title: Fpk1/2 kinases regulate cellular sphingoid long-chain base abundance and alter cellular resistance to LCB elevation or depletion.
abstract: Sphingolipids are a family of eukaryotic lipids biosynthesized from sphingoid long-chain bases (LCBs). Sphingolipids are an essential class of lipids, as their depletion results in cell death. However, acute LCB supplementation is also toxic; thus, proper cellular LCB levels should be maintained. To characterize the "sphingolipid-signaling intercross," we performed a kinome screening assay in which budding yeast protein kinase-knockout strains were screened for resistance to ISP-1, a potent inhibitor of LCB biosynthesis. Here, one pair of such DIR (deletion-mediated ISP-1 resistance) genes, FPK1 and FPK2, was further characterized. Cellular LCB levels increased in the fpk1/2∆ strain, which was hypersensitive to phytosphingosine (PHS), a major LCB species of yeast cells. Concomitantly, this strain acquired resistance to ISP-1. Fpk1 and Fpk2 were involved in two downstream events; that is, ISP-1 uptake due to aminophospholipid flippase and LCB degradation due to LCB4 expression. RSK3, which belongs to the p90-S6K subfamily, was identified as a functional counterpart of Fpk1/2 in mammalian cells as the RSK3 gene functionally complemented the ISP-1-resistant phenotype of fpk1/2∆ cells.
authors: Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, 46-29 Yoshida-shimoadachi, Sakyo, Kyoto, 606-8502, Japan.
authors: Yukari
authors: Y
authors: Yamane-Sando
authors: Etsuko
authors: E
authors: Shimobayashi
authors: Mitsugu
authors: M
authors: Shimobayashi
authors: Yasunori
authors: Y
authors: Kozutsumi
authors: Shogo
authors: S
authors: Oka
authors: Hiromu
authors: H
authors: Takematsu
mesh_terms: D003600:Cytosol / Q000737:chemistry; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006028:Glycosphingolipids / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D006028:Glycosphingolipids; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C533049:Fpk1 protein, S cerevisiae; C533050:Fpk2 protein, S cerevisiae; C001996:thermozymocidin
keywords: DIR screening; long-chain base; protein kinase; sphingolipids; yeast