Heregulin beta1 induces the down regulation and the ubiquitin-proteasome degradation pathway of p185HER2 oncoprotein.
Analysis of the fate of the p185HER2 oncoprotein following activation by heregulin beta1 revealed the induction of the tyrosine-phosphorylation, down-modulation, and polyubiquitination of p185HER2. Receptor ubiquitination was suppressed in cells treated with heregulin beta1 in the presence of sodium azide, an inhibitor of ATP-dependent reactions, or genistein, a tyrosine kinase protein inhibitor, indicating the requirement for kinase activity and ATP in p185HER2 polyubiquitination. Ubiquitinated p185HER2 was degradated by the 26S proteasome proteolytic pathway. Kinetics and inhibition experiments indicated that endocytosis of the receptor occurs downstream of the initiation of the degradation process.
Magnifico
A
A
Division of Experimental Oncology E, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Tagliabue
E
E
Ardini
E
E
Casalini
P
P
Colnaghi
M I
MI
Ménard
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D016227:Benzoquinones; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D047029:Lactams, Macrocyclic; D009097:Multienzyme Complexes / Q000378:metabolism*; D020890:Neuregulin-1; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011809:Quinones / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*
D000255:Adenosine Triphosphate; D016227:Benzoquinones; D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors; D019833:Genistein; D006023:Glycoproteins; D047029:Lactams, Macrocyclic; D009097:Multienzyme Complexes; D020890:Neuregulin-1; D046988:Proteasome Endopeptidase Complex; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D017828:Rifabutin; D014452:Ubiquitins; C087230:heregulin beta1; C020754:herbimycin