Cleavage of the HER2 ectodomain is a pervanadate-activable process that isinhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells

HER2/neu, a M-r 185,000 tyrosine kinase receptor that is overexpressed in b reast cancer, undergoes proteolytic cleavage of its extracellular domain (E CD). In contrast with other membrane-bound proteins, including growth facto r receptors, that are cleaved by a common machinery system, we show that BE RL cleavage is a slow process and is not activated by protein kinase C. Per vanadate, a general inhibitor of protein-tyrosine phosphatases, induces a r apid and potent shedding of HER2 ECD. The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimas tat. The tissue inhibitor of metalloproteases-1; an inhibitor of matrix met alloproteases that does not inhibit cleavage by the general protein kinase C-dependent shedding machinery, also inhibited HER2 ECD shedding, whereas t issue inhibitor of metalloproteases-2 did not. These data suggest that HER2 cleavage is a process regulated by an as-yet-unidentified distinct proteas e.