title: 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.
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.
authors.affiliation: Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Suita, Osaka, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Ikebuchi
authors.forename: Kiyomasa
authors.initials: K
authors.lastname: Oka
authors.forename: Shinya
authors.initials: S
authors.lastname: Mizuno
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fukuta
authors.forename: Daichika
authors.initials: D
authors.lastname: Hayata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity
chemical_list: C066855:HGF protein, human; C553307:HGF protein, mouse; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D019000:Phosphotyrosine; D017228:Hepatocyte Growth Factor