Gamma-heregulin

Abstract

A novel member of the heregulin superfamily has been identified which is designated “γ-HRG”. This molecule, secreted by human breast cancer MDA-MB-175 cells, leads to the formation of a constitutive active receptor complex and stimulates the growth of these cells in an autocrine manner. γ-HRG polypeptide and nucleic acid are disclosed, together with various uses therefor (e.g. use of γ-HRG nucleic acid for the recombinant production of γ-HRG). γ-HRG antagonists (e.g. neutralizing antibodies and antisense nucleic acid molecules) as well as uses therefor are also described.

1 . A method for activating an ErbB receptor comprising contacting a cell which expresses an ErbB receptor with an isolated polypeptide having at least 95% sequence identity to a polypeptide comprising the amino sequence of SEQ ID NO:4, or SEQ ID NO:10, and wherein the polypeptide stimulates tyrosine phosphorylation of the ErbB receptor. 
     
     
         2 . The method of  claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:4. 
     
     
         3 . The method of  claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:10. 
     
     
         4 . The method of  claim 1 , wherein the cell is in cell culture. 
     
     
         5 . The method of  claim 1 , wherein the cell is mammalian. 
     
     
         6 . The method of  claim 5 , wherein the mammal is human. 
     
     
         7 . A method for enhancing proliferation, differentiation, or survival of a cell comprising contacting the cell with a polypeptide having at least 95% sequence identity to a polypeptide comprising an amino acid sequence of SEQ ID NO:4, or SEQ ID NO:10, wherein the polypeptide stimulates tyrosine phosphorylation of a ErbB receptor. 
     
     
         8 . The method of  claim 7 , wherein the cell is a glial cell. 
     
     
         9 . The method of  claim 8 , wherein the cell is a human cell. 
     
     
         10 . The method of  claim 7 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:4. 
     
     
         11 . The method of  claim 7 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:10. 
     
     
         12 . The method of  claim 7 , wherein the cell is a neuron. 
     
     
         13 . The method of  claim 7 , wherein the cell is a muscle cell. 
     
     
         14 . A method of treating a neurologic disease or disorder in a subject comprising administering a γ-Heregulin (γ-HRG) polypeptide having at least 95% sequence identity to a polypeptide comprising SEQ ID NO:2, SEQ ID NO:4 or SEQ ID NO:10 to the subject, wherein the polypeptide stimulates tyrosine phosphorylation of an ErbB receptor. 
     
     
         15 . The method of  claim 14 , wherein the neurologic disease or disorder is due to damage from surgery, trauma, stroke, bulimia, infection, metabolic disease, malignancy, or toxic agents. 
     
     
         16 . The method of  claim 14 , wherein the disease or disorder is amylotrophic lateral sclerosis, Bell's palsy, spinal muscular atrophy, paralysis, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's chorea, Down's syndrome, nerve deafness, or Meniere's disease. 
     
     
         17 . The method of  claim 14 , wherein the disease or disorder is post-polio syndrome, Charcot-Marie-Tooth disease, Abetalipoproteinemia, Tangier disease, Krabbe's disease, Metachromatic leukodystrophy, Fabry's disease or Dejerine-Sottas syndrome. 
     
     
         18 . The method of  claim 14 , wherein the polypeptide comprises a sequence of SEQ ID NO:2. 
     
     
         19 . The method of  claim 14 , wherein the polypeptide comprises a sequence of SEQ ID NO:4. 
     
     
         20 . The method of  claim 14 , wherein the polypeptide comprises a sequence of SEQ ID NO:10.