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

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 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.

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

“…In contrast, loss of Bazooka/Par3 in the context of activated Ras in the eye imaginal disc epithelium can give rise to invasive tumours in Drosophila (Pagliarini and Xu, 2003). In mammalian cells, the dissolution of cell-cell junctions following loss of Par3 (Chen and Macara, 2005) or Par6 (Ozdamar et al, 2005) has been proposed to promote migration and invasion of tumour cells, however, Par6/ aPKC complex function is required for migration of a number of cell types such as astrocytes and fibroblasts (Etienne-Manneville and Hall, 2001;Cau and Hall, 2005).…”

Transcriptional regulation of cell polarity in EMT and cancer

“…Phosphorylated Par6 recruits Smurf1 (an E3 ubiquitin ligase) to the junctional complex that in turn targets the small GTPase RhoA for degradation, provoking EMT (Ozdamar et al, 2005). It is notable that the mechanisms behind Par6 phosphorylation and Smurf1 recruitment, and that are required for TGF-b induced EMT, are independent of the Smad pathway (Ozdamar et al, 2005). This further supports the participation of different pathways downstream of TGF-b in the regulation of cell polarity and EMT.…”

“…However, after exposure to TGF-b, TGF-bRII is recruited to the apical junction complex where it phosphorylates Par6. Phosphorylated Par6 recruits Smurf1 (an E3 ubiquitin ligase) to the junctional complex that in turn targets the small GTPase RhoA for degradation, provoking EMT (Ozdamar et al, 2005). It is notable that the mechanisms behind Par6 phosphorylation and Smurf1 recruitment, and that are required for TGF-b induced EMT, are independent of the Smad pathway (Ozdamar et al, 2005).…”

The epithelial polarity program: machineries involved and their hijacking by cancer

“…The EPP: machineries involved and their hijacking by cancer B Tanos and E Rodriguez-Boulan also promotes a second aspect of EMT through Parindependent transcriptional activation of mesenchymal genes (vimentin, metalloproteases) (Miettinen et al, 1994;Ozdamar et al, 2005), required for cell intravasation and invasion of distant tissues. Cancer promoting viruses, such as human papilloma virus (HPV), also utilize the Scribble and Par complexes for oncogenic purposes (see Thomas et al, 2008).…”