Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells.
HER2/neu, a Mr 185,000 tyrosine kinase receptor that is overexpressed in breast cancer, undergoes proteolytic cleavage of its extracellular domain (ECD). In contrast with other membrane-bound proteins, including growth factor receptors, that are cleaved by a common machinery system, we show that HER2 cleavage is a slow process and is not activated by protein kinase C. Pervanadate, a general inhibitor of protein-tyrosine phosphatases, induces a rapid and potent shedding of HER2 ECD. The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimastat. The tissue inhibitor of metalloproteases-1; an inhibitor of matrix metalloproteases that does not inhibit cleavage by the general protein kinase C-dependent shedding machinery, also inhibited HER2 ECD shedding, whereas tissue inhibitor of metalloproteases-2 did not. These data suggest that HER2 cleavage is a process regulated by an as-yet-unidentified distinct protease.
Codony-Servat
J
J
Laboratory of Oncology Research, Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain.
Albanell
J
J
Lopez-Talavera
J C
JC
Arribas
J
J
Baselga
J
J
D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D010450:Endopeptidases; D006877:Hydroxamic Acids; D008666:Metalloendopeptidases; D010649:Phenylalanine; D011480:Protease Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D013876:Thiophenes; D019715:Tissue Inhibitor of Metalloproteinase-1; D014443:Tyrosine; D014638:Vanadates; C099410:TAPI-2; C076715:pervanadate; C080985:batimastat