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.

Artigiani, S., Barberis, D., Fazzari, P., Longati, P., Angelini, P., Van De Loo, J., Comoglio, P. M., Tamagnone, L., Functional regulation of semaphorin receptors by proprotein convertases, <<THE JOURNAL OF BIOLOGICAL CHEMISTRY>>, 2003; 278 (12): 10094-10101. [doi:10.1074/jbc.M210156200] [http://hdl.handle.net/10807/141408]

Functional regulation of semaphorin receptors by proprotein convertases

Tamagnone, Luca
2003

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.
Inglese
Artigiani, S., Barberis, D., Fazzari, P., Longati, P., Angelini, P., Van De Loo, J., Comoglio, P. M., Tamagnone, L., Functional regulation of semaphorin receptors by proprotein convertases, <<THE JOURNAL OF BIOLOGICAL CHEMISTRY>>, 2003; 278 (12): 10094-10101. [doi:10.1074/jbc.M210156200] [http://hdl.handle.net/10807/141408]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/141408
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