Functional regulation of semaphorin receptors by proprotein convertases.
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 alpha1-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
Stefania
S
Institute for Cancer Research and Treatment (IRCC), University of Torino School of Medicine, 10060 Candiolo, Italy.
Barberis
Davide
D
Fazzari
Pietro
P
Longati
Paola
P
Angelini
Paola
P
van de Loo
Jan-Willem
JW
Comoglio
Paolo M
PM
Tamagnone
Luca
L
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000737:chemistry; D019281:Dimerization; D004285:Dogs; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D043484:Proprotein Convertases; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D013381:Subtilisins / Q000502:physiology*
D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; C492118:Plxnb1 protein, mouse; D011956:Receptors, Cell Surface; D043484:Proprotein Convertases; D013381:Subtilisins