State of the structure address on MET receptor activation by HGF

Biochem Soc Trans. 2021 Apr 30;49(2):645-661. doi: 10.1042/BST20200394.


The MET receptor tyrosine kinase (RTK) and its cognate ligand hepatocyte growth factor (HGF) comprise a signaling axis essential for development, wound healing and tissue homeostasis. Aberrant HGF/MET signaling is a driver of many cancers and contributes to drug resistance to several approved therapeutics targeting other RTKs, making MET itself an important drug target. In RTKs, homeostatic receptor signaling is dependent on autoinhibition in the absence of ligand binding and orchestrated set of conformational changes induced by ligand-mediated receptor dimerization that result in activation of the intracellular kinase domains. A fundamental understanding of these mechanisms in the MET receptor remains incomplete, despite decades of research. This is due in part to the complex structure of the HGF ligand, which remains unknown in its full-length form, and a lack of high-resolution structures of the complete MET extracellular portion in an apo or ligand-bound state. A current view of HGF-dependent MET activation has evolved from biochemical and structural studies of HGF and MET fragments and here we review what these findings have thus far revealed.

Keywords: HGF; MET; RTK; activation; autoinhibition; ligand binding.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Hepatocyte Growth Factor / chemistry*
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Ligands
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Domains*
  • Proto-Oncogene Proteins c-met / chemistry*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Signal Transduction / genetics


  • Ligands
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met