Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor.
Tight control of cell proliferation and morphogenesis is required to ensure normal tissue patterning and prevent cancer formation. Overexpression of the ErbB-2/Neu receptor tyrosine kinase is associated with increased progression in human breast cancer, yet in breast explant cultures, the ErbB-2/Neu receptor contributes to alveolar differentiation. To examine the consequence of deregulated ErbB-2/Neu activation on epithelial morphogenesis, we have expressed a constitutively activated mutant of ErbB-2/Neu in a Madin-Darby canine kidney (MDCK) epithelial cell model. Using two-dimensional cultures we demonstrate that activated ErbB-2/Neu induces breakdown of cell-cell junctions, increased cell motility and dispersal of epithelial colonies. This correlates with reorganization of the actin cytoskeleton and focal adhesions and loss of insoluble cell-cell junction complexes involving E-cadherin. Interestingly, a constitutively activated ErbB-2/Neu receptor promotes an invasive morphogenic program in MDCK cells in a three-dimensional matrix. We show that two tyrosines in the carboxy-terminal tail of ErbB-2/Neu, involved in the phosphorylation of the Shc adapter protein, are each sufficient to promote epithelial-mesenchymal like transition and enhanced cell motility in two-dimensional culture and cell invasion rather than a morphogenic response in matrix culture. This provides a model system to investigate ErbB-2/Neu induced signaling pathways required for epithelial cell dispersal and invasion versus morphogenesis.
Khoury
H
H
Department of Biochemistry, Molecular Oncology Group, McGill University Hospital Centre, Montreal, Quebec H3A 1A1, Canada.
Dankort
D L
DL
Sadekova
S
S
Naujokas
M A
MA
Muller
W J
WJ
Park
M
M
D000199:Actins; D022005:Adherens Junctions; D000818:Animals; D015820:Cadherins; D002454:Cell Differentiation; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D003599:Cytoskeleton; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D008648:Mesoderm / Q000166:cytology*; D009024:Morphogenesis; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D000199:Actins; D015820:Cadherins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine