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MBC in Press, published online ahead of print January 16, 2008
Mol. Biol. Cell 10.1091/mbc.E07-07-0646

A more recent version of this article appeared on April 1, 2008
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Submitted on July 9, 2007
Revised on December 20, 2007
Accepted on January 8, 2008

Protein Kinases Fpk1p and Fpk2p are Novel Regulators of Phospholipid Asymmetry

Kenzi Nakano,* Takaharu Yamamoto,{dagger} Takuma Kishimoto,* Takehiro Noji,* and Kazuma Tanaka{dagger}

Division of Molecular Interaction, Institute for Genetic Medicine, Hokkaido University Graduate Schools of *Medicine and {dagger}Life Science, Sapporo 060-0815, Japan

Monitoring Editor: Sandra Lemmon

Type 4 P-type ATPases (flippases) are implicated in the generation of phospholipid asymmetry in membranes by the inward translocation of phospholipids. In budding yeast, the DRS2/DNF family members Lem3p-Dnf1p/Dnf2p and Cdc50p-Drs2p are putative flippases that are respectively localized to the plasma membrane and endosomal/trans-Golgi network (TGN) compartments. Herein, we identified a protein kinase gene, FPK1, as a mutation that exhibited synthetic lethality with the cdc50{Delta} mutation. The kinase domain of Fpk1p exhibits high homology to plant phototropins and the fungus N. crassa NRC-2, both of which have membrane-associated functions. Simultaneous disruption of FPK1 and its homolog FPK2 phenocopied the lem3{Delta}/dnf1{Delta} dnf2{Delta} mutants, exhibiting the impaired NBD-labeled phospholipid uptake, defects in the early endosome-to-TGN pathway in the absence of CDC50, and hyperpolarized bud growth following exposure of phosphatidylethanolamine at the bud tip. The fpk1{Delta} fpk2{Delta} mutation did not affect the subcellular localization of Lem3p-Dnf1p or Lem3p-Dnf2p. Further, the purified glutathione S-transferase (GST)-fused kinase domain of Fpk1p phosphorylated immunoprecipitated Dnf1p and Dnf2p to a greater extent than Drs2p. We propose that Fpk1p/Fpk2p are upstream activating protein kinases for Lem3p-Dnf1p/Dnf2p.

Address correspondence to: Kazuma Tanaka (k-tanaka{at}igm.hokudai.ac.jp)






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