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[Cancer Research 59, 1196-1201, March 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 1196-1201, March 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Cleavage of the HER2 Ectodomain Is a Pervanadate-activable Process That Is Inhibited by the Tissue Inhibitor of Metalloproteases-1 in Breast Cancer Cells1

Jordi Codony-Servat, Joan Albanell, Juan Carlos Lopez-Talavera, Joaquín Arribas and José Baselga2

Laboratory of Oncology Research, Medical Oncology Service [J. C-S., J. Al., J. Ar., J. B], Liver Unit [J. C. L-T.], and Universidad Autonoma de Barcelona [J. B.], Vall d’Hebron University Hospital, Barcelona 08035, Spain

The 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.




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