar 11;32(2):117-22. doi: 10.1016/j.matbio.2012.11.009. Epub 2012 Nov 29.

Abstract

Microfibril-associated glycoprotein 2 (MAGP2) is a secreted protein associated with multiple cellular activities including the organization of elastic fibers in the extracellular matrix (ECM), angiogenesis, as well as regulating Notch and integrin signaling. Importantly, increases in MAGP2 positively correlate with poor prognosis for some ovarian cancers. It has been assumed that full-length MAGP2 is responsible for all reported effects; however, here we show MAGP2 is a substrate for the proprotein convertase (PC) family of endoproteases. Proteolytic processing of MAGP2 by PC cleavage could serve to regulate secretion and thus, activity and function as reported for other extracellular and cell-surface proteins. In support of this idea, MAGP2 contains an evolutionarily conserved PC consensus cleavage site, and amino acid sequencing of a newly identified MAGP2 C-terminal cleavage product confirmed functional PC cleavage. Additionally, mutagenesis of the MAGP2 PC consensus cleavage site or treatment with PC inhibitors prevented MAGP2 proteolytic processing. Finally, both cleaved and uncleaved MAGP2 were detected extracellularly and MAGP2 secretion appeared independent of PC cleavage, suggesting that PC processing occurs mainly outside the cell. Our characterization of alternative forms of MAGP2 present in the extracellular space not only enhances diversity of this ECM protein but also provides a previously unrecognized molecular mechanism for regulation of MAGP2 biological activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Contractile Proteins / genetics
  • Contractile Proteins / metabolism*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Humans
  • Integrins
  • Intercellular Signaling Peptides and Proteins
  • Microfibrils / metabolism
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • Protein Isoforms / metabolism
  • Proteolysis*

Substances

  • Contractile Proteins
  • Glycoproteins
  • Integrins
  • Intercellular Signaling Peptides and Proteins
  • MFAP5 protein, human
  • Protein Isoforms
  • Proprotein Convertases