Illuminating the Regulation of the Dark Kinase PSKH1

McAloon, L.

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Illuminating the Regulation of the Dark Kinase PSKH1

McAloon, L.

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McAloon, L.

Abstract

PSKH1 is a 48 kDa serine/threonine-protein kinase whose function, regulation and downstream effectors remain undefined. Discovered in the late 1980’s, PSKH1 is increasingly implicated in an appreciating number of cellular processes, including vesicle trafficking, cell migration, and pre-mRNA splicing. More recently, PSKH1 was classified as a top-6 driver of prostate cancer progression. Precisely how PSKH1 mediates these effects is not currently understood. This thesis sought to resolve these questions using a combination of in vitro and in vivo experimental methodologies. Chapter 3 details efforts to elucidate the mechanisms by which PSKH1 activity is regulated. It was revealed that PSKH1 autophosphorylates itself in a cis¬-apparent mechanism, a process that significantly enhances its catalytic activity in vitro. Further, as a bona fide CaM-kinase family members, PSKH1 is regulated by calmodulin, albeit via a distinct mechanism. Lastly, PSKH1 is negatively regulated by a novel family of low-affinity Ca2+-binding proteins. Chapter 4 established, for the first time, a function for PSKH1, providing a direct causative link between PSKH1 and prostate cancer progression. PSKH1 is a metabolic sensor kinase that is activated in response to glucose deprivation and drives prostate cancer cell growth by mediating fuel switching to alternative energy sources (fatty acids). Furthermore, PSKH1 may mediate these effects by modulating the action of RSK1/eEF2K, two proteins we recently identified as PSKH1 interacting. PSKH1 regulation of the RSK1/eEF2K signalling axis is currently preliminary but corroborates the growth-promotive phenotype of PSKH1 expression in prostate cancer. These data provide critical insights into PSKH1 regulation of prostate cancer progression.