title: An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling.
abstract: Hundreds, if not thousands, of uncharacterized enzymes currently populate the human proteome. Assembly of these proteins into the metabolic and signaling pathways that govern cell physiology and pathology constitutes a grand experimental challenge. Here, we address this problem by using a multidimensional profiling strategy that combines activity-based proteomics and metabolomics. This approach determined that KIAA1363, an uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and lysophosphatidic acid. Biochemical studies confirmed that KIAA1363 regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of KIAA1363 disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo. The integrated molecular profiling method described herein should facilitate the functional annotation of metabolic enzymes in any living system.
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism*; D010742:Phospholipid Ethers / Q000737:chemistry / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism; D034622:RNA Interference; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D002787:Sterol Esterase
chemical_list: C480312:11-hexadecenyl trifluoromethyl ketone; C515678:AS 115; D002219:Carbamates; D004791:Enzyme Inhibitors; D007659:Ketones; D008246:Lysophospholipids; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D002265:Carboxylic Ester Hydrolases; C515677:NCEH1 protein, human; D002787:Sterol Esterase