Receptor for activated C-kinase 1 regulates the cellular localization and function of ABCB4
Yuki Ikebuchi
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorTappei Takada
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorKousei Ito
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorTakashi Yoshikado
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorNaohiko Anzai
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, and
Search for more papers by this authorYoshikatsu Kanai
Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Search for more papers by this authorCorresponding Author
Hiroshi Suzuki
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Dr Hiroshi Suzuki, Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected]Search for more papers by this authorYuki Ikebuchi
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorTappei Takada
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorKousei Ito
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorTakashi Yoshikado
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Search for more papers by this authorNaohiko Anzai
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, and
Search for more papers by this authorYoshikatsu Kanai
Department of Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Search for more papers by this authorCorresponding Author
Hiroshi Suzuki
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Bunkyo-ku,
Dr Hiroshi Suzuki, Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected]Search for more papers by this authorAbstract
Aim: Multidrug resistance protein 3 (MDR3/ABCB4), located on the bile canalicular membrane of hepatocytes, is responsible for the translocation of phosphatidylcholine across the plasma membrane, and its hereditary defect causes liver disorders, such as progressive familial intrahepatic cholestasis type 3. We aimed to identify the proteins responsible for the surface expression of human ABCB4.
Methods: We performed yeast two-hybrid screening with the cytoplasmic linker region of ABCB4 against a human liver cDNA library. This screening allowed us to identify the receptor for activated C-kinase 1 (RACK1) as a novel binding partner of ABCB4. The association of RACK1 with the linker region of ABCB4 was further confirmed by GST-pulldown assay, although we could not find out the interaction of full length of ABCB4 and RACK1 in co-immunoprecipitation assay in HeLa cells.
Results: Down-regulation of endogenous RACK1 expression by siRNA in HeLa cells resulted in the localization of ABCB4 in the cytosolic compartment as well as reduced protein expression of ABCB4, although mRNA expression and the protein stability of ABCB4 were not affected by the suppression of endogenous RACK1. Similar alterations in cellular localization of ABCB4 were also found by suppressing endogenous RACK1 expression in HepG2 cells. Consequently, ABCB4-mediated phosphatidylcholine translocation activity was significantly reduced when endogenous RACK1 expression was suppressed in HeLa cells. In contrast, the membrane surface localization and the protein expression of ABCB1 were not affected by the suppression of endogenous RACK1 expression.
Conclusion: These results suggest that RACK1 may have a functional significance as a regulatory cofactor of ABCB4 and is indispensable for the plasma membrane localization and translocation function of ABCB4.
ACKNOWLEDGEMENT
This work was supported in part by Grant-in-Aid 17081006 for Scientific Research on Priority Areas transportsome from the Ministry of Education, Science and Culture of Japan.
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