Methods and compositions for modulating hepatocyte growth factor activation

Abstract

The invention provides methods and compositions for modulating hepsin activity and the HGF/c-met signaling pathway, in particular by regulating pro-HGF activation by hepsin.

1 . A method of identifying a candidate inhibitor substance that inhibits hepsin activation of HGF, said method comprising: (a) contacting a candidate substance with a first sample comprising hepsin and a pro-HGF substrate, and (b) comparing amount of pro-HGF substrate activation in the sample with amount of pro-HGF substrate activation in a reference sample comprising similar amounts of hepsin and pro-HGF substrate as the first sample but that has not been contacted with said candidate substance, whereby a decrease in amount of pro-HGF substrate activation in the first sample compared to the reference sample indicates that the candidate substance is capable of inhibiting hepsin activation of single chain HGF (pro-HGF). 
     
     
         2 . The method of  claim 1 , wherein hepsin in the sample is in an effective amount for activating said pro-HGF. 
     
     
         3 . The method of  claim 1 , wherein the pro-HGF substrate is a polypeptide comprising HGF or fragment thereof comprising a wild type form of the R494-V495 peptide linkage. 
     
     
         4 . The method of  claim 1 , wherein the pro-HGF substrate comprises a cleavage site of human HGF that fits the consensus cleavage site of proteases wherein the cleavage site comprises basic residue at position P 1  and two hydrophobic amino acid residues in positions P 1 ′ and P 2 ′. 
     
     
         5 . An antagonist molecule that inhibits interaction of hepsin and hepatocyte growth factor. 
     
     
         6 . The antagonist molecule of  claim 5 , wherein the molecule comprises an antibody or fragment thereof. 
     
     
         7 . The antagonist molecule of  claim 5 , wherein the molecule comprises a polypeptide comprising a kunitz domain 1 sequence.