Functional regulation of semaphorin receptors by proprotein convertases

Stefania Artigiani, Davide Barberis, Pietro Fazzari, Paola Longati, Paola Angelini, Jan Willem Van de Loo, Paolo M. Comoglio, Luca Tamagnone

Research output: Contribution to journalArticlepeer-review

Abstract

PLEXIN genes encode receptors for secreted and membrane-bound semaphorins. It was proposed that the extracellular domain of plexins acts as an inhibitory moiety, preventing receptor activation. Here we show that plexin-B1 and plexin-B2 undergo proteolytic processing in their extracellular portion, thereby converting single-chain precursors into non-disulfide-linked, heterodimeric receptors. We demonstrate that plexin processing is mediated by subtilisin-like proprotein convertases, by inhibition with a1-antitrypsin Portland, and by mutagenesis of the substrate-cleavage sites. We provide evidence indicating that proprotein convertases cleave plexins in a post-Golgi compartment and, likely, at the cell surface. In addition, we find that both cell surface targeting and proteolytic processing of plexin-B1 depend on protein-protein interaction motifs in the cytoplasmic domain of the receptor. We then show that proteolytic conversion of plexin-B1 into a heterodimeric receptor greatly increases the binding and the functional response to its specific ligand semaphorin 4D/CD100. Thus, we conclude that cleavage by proprotein convertases is a novel regulatory step for semaphorin receptors localized at the cell surface.

Original languageEnglish
Pages (from-to)10094-10101
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number12
DOIs
Publication statusPublished - Mar 21 2003

ASJC Scopus subject areas

  • Biochemistry

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