The long-term objective of this work is to understand the molecular basis by which cells are polarized. Polarity is a fundamental property of cells that is required for proper development as well as adult physiology. For example, during development cell fate determinants are polarized in dividing cells as a mechanism for generating cell type diversity and the loss of cell polarity is a hallmark of many disease states, including cancer. For spatially and temporally precise establishment of cell polarity to occur, cellular signals must be interpreted and ultimately coupled to the segregation of the relevant cellular components. In diverse cell types, polarity is controlled by the evolutionarily conserved Par complex consisting of Bazooka (Baz;aka Par-3), Par-6, and atypical Protein Kinase C (aPKC). It has recently become clear that aPKC activity is the primary output of the Par complex. In this grant we seek to answer three fundamental aspects of aPKC-how it is targeted to specific cellular sites, how its activity is regulated, and how phosphorylation of substrates regulate their localization. Understanding the molecular events that lead to the coupled recruitment and activation of the Par complex will yield new insight into cell polarity.
Many cells in our body, such as skin cells that provide a physical barrier to the environment, are polarized and loss of polarity is a hallmark of many diseases, including cancer. In this work, we are investigating a set of three proteins, known as the Par complex, that regulate cellular polarities required for proper development and adult physiology. As the loss of polarity is associated with human disease, improving our understanding of the molecules that control this process will contribute to our knowledge of the mechanisms of disease states.
|Drummond, Michael L; Prehoda, Kenneth E (2016) Molecular Control of Atypical Protein Kinase C: Tipping the Balance between Self-Renewal and Differentiation. J Mol Biol 428:1455-64|
|Bailey, Matthew J; Prehoda, Kenneth E (2015) Establishment of Par-Polarized Cortical Domains via Phosphoregulated Membrane Motifs. Dev Cell 35:199-210|
|Graybill, Chiharu; Prehoda, Kenneth E (2014) Ordered multisite phosphorylation of lethal giant larvae by atypical protein kinase C. Biochemistry 53:4931-7|
|Lu, Michelle S; Mauser, Jonathon F; Prehoda, Kenneth E (2012) Ultrasensitive synthetic protein regulatory networks using mixed decoys. ACS Synth Biol 1:65-72|
|Graybill, Chiharu; Wee, Brett; Atwood, Scott X et al. (2012) Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement. J Biol Chem 287:21003-11|
|Mauser, Jonathon F; Prehoda, Kenneth E (2012) Inscuteable regulates the Pins-Mud spindle orientation pathway. PLoS One 7:e29611|
|Smith, Nicholas R; Prehoda, Kenneth E (2011) Robust spindle alignment in Drosophila neuroblasts by ultrasensitive activation of pins. Mol Cell 43:540-9|
|Wee, Brett; Johnston, Christopher A; Prehoda, Kenneth E et al. (2011) Canoe binds RanGTP to promote Pins(TPR)/Mud-mediated spindle orientation. J Cell Biol 195:369-76|
|Johnston, Christopher A; Whitney, Dustin S; Volkman, Brian F et al. (2011) Conversion of the enzyme guanylate kinase into a mitotic-spindle orienting protein by a single mutation that inhibits GMP-induced closing. Proc Natl Acad Sci U S A 108:E973-8|
|Cabernard, Clemens; Prehoda, Kenneth E; Doe, Chris Q (2010) A spindle-independent cleavage furrow positioning pathway. Nature 467:91-4|
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