The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation

Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):928-33. doi: 10.1073/pnas.0335507100. Epub 2003 Jan 27.


Seven secretory mammalian kexin-like subtilases have been identified that cleave a variety of precursor proteins at monobasic and dibasic residues. The recently characterized pyrolysin-like subtilase SKI-1 cleaves proproteins at nonbasic residues. In this work we describe the properties of a proteinase K-like subtilase, neural apoptosis-regulated convertase 1 (NARC-1), representing the ninth member of the secretory subtilase family. Biosynthetic and microsequencing analyses of WT and mutant enzyme revealed that human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 at the (Y,I)VV(V,L)(L,M) downward arrow motif, a site that is representative of its enzymic specificity. In vitro peptide processing studies andor Ala substitutions of the P1-P5 sites suggested that hydrophobicaliphatic residues are more critical at P1, P3, and P5 than at P2 or P4. NARC-1 expression is highest in neuroepithelioma SK-N-MCIXC, hepatic BRL-3A, and in colon carcinoma LoVo-C5 cell lines. In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. These include hepatocytes, kidney mesenchymal cells, intestinal ileum, and colon epithelia as well as embryonic brain telencephalon neurons. Accordingly, transfection of NARC-1 in primary cultures of embryonic day 13.5 telencephalon cells led to enhanced recruitment of undifferentiated neural progenitor cells into the neuronal lineage, suggesting that NARC-1 is implicated in the differentiation of cortical neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Northern
  • CHO Cells
  • Cell Differentiation
  • Cells, Cultured
  • Cricetinae
  • Electrophoresis, Polyacrylamide Gel
  • Hepatocytes / cytology
  • Humans
  • In Situ Hybridization
  • Liver / metabolism*
  • Liver / physiology*
  • Mice
  • Models, Genetic
  • Mutation
  • Neurons / metabolism*
  • Neurons / physiology
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Rats
  • Regeneration
  • Serine Endopeptidases / biosynthesis*
  • Serine Endopeptidases / physiology*
  • Time Factors
  • Tissue Distribution
  • Transfection
  • Tumor Cells, Cultured


  • PCSK9 protein, human
  • PCSK9 protein, rat
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases