title: Human Type IV P-type ATPases That Work as Plasma Membrane Phospholipid Flippases and Their Regulation by Caspase and Calcium.
abstract: In plasma membranes, flippases translocate aminophospholipids such as phosphatidylserine and phosphatidylethanolamine from the extracellular to the cytoplasmic leaflet. Mammalian ATP11C, a type IV P-type ATPase, acts as a flippase at the plasma membrane. Here, by expressing 12 human type IV P-type ATPases in ATP11C-deficient cells, we determined that ATP8A2 and ATP11A can also act as plasma membrane flippases. As with ATP11C, ATP8A2 and ATP11A localized to the plasma membrane in a CDC50A-dependent manner. ATP11A was cleaved by caspases during apoptosis, and a caspase-resistant ATP11A blocked apoptotic PtdSer exposure. In contrast, ATP8A2 was not cleaved by caspase, and cells expressing ATP8A2 did not expose PtdSer during apoptosis. Similarly, high Ca(2+) concentrations inhibited the ATP11A and ATP11C PtdSer flippase activity, but ATP8A2 flippase activity was relatively resistant to Ca(2+). ATP11A and ATP11C were ubiquitously expressed in human and mouse adult tissues. In contrast, ATP8A2 was expressed in specific tissues, such as the brain and testis. Thus, ATP8A2 may play a specific role in translocating PtdSer in these tissues.
authors.affiliation: From the Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Katsumori
authors.initials: K
authors.lastname: Segawa
authors.affiliation: From the Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kurata
authors.affiliation: From the Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan snagata@ifrec.osaka-u.ac.jp.
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010718:Phosphatidylserines / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; D053148:Caspase 3; D000251:Adenosine Triphosphatases; D002118:Calcium
keywords: P4-ATPase; apoptosis; calcium; caspase; flippase; phosphatidylserine; plasma membrane