Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+-mediated protein kinase C activation

Hiroyuki Takatsu, Masahiro Takayama, Tomoki Naito, Naoto Takada, Kazuya Tsumagari, Yasushi Ishihama, Kazuhisa Nakayama and Hye-Won Shin ()
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Hiroyuki Takatsu: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
Masahiro Takayama: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
Tomoki Naito: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
Naoto Takada: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
Kazuya Tsumagari: Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University
Yasushi Ishihama: Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University
Kazuhisa Nakayama: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University
Hye-Won Shin: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells. Here we report that the PS-flippase ATP11C, but not ATP11A, is sequestered from the plasma membrane via clathrin-mediated endocytosis upon Ca2+-mediated PKC activation. Importantly, we show that a characteristic di-leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKC activation. Moreover endocytosis of ATP11C is induced by Ca2+-signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase.

Date: 2017
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DOI: 10.1038/s41467-017-01338-1

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