Dissociation of c-Met phosphotyrosine sites in human cells in response to mouse hepatocyte growth factor but not human hepatocyte growth factor: the possible roles of different amino acids in different species

Cell Biochem Funct. 2013 Jun;31(4):298-304. doi: 10.1002/cbf.2898. Epub 2012 Sep 20.

Abstract

Hepatocyte growth factor (HGF) is essential for embryogenesis, tissue regeneration and tumour malignancy through the activation of its receptor, c-Met. We previously demonstrated that HGF α-chain hairpin-loop, K1 domain and β-chain are required for c-Met signalling. The sequential phosphorylation of tyrosine residues, from c-Met kinase domain to multidocking regions, is required for HGF-signalling transduction. Herein, we provide evidence that the disconcerted activation of c-Met tyrosine regions fails to induce biological functions. When human cells were incubated with 'mouse HGF', kinase domain activation (i.e. phospho-Tyr-1230/34/35) became evident, but the multidocking site (i.e. Tyr-1349) was not phosphorylated, resulting in unsuccessful induction of migration and mitogenesis. The binding ability of mouse HGF α-chain, or of β-chain, to human c-Met was lower than that of human HGF, as evidenced by HGF-chimera assay. Notably, only four amino acid positions in HGF α-chain hairpin-loop and K1 domain and six positions in β-chain differed between human HGF and mouse HGF. The human-specific amino acids (such as Gln-95 in hairpin-loop, Arg-134 in K1 domain and Cys-561 in β-chain) may be important for accurate c-Met assembly and signalling transduction.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Dogs
  • Hepatocyte Growth Factor / chemistry
  • Hepatocyte Growth Factor / metabolism*
  • Hepatocytes / chemistry
  • Hepatocytes / metabolism
  • Humans
  • Kinetics
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphotyrosine / chemistry
  • Phosphotyrosine / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / chemistry*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Species Specificity

Substances

  • HGF protein, human
  • HGF protein, mouse
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Phosphotyrosine
  • Hepatocyte Growth Factor