An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist

FEBS Lett. 2014 Dec 20;588(24):4831-7. doi: 10.1016/j.febslet.2014.11.018. Epub 2014 Nov 21.

Abstract

Hepatocyte growth factor (HGF), through activation of the c-MET receptor, mediates biological processes critical for tissue regeneration; however, its clinical application is limited by protein instability and poor recombinant expression. We previously engineered an HGF fragment (eNK1) that possesses increased stability and expression yield and developed a c-MET agonist by coupling eNK1 through an introduced cysteine residue. Here, we further characterize this eNK1 dimer and show it elicits significantly greater c-MET activation, cell migration, and proliferation than the eNK1 monomer. The efficacy of the eNK1 dimer was similar to HGF, suggesting its promise as a c-MET agonist.

Keywords: Hepatocyte growth factor; Ligand/receptor interaction; Protein engineering; Receptor agonist; Tissue regeneration; c-MET receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Hepatocyte Growth Factor / chemistry*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Protein Engineering*
  • Protein Multimerization*
  • Protein Stability
  • Protein Structure, Quaternary
  • Proto-Oncogene Proteins c-met / agonists*
  • Proto-Oncogene Proteins c-met / metabolism
  • Signal Transduction / drug effects
  • Temperature

Substances

  • Peptide Fragments
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met