Differential utilization and localization of ErbB receptor tyrosine kinases in skin compared to normal and malignant keratinocytes

Induction of heparin-binding epidermal growth factor-like growth factor (HB -EGF) mRNA in mouse skin organ culture was blocked by two pan-ErbB receptor tyrosine kinase (RTK) inhibitors but not by genetic ablation of ErbB1, sug gesting involvement of multiple ErbB species in skin physiology. Human skin , cultured normal keratinocytes, and A431 skin carcinoma cells expressed Er bB1, ErbB2, and ErbB3, but not ErbB4. Skin and A431 cells expressed more Er bB3 than did keratinocytes. Despite strong expression of ErbB2 and ErbB3, h eregulin was inactive In stimulating tyrosine phosphorylation in A431 cells . In contrast, it was highly active in MDA-MB-453 breast carcinoma cells. E rbB2 displayed punctate cytoplasmic staining in A431 and keratinocytes, com pared to strong cell surface staining in MDA-MB-453. In skin, ErbB2 was cyt oplasmic in basal keratinocytes, assuming a cell surface pattern in the upp er suprabasal layers. In contrast, ErbB1 retained a cell surface distributi on in all epidermal layers. Keratinocyte proliferation in culture was found to be ErbB1-RTK-dependent, using a selective inhibitor. These results sugg est that in skin keratinocytes, ErbB2 transduces ligand-dependent different iation signals, whereas ErbB1 transduces ligand-dependent proliferation/sur vival signals. Intracellular sequestration of ErbB2 may contribute to the m alignant phenotype of A431 cells, by allowing them to respond to ErbB1 depe ndent growth/survival signals, while evading ErbB2-dependent differentiatio n signals.