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Atypical protein kinase C phosphorylates Par6 and facilitates transforming growth factor β-induced epithelial-to-mesenchymal transition.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2013 Mar; Vol. 33 (5), pp. 874-86. Date of Electronic Publication: 2012 Dec 17. - Publication Year :
- 2013
-
Abstract
- Epithelial-to-mesenchymal transition (EMT) is controlled by cellular signaling pathways that trigger the loss of cell-cell adhesion and lead to the restructuring of the cell cytoskeleton. Transforming growth factor β (TGF-β) has been shown to regulate cell plasticity through the phosphorylation of Par6 on a conserved serine residue (S345) by the type II TGF-β receptor. We show here that atypical protein kinase C (aPKC) is an essential component to this signaling pathway in non-small-cell lung cancer (NSCLC) cells. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. In effect, small interfering RNA-targeting aPKC reduces TGF-β-induced RhoA and E-cadherin loss, cell morphology changes, stress fiber production, and the migration of NSCLC cells. Interestingly, reintroduction of a phosphomimetic Par6 (Par6-S345E) into aPKC-silenced cells rescues both RhoA and E-cadherin loss with TGF-β stimulation. In conclusion, our results suggest that aPKCs cooperate with TGF-β receptors to regulate phospho-Par6-dependent EMT and cell migration.
- Subjects :
- Animals
Cadherins metabolism
Carcinoma, Non-Small-Cell Lung genetics
Cell Line
Cell Line, Tumor
Cell Movement
Humans
Lung cytology
Lung metabolism
Lung Neoplasms genetics
Phosphorylation
Protein Interaction Mapping
Protein Kinase C analysis
Protein Kinase C genetics
RNA Interference
Rats
Receptors, Transforming Growth Factor beta analysis
Receptors, Transforming Growth Factor beta metabolism
Signal Transduction
rhoA GTP-Binding Protein metabolism
Adaptor Proteins, Signal Transducing metabolism
Carcinoma, Non-Small-Cell Lung metabolism
Epithelial-Mesenchymal Transition
Lung Neoplasms metabolism
Protein Kinase C metabolism
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 33
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 23249950
- Full Text :
- https://doi.org/10.1128/MCB.00837-12