DISTINCT RESPONSES OF PROTEIN-KINASE-C ISOZYMES TO C-ERBB-2 ACTIVATION IN SKBR-3 HUMAN BREAST-CARCINOMA CELLS

We have studied the effect of activation of the c-erbB-2 receptor tyro sine kinase on protein kinase C (PKC) in cultured SKBR-3 human breast cancer cells. Treatment with the agonistic anti-receptor monoclonal an tibody TAb 250 induces receptor autophosphorylation and stimulates pho spholipase C-gamma1 (L. K. Shawver et al. Cancer Res., 54:1367-1373, 1 994). TAb 250 induced a rapid and marked translocation of PKC histone phosphorylation activity to the particulate fraction of SKBR-3 cells. By immunoblot, however, this translocation was limited to specific PKC isozymes. betaPKC and zetaPKC translocated to the particulate fractio n, whereas epsilonPKC underwent ''partial reversed translocation'' to the cell soluble fraction after receptor stimulation. Furthermore, bet aPKC was rapidly degraded following TAb 250 treatment. By immunocytoch emistry, beta1PKC translocated from the perinuclear area to the cytoso l and into the nucleus, whereas zetaPKC translocated to the perinuclea r region and into the nucleus. Consistent with the Western blot result s, epsilonPKC translocated from the nucleus to the perinuclear area an d the cytosol. These changes in the localization of PKC isozymes were not observed after addition of normal IgG1 or a nonagonistic anti-c-er bB-2 monoclonal antibody to SKBR-3 cells. Alpha, betaII, or deltaPKC p resent in these cells did not translocate following receptor stimulati on. These data indicate that c-erbB-2 signal transduction may involve the activation of specific PKC isozymes. The biological role of these enzymes in the phenotype and cellular responses of c-erbB-2-overexpres sing carcinoma cells remains to be studied.