PMID- 17258232
OWN - NLM
STAT- MEDLINE
DCOM- 20070518
LR  - 20220129
IS  - 0022-2836 (Print)
IS  - 0022-2836 (Linking)
VI  - 367
IP  - 2
DP  - 2007 Mar 23
TI  - Insights into the structure/function of hepatocyte growth factor/scatter factor 
      from studies with individual domains.
PG  - 395-408
AB  - 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.
FAU - Holmes, O
AU  - Holmes O
AD  - MRC Centre, Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.
FAU - Pillozzi, S
AU  - Pillozzi S
FAU - Deakin, J A
AU  - Deakin JA
FAU - Carafoli, F
AU  - Carafoli F
FAU - Kemp, L
AU  - Kemp L
FAU - Butler, P J G
AU  - Butler PJ
FAU - Lyon, M
AU  - Lyon M
FAU - Gherardi, E
AU  - Gherardi E
LA  - eng
GR  - G9704528/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070126
PL  - Netherlands
TA  - J Mol Biol
JT  - Journal of molecular biology
JID - 2985088R
RN  - 0 (MAS1 protein, human)
RN  - 0 (Proto-Oncogene Mas)
RN  - 24967-94-0 (Dermatan Sulfate)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.4.21.- (Serine Endopeptidases)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - Cell Movement
MH  - Cricetinae
MH  - Cricetulus
MH  - Dermatan Sulfate/*metabolism
MH  - Dogs
MH  - Electrophoretic Mobility Shift Assay
MH  - Enzyme Activation
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Heparitin Sulfate/*metabolism
MH  - Hepatocyte Growth Factor/genetics/metabolism/*physiology
MH  - Humans
MH  - Kringles
MH  - Mice
MH  - Mutation
MH  - Phosphorylation
MH  - Pichia
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Mas
MH  - Proto-Oncogene Proteins c-met/*metabolism
MH  - Serine Endopeptidases/genetics
MH  - Structure-Activity Relationship
EDAT- 2007/01/30 09:00
MHDA- 2007/05/19 09:00
CRDT- 2007/01/30 09:00
PHST- 2006/09/06 00:00 [received]
PHST- 2006/12/14 00:00 [revised]
PHST- 2006/12/19 00:00 [accepted]
PHST- 2007/01/30 09:00 [pubmed]
PHST- 2007/05/19 09:00 [medline]
PHST- 2007/01/30 09:00 [entrez]
AID - S0022-2836(06)01751-7 [pii]
AID - 10.1016/j.jmb.2006.12.061 [doi]
PST - ppublish
SO  - J Mol Biol. 2007 Mar 23;367(2):395-408. doi: 10.1016/j.jmb.2006.12.061. Epub 2007 
      Jan 26.