Engineering the NK1 fragment of hepatocyte growth factor/scatter factor as a MET receptor antagonist.
J Mol Biol
; 377(3): 616-22, 2008 Mar 28.
Article
in En
| MEDLINE
| ID: mdl-18291418
ABSTRACT
The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor MET, the tyrosine kinase encoded by the c-MET proto-oncogene, exert major roles in cancer invasion and metastasis and are key targets for therapy. NK1 is an alternative spliced variant of HGF/SF that consists of the N-terminal (N) and first kringle (K1) domains and has partial agonistic activity. NK1 crystallizes as a head-to-tail dimer with an extensive inter-protomeric interface resulting from contacts between the two short interdomain linkers and reciprocal contacts between the N and K1 domains. Here we show that a subset of mutants at the NK1 dimer interface, such as the linker mutants Y124A or N127A or the kringle mutant V140AI142A, bind the MET receptor with affinities comparable to wild-type NK1 but fail to assemble a dimeric, signalling competent NK1-MET complex. These NK1 variants have no detectable agonistic activity on, behave as bona fide receptor antagonists by blocking cell migration and DNA synthesis in target cells and have strong prospects as therapeutics for human cancer.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hepatocyte Growth Factor
/
Proto-Oncogene Proteins c-met
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Mol Biol
Year:
2008
Document type:
Article
Affiliation country:
United kingdom