Palmitoylation And Polarity: Regulation Of Asymmetric Partitioning Of Notch And Wnt Signaling By Reversible Lipid Modification In Dividing Cells

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell & Molecular Biology
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Asymmetric cell division
Cell fate
Notch
Palmitoylation
Tumor heterogeneity
Wnt
Cell Biology
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2018-09-27T20:18:00-07:00
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Abstract

Protein palmitoylation is a reversible lipid modification that regulates protein-membrane interaction, activity, trafficking, and stability in a spatio-temporal manner similar to phosphorylation and ubiquitination. Asymmetric cell division results in two distinctly fated daughter cells, by unequally partitioning proteins known as cell fate determinants. I have characterized a mechanism for protein palmitoylation to asymmetrically partition cell fate determinants, e.g. Numb and β-catenin, through the activity of the depalmitoylating enzyme APT1. Using point mutations, I have found specific palmitoylated residues on Numb are required for its asymmetric localization in dividing cells. By live-cell imaging, I have also identified a reciprocal interaction between APT1 and the Rho family GTPase, CDC42, which promotes asymmetric localization of Numb and β-catenin to the plasma membrane. In turn, this mechanism restricts Notch- or Wnt-responsive transcriptional activity to one daughter cell. Moreover, I show that altering APT1 expression levels alters the transcriptional signatures of MDA-MB-231 triple receptor-negative breast cancer cells, resembling altered Notch and β-catenin-mediated Wnt signaling. Furthermore, loss of APT1 depletes a specific subpopulation of tumorigenic cells. Together, this dissertation presents palmitoylation as a major mechanism of asymmetric cell division that maintains Notch- and Wnt-associated protein dynamics, gene expression, and cellular functions.

Advisor
Eric S. Witze
Date of degree
2018-01-01
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