Crossed Wires: PKMζ Antagonizes Apkc And The Par Complex To Regulate Morphological Polarity

Persistent Link:
http://hdl.handle.net/10150/594959
Title:
Crossed Wires: PKMζ Antagonizes Apkc And The Par Complex To Regulate Morphological Polarity
Author:
Parker, Sara Shannon
Issue Date:
2015
Publisher:
The University of Arizona.
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.
Embargo:
Dissertation not available (per author's request)
Abstract:
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.
Type:
text; Electronic Dissertation
Keywords:
axon; epithelia; morphogenesis; neuron; polarity; Cell Biology & Anatomy; apical
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cell Biology & Anatomy
Degree Grantor:
University of Arizona
Advisor:
Wilson, Jean M.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleCrossed Wires: PKMζ Antagonizes Apkc And The Par Complex To Regulate Morphological Polarityen_US
dc.creatorParker, Sara Shannonen
dc.contributor.authorParker, Sara Shannonen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © 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.en
dc.description.releaseDissertation not available (per author's request)en_US
dc.description.abstractA 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.en
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectaxonen
dc.subjectepitheliaen
dc.subjectmorphogenesisen
dc.subjectneuronen
dc.subjectpolarityen
dc.subjectCell Biology & Anatomyen
dc.subjectapicalen
thesis.degree.namePh.D.en
thesis.degree.leveldoctoralen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineCell Biology & Anatomyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorWilson, Jean M.en
dc.contributor.committeememberWilson, Jean M.en
dc.contributor.committeememberGregorio, Carolen
dc.contributor.committeememberMouneimne, Ghassanen
dc.contributor.committeememberZinsmaier, Konraden
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