Alternative proteolytic processing of hepatocyte growth factor during wound repair

Am J Pathol. 2009 Jun;174(6):2116-28. doi: 10.2353/ajpath.2009.080597. Epub 2009 Apr 23.


Wound healing is a crucial regenerative process in all organisms. We examined expression, integrity, and function of the proteins in the hepatocyte growth factor (HGF)/c-Met signaling pathway in normally healing and non-healing human skin wounds. Whereas in normally healing wounds phosphorylation of c-Met was most prominent in keratinocytes and dermal cells, in non-healing wounds phosphorylation of c-Met was barely detectable, suggesting reduced c-Met activation. In wound exudates obtained from non-healing, but not from healing wounds, HGF protein was a target of substantial proteolytic processing that was different from the classical activation by known serine proteases. Western blot analysis and protease inhibitor studies revealed that HGF is a target of neutrophil elastase and plasma kallikrein during skin repair. Proteolytic processing of HGF by each of these proteases significantly attenuated keratinocyte proliferation, wound closure capacity in vitro, and c-Met signal transduction. Our findings reveal a novel pathway of HGF processing during skin repair. Conditions in which proteases are imbalanced and tend toward increased proteolytic activity, as in chronic non-healing wounds, might therefore compromise HGF activity due to the inactivation of the HGF protein and/or the generation of HGF fragments that ultimately mediate a dominant negative effect and limit c-Met activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blotting, Western
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme-Linked Immunosorbent Assay
  • Exudates and Transudates / chemistry
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Immunohistochemistry
  • Keratinocytes / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-met / metabolism
  • Serine Endopeptidases / metabolism
  • Signal Transduction / physiology*
  • Skin / metabolism
  • Wound Healing / physiology*


  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Serine Endopeptidases