Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2. Both ErbB-1 and ErbB-2 contribute significantly to tumorigenicity.
This article examines differential expression and heterodimer formation of ErbB family members in tumorigenic and nontumorigenic human bronchial epithelial cells (HBECs). This cell system was developed previously as a model for lung adenocarcinoma by overexpression of c-erbB-2 in nontumorigenic, T antigen-immortalized HBECs. Earlier studies demonstrated that a tumorigenic clone from T antigen-immortalized nontumorigenic cells overexpressing ErbB-2 endogenously produced high levels of transforming growth factor (TGF)-alpha, and that reducing TGF-alpha by 93% eliminated tumorigenicity. In the present report, comparison of ErbB species between the tumorigenic cells (E6T) and their nontumorigenic derivatives (E6TA) demonstrated all four receptors in both cell types. However, in E6TA cells, ErbB-3 and -4 were present primarily in ErbB-1 heterodimers, suggesting that ErbB-1 is a preferred heterodimer partner within this cell system, expressing endogenous ErbB receptors and ligands and overexpressing ErbB-2. The ErbB-1/-2 species was present at high levels in E6T and absent in E6TA cells. Mitogen-activated protein kinase activity was elevated in E6T relative to E6TA. Elevated activity was eliminated by blocking surface expression of either ErbB-1 or ErbB-2. Endoplasmic reticulum trapping of ErbB-1 eliminated tumorigenicity, whereas ErbB-2 internalization was selected against during tumor formation. These data demonstrate the importance of TGF-alpha-mediated signaling through the ErbB-1/-2 heterodimer in development of the tumorigenic phenotype. This work further suggests that ErbB-3 and -4 species may also contribute to tumorigenic conversion and that their expression levels may be increased by signaling initiated by TGF-alpha.
Fernandes
A M
AM
Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, USA.
Hamburger
A W
AW
Gerwin
B I
BI
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008168:Lung; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D014162:Transfection
D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse