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A proteomics approach to NIMA-related kinase signaling in mitosis / by Sierra N. Cullati

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Author	Cullati, Sierra N.
Title	A proteomics approach to NIMA-related kinase signaling in mitosis / by Sierra N. Cullati
Date	2016
Abstract	NIMA-related kinases (Neks) control several aspects of cell division downstream of master mitotic regulators such as Cdk1 and Plk1. Though depletion of Nek6, Nek7, or Nek9 results in cytokinesis failure, to date no molecular mechanism has been elucidated to explain this observation. Cytokinesis failure results in tetraploidy, which is often the precursor to aneuploidy and chromosome instability, hallmarks of cancer that correlate with poor prognosis and patient outcomes. To investigate how Neks may interact with known mitotic proteins to affect the outcome of cytokinesis, we identified the binding partners of Nek9, which is upstream of Nek6 and Nek7 and contains several protein-protein interaction domains. We identified a variety of proteins known to be involved in cytokinesis, including two kinesins, Mklp2 and Kif14, which depend upon Nek9 for their localization to the central spindle in anaphase. Though both proteins retain midbody localization in telophase, prior residence at the central spindle was essential for successful completion of cytokinesis. We discovered that Mklp2 was a substrate of Nek6 while Kif14 was a substrate of Nek7, highlighting the potential differences in substrate specificity between these two related, effector kinases. To further investigate the distinction between Nek6 and Nek7, an ongoing goal is to determine the substrateomes of these kinases using mass spectrometrybased quantitative phosphoproteomics. Lacking small molecule Nek inhibitors, we pursued analogue-sensitive kinase, baculovirus-delivered shRNA, and auxininducible degron strategies for kinase knockdown. Overall, our work combined unbiased, proteome-wide analysis with targeted cell biology to uncover the role of NIMA-related kinases in cytokinesis.
Description	1 online resource (xi, 229 leaves) : illustrations (mostly color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	Made available by the author under a Creative Commons Attribution-NonCommercial License.; Made available by the Trustees of Dartmouth College under a Creative Commons Attribution-NonCommercial License. https://creativecommons.org/licenses/by-nc/4.0/
DOI	https://doi.org/10.1349/ddlp.1951

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A proteomics approach to NIMA-related kinase signaling in mitosis / by Sierra N. Cullati

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