A cell's composition is not uniform, but is comprised of many molecular gradients to compartmentalize functions into specialized subcellular domains. This organization is called polarity–the asymmetry of morphology and composition. Though it's a feature of nearly all prokaryotic and eukaryotic cells, polarity is plastic and highly dynamic, and is continuously instructed by the crosstalk between extracellular cues and internal effector pathways. One of the master regulators of polarity is the Par complex, canonically comprised of Cdc42, Par6, Par3 and atypical protein kinase C (aPKC). The Par complex defines the apical domain of epithelia and the neuronal axon, directs cell migration and the assembly of cell junctions, and restricts other polarity complexes to their respective domains. We have identified a novel polarity protein that counteracts the activities of the Par complex in cells. PKMζ, a truncated isoform of aPKC normally found in neurons, competes with full-length aPKC for substrate interactions. This competition results in the disruption of the canonical Par complex and its instruction of cell polarity, manifesting as a block in axon specification in developing neurons, or as a loss of the apical-basal axis of epithelial polarity. By eliminating PKMζ's ability to compete with aPKC for interaction with Par3, the effect on polarity is mitigated, while RNAi-mediated reduction of Par3 levels similarly rescues PKMζ-associated defects. We further report that PKMζ is aberrantly transcribed in certain epithelial cancers, and its expression correlates with grade. Malignant epithelial phenotypes are driven by PKMζ's Par3-dependent disruption of polarity, and its Par3- independent promotion of anoikis resistance. We demonstrate that PKMζ, as the catalytic fragment of aPKC, is surprisingly competent to influence polarity independently of its kinase activity, while other aPKC isoforms require their catalytic function to permit apical development. Together, this body of work presents PKMζ as an endogenous inhibitor of Par complex function, whose presence provides bistability to the dynamics of symmetry-breaking.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/594959 |
| Date | January 2015 |
| Creators | Parker, Sara Shannon |
| Contributors | Wilson, Jean M., Wilson, Jean M., Gregorio, Carol, Mouneimne, Ghassan, Zinsmaier, Konrad |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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