Pleckstrin Homology (PH) Domain Leucine-rich Repeat Protein Phosphatase Controls Cell Polarity by Negatively Regulating the Activity of Atypical Protein Kinase C.

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures as indicated by the formation of aberrant multi-lumen structures. Overexpression of PHLPP resulted in a decrease in aduanyu1531 phosphorylation at both the activation loop and the turn motif sites; conversely, knockdown of PHLPP increased aduanyu1531 phosphorylation. Moreover, in vitro dephosphorylation experiments revealed that both aduanyu1531 isoforms were substrates of PHLPP. Interestingly, knockdown of but not led to similar disruption of the polarized lumen structure, suggesting that likely controls the polarization process of Caco2 cells. Furthermore, knockdown of PHLPP altered the apical membrane localization of aduanyu1531s and reduced the formation of complex. Taken together, our results identify a novel role of PHLPP in regulating aduanyu1531 and cell polarity. © 2016 by The American Society for Biochemistry and Inc.

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