Title of article :
Insights into the Structure/Function of Hepatocyte Growth Factor/Scatter Factor from Studies with Individual Domains
Author/Authors :
O. Holmes، نويسنده , , S. Pillozzi، نويسنده , , J.A. Deakin، نويسنده , , F. Carafoli، نويسنده , , L. Kemp، نويسنده , , P.J.G. Butler، نويسنده , , M. Lyon، نويسنده , , E. Gherardi، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2007
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 β-propeller domain of Met. The N, K1 and SP domains bound Met directly with comparable affinities (Kd = 2.4, 3.3 and 1.4 μM). 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 β-chain moiety (amino acid residues 308–514) of the Met β-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.
Keywords :
c-Met , glycosaminoglycans , Receptor tyrosine kinase , HGF/SF
Journal title :
Journal of Molecular Biology
Journal title :
Journal of Molecular Biology