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First published online July 2, 2007
doi: 10.1242/10.1242/jcs.007443

Journal of Cell Science 120, 2309-2317 (2007)
Published by The Company of Biologists 2007
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Research Article

Polarity proteins PAR6 and aPKC regulate cell death through GSK-3beta in 3D epithelial morphogenesis

Minji Kim1, Anirban Datta1, Paul Brakeman2, Wei Yu1 and Keith E. Mostov1,*

1 Departments of Anatomy, and Biochemistry and Biophysics, University of California School of Medicine, San Francisco, CA 94158, USA
2 Department of Pediatrics, University of California School of Medicine, San Francisco, CA, USA

* Author for correspondence (e-mail: keith.mostov{at}ucsf.edu)

Accepted 9 May 2007

Epithelial cells are polarized, with an apical surface facing a lumen or outer surface and a basolateral surface facing other cells and extracellular matrix (ECM). Hallmarks of epithelial carcinogenesis include loss of polarity, as well as uncontrolled proliferation and resistance to apoptosis. Are these features controlled by a common molecular mechanism? The partitioning-defective 3 (PAR3)-PAR6-atypical PKC (aPKC) complex is a master regulator that controls polarization in many animal cells. Here we show that PAR6 is involved in apoptosis by regulating aPKC and glycogen synthase kinase 3beta (GSK-3beta) activity. During epithelial morphogenesis in 3D culture of Madin-Darby canine kidney (MDCK) cells, expression of an N-terminally deleted PAR6 (PAR6{Delta}N) leads to a significant increase in caspase-dependent cell death by downregulating aPKC activity. Accordingly, inhibition of aPKC in wild-type (WT) MDCK cells with either a cell-permeable PKC{zeta} pseudosubstrate or RNAi promotes apoptosis, which suggests that PAR6 regulates apoptosis via an aPKC-mediated pathway. GSK-3beta, a substrate of aPKC, is hyper-activated by expressing PAR6{Delta}N. GSK-3beta inhibitors block PAR6{Delta}N-induced apoptosis while expression of constitutively active GSK-3beta (S9A) promotes apoptosis, which is rescued by ectopic expression of aPKC. We conclude that a PAR6-aPKC-GSK-3beta mechanism links cell polarity and apoptosis.

Key words: Apoptosis, Cyst formation, Epithelial cell, Polarity


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