ErbB receptor dimerization, localization, and co-localization in mouse lung type II epithelial cells.

Abstract

ErbB receptors are crucial for embryonic neuronal and cardiac development. ErbB receptor ligands neuregulin (NRG) and epidermal growth factor (EGF) play a major role in the developing lung, specifically in mesenchymal induced fetal surfactant synthesis by type II epithelial cells. Different erbB receptor ligands cause diverse biologic effects by stimulating specific erbB-dimers. It is not known how dimerization, cellular localization, and co-localization of erbB dimers are regulated in type II epithelial cells. We hypothesized that erbB receptors have a distinct dimerization, localization, and co-localization pattern in type II cells. In mouse type II epithelial cells, which express all four erbB receptors, erbB1 and erbB4 were the preferred dimerization partners. These dimerization patterns were ligand independent. Confocal microscopy showed these transmembrane receptors exhibited a strong nuclear localization. In non-stimulated cells, both erbB1 and erbB2 were predominantly localized to the nucleus and less intensely to the cytoplasm. However, erbB1 was mainly found in the nucleoli, whereas erbB2 spared the nucleolar region. ErbB3 was exclusively located in the nucleoli. ErbB4 was diffusely located in nucleus and cytoplasm, and like erbB2 spared the nucleolar region. Short stimulation with either EGF or NRG led to a more pronounced nuclear staining for erbB1, erbB2, and erbB4. All four receptors co-localized with each other after stimulation, but with varying intensity. The two known stimulators of fetal surfactant synthesis, NRG and NRG-containing fibroblast conditioned medium, changed cellular localization of the dimerization partners erbB4 and erbB2 in a distinct fashion. We conclude that erbB receptors have a receptor-specific localization and dimerization pattern in type II epithelial cells.