Functional Characterization of Human Hepatocyte Growth Factor Mutants Obtained by Deletion of Structural Domains

Mitsuhiko Okigaki, Masayuki Komada, Yoshihiko Uehara, Keiji Miyazawa, Naomi Kitamura

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

Abstract

Human hepatocyte growth factor (hHGF) consists of characteristic structural domains. In this study, we prepared mutant proteins lacking each of these domains and examined their biological activities for stimulation of hepatocyte DNA synthesis, inhibition of Meth A cell growth, and induction of MDCK cell dissociation. We also examined their interactions with the c-met/HGF receptor by competition analysis and by analysis of levels of tyrosine phosphorylation. The mutant proteins lacking the N-terminal, the first kringle, or the second kringle domain were not biologically effective and could not compete with hHGF bound to the c-met/HGF receptor. The results indicate that these domains are necessary for the biological activities of hHGF mediated by binding to the c-met/HGF receptor. The mutant proteins lacking the third or fourth kringle domain moderately retained biological activities and the receptor binding. The relative levels of the tyrosine phosphorylation of the c-met/HGF receptor by these mutant proteins correlated well with the relative potencies of the biological activities when compared with that of the wild-type hHGF. The mutant protein lacking the light chain was not effective in the biological activities and tyrosine phosphorylation of the c-met/HGF receptor, but competed with hHGF bound to the c-mef/HGF receptor. These results suggest that the heavy chain plays an important role in the interaction of hHGF with the c-met/HGF receptor and that the light chain is further required for the tyrosine phosphorylation of the c-met/HGF receptor.

Original languageEnglish
Pages (from-to)9555-9561
Number of pages7
JournalBiochemistry
Volume31
Issue number40
DOIs
Publication statusPublished - 1992 Feb 1

ASJC Scopus subject areas

  • Biochemistry

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