Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.
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 beta (TGFbeta) 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 TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. Phosphorylation of Par6 is required for TGFbeta-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.
Ozdamar
Barish
B
Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Canada.
Bose
Rohit
R
Barrios-Rodiles
Miriam
M
Wang
Hong-Rui
HR
Zhang
Yue
Y
Wrana
Jeffrey L
JL
D030201:Activin Receptors, Type I / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D051899:Smad2 Protein; D019108:Tight Junctions / Q000378:metabolism / Q000648:ultrastructure; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D004268:DNA-Binding Proteins; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C497256:Prkce protein, mouse; D017346:Protein Serine-Threonine Kinases; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020742:rhoA GTP-Binding Protein