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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}

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J. B. Cordero, D. E. Larson, C. R. Craig, R. Hays, and R. Cagan (2007)
Development 134, 1861-1871
   Abstract »    Full Text »    PDF »
Regulatory mechanisms governing the oocyte-specific synthesis of the karyoskeletal protein NO145.
S. Voltmer-Irsch, S. Kneissel, P. G. Adenot, and M. S. Schmidt-Zachmann (2007)
J. Cell Sci. 120, 1412-1422
   Abstract »    Full Text »    PDF »
Sequestration and Segregation of Receptor Kinases in Epithelial Cells: Implications for ErbB2 Oncogenesis.
C. A. C. Carraway and K. L. Carraway (2007)
Sci. STKE 2007, re3
   Abstract »    Full Text »    PDF »
PAR-6 is required for junction formation but not apicobasal polarization in C. elegans embryonic epithelial cells.
R. Totong, A. Achilleos, and J. Nance (2007)
Development 134, 1259-1268
   Abstract »    Full Text »    PDF »
Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity.
J. C. Schwamborn, M. Muller, A. H. Becker, and A. W. Puschel (2007)
EMBO J. 26, 1410-1422
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Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility.
E. Sahai, R. Garcia-Medina, J. Pouyssegur, and E. Vial (2007)
J. Cell Biol. 176, 35-42
   Abstract »    Full Text »    PDF »
Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling.
Y. Wang, D. Du, L. Fang, G. Yang, C. Zhang, R. Zeng, A. Ullrich, F. Lottspeich, and Z. Chen (2006)
EMBO J. 25, 5058-5070
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