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J. Biol. Chem., Vol. 280, Issue 25, 23741-23747, June 24, 2005

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Myosin II Regulatory Light Chain Is Required for Trafficking of Bile Salt Export Protein to the Apical Membrane in Madin-Darby Canine Kidney Cells^*

Wayne Chan, German Calderon, Amy L. Swift, Jamie Moseley, Shaohua Li, Hiroshi Hosoya, Irwin M. Arias¶, and Daniel F. Ortiz||

From the Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, the Department of Biological Science, Graduate School of Science, Hiroshima University, Higashi-Hiroshima 739-8526, Japan, and the ^¶Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

BSEP, MDR1, and MDR2 ATP binding cassette transporters are targeted to the apical (canalicular) membrane of hepatocytes, where they mediate ATP-dependent secretion of bile acids, drugs, and phospholipids, respectively. Sorting to the apical membrane is essential for transporter function; however, little is known regarding cellular proteins that bind ATP binding cassette proteins and regulate their trafficking. A yeast two-hybrid screen of a rat liver cDNA library identified the myosin II regulatory light chain, MLC2, as a binding partner for BSEP, MDR1, and MDR2. The interactions were confirmed by glutathione S-transferase pulldown and co-immunoprecipitation assays. BSEP and MLC2 were overrepresented in a rat liver subcellular fraction enriched in canalicular membrane vesicles, and MLC2 colocalized with BSEP in the apical domain of hepatocytes and polarized WifB, HepG2, and Madin-Darby canine kidney cells. Expression of a dominant negative, non-phosphorylatable MLC2 mutant reduced steady state BSEP levels in the apical domain of polarized Madin-Darby canine kidney cells. Pulse-chase studies revealed that Blebbistatin, a specific myosin II inhibitor, severely impaired delivery of newly synthesized BSEP to the apical surface. These findings indicate that myosin II is required for BSEP trafficking to the apical membrane.

Received for publication, March 14, 2005

^* This work was supported in part by National Institutes of Health Grants RO1DK35652 and T32DK07542 (to I. M. A.) and R01 DK060719 (to D. F. O.) and by a pilot grant (to D. F. O.) from the Center for Gastroenterology Research on Absorptive and Secretory Processes (GRASP) at Tufts University and the New England Medical Center, supported by National Institutes of Health Grant P30 DK34928. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 617-636-3828; Fax: 617-636-0445; E-mail: daniel.ortiz{at}tufts.edu.

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