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Science 307 (5715): 1603-1609

Copyright © 2005 by the American Association for the Advancement of Science

Regulation of the Polarity Protein Par6 by TGFß Receptors Controls Epithelial Cell Plasticity

Barish Ozdamar,1,2* Rohit Bose,1,2* Miriam Barrios-Rodiles,2 Hong-Rui Wang,2 Yue Zhang,2 Jeffrey L. Wrana1,2{ddagger}

Abstract: The transition of cells from an epithelial to a mesenchymal phenotype is a critical event during morphogenesis in multicellular organisms and underlies the pathology of many diseases, including the invasive phenotype associated with metastatic carcinomas. Transforming growth factor ß (TGFß) is a key regulator of epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms that control the dissolution of tight junctions, an early event in EMT, remain elusive. We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFß receptors and is a substrate of the type II receptor, TßRII. Phosphorylation of Par6 is required for TGFß-dependent EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets the guanosine triphosphatase RhoA for degradation, thereby leading to a loss of tight junctions. These studies define how an extracellular cue signals to the polarity machinery to control epithelial cell morphology.

1 Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Canada.
2 Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.

* These authors contributed equally to this work.

{ddagger} To whom correspondence may be addressed. E-mail: wrana{at}mshri.on.ca

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The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs..
M. C Fleisch, C. A Maxwell, and M.-H. Barcellos-Hoff (2006)
Endocr. Relat. Cancer 13, 379-400
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CNF1-induced Ubiquitylation and Proteasome Destruction of Activated RhoA Is Impaired in Smurf1-/- Cells.
L. Boyer, L. Turchi, B. Desnues, A. Doye, G. Ponzio, J.-L. Mege, M. Yamashita, Y. E. Zhang, J. Bertoglio, G. Flatau, et al. (2006)
Mol. Biol. Cell 17, 2489-2497
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Role of Ubiquitylation in Cellular Membrane Transport.
O. Staub and D. Rotin (2006)
Physiol Rev 86, 669-707
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Cooperation between Snail and LEF-1 Transcription Factors Is Essential for TGF-beta1-induced Epithelial-Mesenchymal Transition.
D. Medici, E. D. Hay, and D. A. Goodenough (2006)
Mol. Biol. Cell 17, 1871-1879
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Src Activation Is Not Necessary for Transforming Growth Factor (TGF)-{beta}-mediated Epithelial to Mesenchymal Transitions (EMT) in Mammary Epithelial Cells: PP1 DIRECTLY INHIBITS TGF-{beta} RECEPTORS I AND II.
M. Maeda, Y. Shintani, M. J. Wheelock, and K. R. Johnson (2006)
J. Biol. Chem. 281, 59-68
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Tight junction biology and kidney dysfunction.
D. B. N. Lee, E. Huang, and H. J. Ward (2006)
Am J Physiol Renal Physiol 290, F20-F34
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