EGF RECEPTOR TRANSACTIVATION BY G-PROTEIN-COUPLED RECEPTORS REQUIRES METALLOPROTEINASE CLEAVAGE OF proHB-EGF

Abstract

The present invention relates to agents and methods for growth-factor receptor activation by modulating the G-protein mediated signal transduction pathway.

1 . A method for modulating growth-factor activation comprising contacting a cell or an organism which contains a growth-factor receptor capable of being activated with a modulator of G-protein mediated signal transduction. 
   
   
       2 . The method of use of  claim 1 , wherein the activation of the growth factor receptor is mediated by its extracellular domain. 
   
   
       3 . The method of  claim 1 , wherein the activation of the growth factor receptor is mediated via an extracellular signal pathway. 
   
   
       4 . The method of  claim 1 , wherein the growth-factor receptor is activated by tyrosine phosphorylation. 
   
   
       5 . The method of  claim 1 , wherein said growth-factor receptor is EGFR. 
   
   
       6 . The method of  claim 1  wherein the modulator acts on a G-protein, a G-protein coupled receptor and/or a proteinase. 
   
   
       7 . The method of  claim 6 , wherein the modulator acts on a proteinase. 
   
   
       8 . The method of  claim 7 , wherein said modulator acts on said proteinase by directly stimulating or inhibiting the proteinase activity. 
   
   
       9 . The method of  claim 7 , wherein said proteinase cleaves a growth-factor ligand precursor. 
   
   
       10 . The method of  claim 9 , wherein said precursor is a membrane associated molecule. 
   
   
       11 . The method of  claim 9 , wherein said growth factor ligand precursor is proHB-EGF and said growth-factor receptor is EGFR. 
   
   
       12 . The method of  claim 7 , wherein said proteinase is a membrane-associated proteinase. 
   
   
       13 . The method of  claim 7 , wherein said proteinase is a metalloproteinase. 
   
   
       14 . The method of  claim 13 , wherein said metalloproteinase is a zinc dependent proteinase. 
   
   
       15 . The method of  claim 7 , wherein said proteinase activity is inhibited by batimastat. 
   
   
       16 . The method of  claim 1 , wherein said modulator acts on cell which is different from the cell which contains the growth-factor. 
   
   
       17 . The method of  claim 1  for the prevention or treatment of disorders associated with or accompanied by a disturbed, e.g. pathologically enhanced growth-factor receptor activation. 
   
   
       18 . The method of  claim 17  for the treatment of cancer or asthma. 
   
   
       19 . The method of  claim 1 , wherein said modulator is administered as a pharmaceutically acceptable composition. 
   
   
       20 . A method for identifying and providing modulators of G-protein mediated signal transduction comprising contacting a cell which contains a growth-factor receptor capable of being activated with a test compound suspected to be a modulator of G-protein mediated signal transduction and determining the degree of growth-factor receptor activation.