title: A chemical biology strategy to analyze rheostat-like protein kinase-dependent regulation.
abstract: Protein kinases may function more like variable rheostats rather than two-state switches. However, we lack approaches to properly analyze this aspect of kinase-dependent regulation. To address this, we develop a strategy in which a kinase inhibitor is identified using genetics-based screens, kinase mutations that confer resistance are characterized, and dose-dependent responses of isogenic drug-sensitive and resistant cells to inhibitor treatments are compared. This approach has the advantage that function of wild-type kinase, rather than mutants, is examined. To develop this approach, we focus on Ark1, the fission yeast member of the conserved Aurora kinase family. Applying this approach reveals that proper chromosome compaction in fission yeast needs high Ark1 activity, while other processes depend on significantly lower activity levels. Our strategy is general and can be used to examine the functions of other molecular rheostats.
authors: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors: Shigehiro A
authors: SA
authors: Kawashima
authors: Ai
authors: A
authors: Takemoto
authors: Paul
authors: P
authors: Nurse
authors: Tarun M
authors: TM
authors: Kapoor
mesh_terms: D064096:Aurora Kinase A; D064127:Aurora Kinases; D025141:Drug Resistance, Fungal; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D029702:Schizosaccharomyces pombe Proteins; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C576962:ark1 protein, S pombe