Truncated ErbB2 receptor enhances ErbB1 signaling and induces reversible, ERK-independent loss of epithelial morphology.
Shedding of the extracellular domain of the ErbB2 tyrosine kinase receptor and expression of the remaining NH(2)-terminally truncated ErbB2 correlates with lymph node metastases and adverse outcome in human breast cancer. To study the possible signaling from such a truncated receptor, MCF-7 human breast cancer cells expressing NH(2)-terminally truncated ErbB2 (DeltaNErbB2) were compared with cells overexpressing wild-type ErbB2. Expression of DeltaNErbB2 in MCF-7 cells resulted in sustained activation of extracellular signal-regulated kinases (ERK) 1/2, extensive loss of the epithelial morphology, appearance of vesicles and long protrusions as well as pronounced scattering of the cells. Similar alterations were observed upon ErbB2 overexpression but at much lower levels. Employing cell clones with inducible expression of DeltaNErbB2, it was revealed that the morphological changes were fully reversible and depended on continuous expression of DeltaNErbB2 but not on the activation of the ERK1/2 pathway. Interestingly, the expression of DeltaNErbB2 resulted also in the increased expression and phosphorylation of ErbB1 as well as in the prolonged ligand-induced activation of the ErbB1 signaling pathway. In conclusion, constitutive signaling upon expression of the truncated ErbB2 receptor in human breast cancer cells promotes morphological changes indicative of a more motile and aggressive phenotype.
Egeblad
M
M
Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Denmark.
Mortensen
O H
OH
Jäättelä
M
M
D001943:Breast Neoplasms / Q000473:pathology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000473:pathology; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases