Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Biochemistry

Language

English (en)

Date of Award

9-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Helen Piwnica-Worms

Abstract

The Par-1 family of serine/threonine protein kinases functions to regulate cell polarity and is conserved from yeast to humans. Par-1 is encoded by one of six Par: partitioning-defective) genes: Par-1-6) originally identified in a genetic screen conducted in Caenorhabditis elegans: C. elegans). The mammalian Par-1 family is comprised of four members: Par-1a, b, c and d). Par-1 kinases are regulated by two arms of the Protein Kinase C: PKC) pathway. Atypical Protein Kinase C: aPKC) phosphorylates Par-1b on a conserved threonine residue: T595) and I participated in studies demonstrating that novel Protein Kinase C: nPKC) activates Protein Kinase D: PKD) to directly phosphorylate Par-1b on serine 400: S400), a residue that is conserved in all four mammalian Par-1 kinases as well as the fly ortholog. Phosphorylation of Par-1b on T595 and S400 causes Par-1b to relocate from membranes to the cytosol and to bind 14-3-3 proteins. In 2004, Brajenovic, et al. reported the results of a study that used tandem affinity purification: TAP) to isolate human Par-1d along with associated proteins. Nrdp1/RNF41, a RING finger E3 ligase was identified in their screen along with 14-3-3 and aPKC. I found that Par-1b binds to RNF41 and I identified RNF41 as a novel cell polarity determinant. My work demonstrated that phosphorylation of RNF41 on S254 by Par-1b is necessary for establishing epithelial cell polarity.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7KD1VW1

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