The proteolytic processing of pro-platelet-derived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity

Cancer Res. 2003 Apr 1;63(7):1458-63.

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