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    Insights into the structure/function of hepatocyte growth factor/scatter factor from studies with individual domains.

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    Authors
    Holmes, O
    Pillozzi, S
    Deakin, Jon A
    Carafoli, F
    Kemp, L
    Butler, P J G
    Lyon, Malcolm
    Gherardi, Ermanno
    Affiliation
    MRC Centre, Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.
    Issue Date
    2007-03-23
    
    Metadata
    Show full item record
    Abstract
    Hepatocyte growth factor/scatter factor (HGF/SF), the ligand for the receptor tyrosine kinase encoded by the c-Met proto-oncogene, is a multidomain protein structurally related to the pro-enzyme plasminogen and with major roles in development, tissue regeneration and cancer. We have expressed the N-terminal (N) domain, the four kringle domains (K1 to K4) and the serine proteinase homology domain (SP) of HGF/SF individually in yeast or mammalian cells and studied their ability to: (i) bind the Met receptor as well as heparan sulphate and dermatan sulphate co-receptors, (ii) activate Met in target cells and, (iii) map their binding sites onto the beta-propeller domain of Met. The N, K1 and SP domains bound Met directly with comparable affinities (K(d)=2.4, 3.3 and 1.4 microM). The same domains also bound heparin with decreasing affinities (N>K1>>SP) but only the N domain bound dermatan sulphate. Three kringle domains (K1, K2 and K4) displayed agonistic activity on target cells. In contrast, the N and SP domains, although capable of Met binding, displayed no or little activity. Further, cross-linking experiments demonstrated that both the N domain and kringles 1-2 bind the beta-chain moiety (amino acid residues 308-514) of the Met beta-propeller. In summary, the K1, K2 and K4 domains of HGF/SF are sufficient for Met activation, whereas the N and SP domains are not, although the latter domains contribute additional binding sites necessary for receptor activation by full length HGF/SF. The results provide new insights into the structure/function of HGF/SF and a basis for engineering the N and K1 domains as receptor antagonists for cancer therapy.
    Citation
    Insights into the structure/function of hepatocyte growth factor/scatter factor from studies with individual domains. 2007, 367 (2):395-408 J. Mol. Biol.
    Journal
    Journal of Molecular Biology
    URI
    http://hdl.handle.net/10541/70413
    DOI
    10.1016/j.jmb.2006.12.061
    PubMed ID
    17258232
    Type
    Article
    Language
    en
    ISSN
    0022-2836
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jmb.2006.12.061
    Scopus Count
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    All Paterson Institute for Cancer Research

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