Publication Date

2017-01-27

Availability

Open access

Embargo Period

2017-01-27

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2016-11-16

First Committee Member

Fulvia Verde

Second Committee Member

Sandra Lemmon

Third Committee Member

Mary Lou King

Fourth Committee Member

Arun Malhotra

Fifth Committee Member

Sheyum Syed

Abstract

During many cellular processes, such as cell morphogenesis, migration, and asymmetric cell division, eukaryotic cells modulate their growth and polarity. Understanding the molecular mechanisms that govern polarized cell growth has the potential to reveal important insights into diseases such as neurodegeneration, heart disease, and cancer. The model organism fission yeast Schizosaccharomyces pombe, with its cylindrical shape and bipolar growth zones, enables straightforward evaluation of changes in growth and polarity upon genetic or pharmacological manipulation. In addition, S. pombe has a characteristic response to nutrient starvation, which causes cells to alter their morphology by dividing at a shorter cell length and growing from only one cell tip. An important and highly conserved class of regulators of cell growth and polarity is the NDR (nuclear Dbf2-related) kinase family, which has been demonstrated to function in cell morphogenesis, cell growth and proliferation, mitosis, and development. Our lab previously showed that the NDR kinase Orb6 spatially restricts the activation of Cdc42 GTPase, a key regulator of cell polarization, to prevent ectopic cell growth. Here we show that Orb6 kinase inhibits Cdc42 GEF Gef1 to limit the distribution of Cdc42 at the cell tips, define cell dimensions, and delay bipolar growth. This work also identifies the mRNA binding protein Sts5 as a novel target of Orb6 kinase in the control of cell growth. We show that Orb6 kinase prevents the recruitment of Sts5 into cytoplasmic granules and its localization to P-bodies, sites of mRNA storage and degradation. This negative control of Sts5 granule formation is spatially biased toward growing cell tips, which are enriched in cortical Orb6 kinase. By illuminating details of NDR kinase regulation of cell polarity and cell growth in fission yeast, this work has the potential to inform research into mammalian NDR kinases with implications for human disease.

Keywords

polarized growth; NDR kinase; Schizosaccharomyces pombe; Processing bodies; Cdc42

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