Abstract
Although altered expression of platelet-derived growth factor (PDGF)-A is a hallmark of many cancers, the importance of pro-PDGF-A conversion to PDGF-A in tumorigenesis and the cognate protease(s) is unknown. Pro-PDGF-A processing occurs at pairs of basic residues, likely involving the proprotein convertases (PCs). In the colon carcinoma cell line LoVo, we found that Furin is the most potent PDGF-A convertase. Mutation of the PC-site RRKR(86) to ARKA(86) inhibited pro-PDGF-A processing, its receptor tyrosine phosphorylation, and cell proliferation. This processing is also blocked by the PC preprosegments (pps) ppFurin, ppPC5, and ppPACE4, and by the Furin-variants of alpha2-macroglobulin and alpha1-antitrypsin. Chinese hamster ovary cells overexpressing pro-PDGF-A (ARKA(86)) failed to induce tumors in nude mice. Thus, PC-directed inhibitors might represent new agents for therapy in neoplasia induced by PDGF-A.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3T3 Cells
-
Adenocarcinoma / enzymology
-
Adenocarcinoma / metabolism
-
Animals
-
Binding Sites
-
CHO Cells
-
Colonic Neoplasms / enzymology
-
Colonic Neoplasms / metabolism
-
Cricetinae
-
Furin
-
Humans
-
Male
-
Mice
-
Mice, Inbred BALB C
-
Mice, Nude
-
Mutagenesis, Site-Directed
-
Phosphorylation
-
Platelet-Derived Growth Factor / biosynthesis*
-
Platelet-Derived Growth Factor / physiology
-
Polymerase Chain Reaction
-
Proprotein Convertase 5
-
Proprotein Convertases
-
Protein Precursors / metabolism*
-
Serine Endopeptidases / genetics
-
Serine Endopeptidases / metabolism*
-
Serine Proteinase Inhibitors / genetics
-
Serine Proteinase Inhibitors / physiology
-
Substrate Specificity
-
Subtilisins / antagonists & inhibitors
-
Subtilisins / genetics
-
Subtilisins / metabolism
-
Transfection
-
Tumor Cells, Cultured
-
Tyrosine / metabolism
Substances
-
Platelet-Derived Growth Factor
-
Protein Precursors
-
Serine Proteinase Inhibitors
-
platelet-derived growth factor A
-
Tyrosine
-
PCSK6 protein, human
-
Pcsk6 protein, mouse
-
Proprotein Convertase 5
-
Proprotein Convertases
-
Serine Endopeptidases
-
Subtilisins
-
propeptide convertase 5, mouse
-
Furin