Joint Study on the Tumorigenicity of HGF and c-met Receptor

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Hepatocyte growth factor (HGF) is a pleiotropic factor, which act as a mitogen, motogen, and morphogen for various epithelial cells. The c-Met protooncogene product was identified as the receptor for HGF.In this study, we analyzed the tumorigenicity of HGF and c-Met receptor. Various sarcoma cell lines were found to express high level of c-Met receptor, indicating that the HGF-Met autocrine signaling contributes to the tumorigenic process of sarcoma.HGF converting enzyme, which converts an inactive single-chain precursor (pro-HGF) to a two-chain active form HGF,was purified and identified as a heterodimer protein composed of a 65-kDa heavy chain and a 32-kDa light chain. A synthetic peptide derivative, Ac-Lys-Gln-Leu-Arg-chloromethylketone, containing the sequence of pro-HGF cleavage site strongly inhibited the converting enzyme activity, and the mitogenic activity of pro-HGF.However, this inhibitor could not block the growth of sarcoma cells, probably because of the instability in the conditioned medium. Using the chicken c-sea tyrosine kinase gene (the gene closely related to c-Met) as a probe, we obtained the cDNAs encoding three novel protein kinases, c-Sea, Sky and LIMK.c-Sea is highly related to the c-Met receptor and seems to be a receptor for a HGF-related growth factor. Sky is a novel receptor tyrosine kinase related to Axl/Ufo/Ark. Identification of the ligands for c-Sea and Sky is the subject of ongoing studies. LIMK is a cytoplasmic serine/threonine kinase containing two repeats of LIM/double zinc finger motif at the N-terminus and a protein kinase domain at the C-terminus. LIMK may be involved in the oncogenic process through interactions with other LIM-containing proteins.