Several adaptor proteins promote intracellular localisation of the transporter MRP4/ABCC4 in platelets and haematopoietic cells

Yvonne Schaletzki; Marie-Luise Kromrey; Susanne Bröderdorf; Elke Hammer; Markus Grube; Paul Hagen; Sonja Sucic; Michael Freissmuth; Uwe Völker; Andreas Greinacher; Bernhard H. Rauch; Heyo K. Kroemer; Gabriele Jedlitschky

doi:10.1160/TH16-01-0045

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2017; 117(01): 105-115
DOI: 10.1160/TH16-01-0045

Cellular Haemostasis and Platelets

Schattauer GmbH

Several adaptor proteins promote intracellular localisation of the transporter MRP4/ABCC4 in platelets and haematopoietic cells

Authors

Yvonne Schaletzki

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Marie-Luise Kromrey

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Susanne Bröderdorf

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Elke Hammer

²Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Markus Grube

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Paul Hagen

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Sonja Sucic

³Department of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Michael Freissmuth

³Department of Pharmacology, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Uwe Völker

²Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Andreas Greinacher

⁴Department of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
Bernhard H. Rauch

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Heyo K. Kroemer^*

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany
Gabriele Jedlitschky

¹Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Germany

Abstract

Summary

The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as an important transporter for signalling molecules including cyclic nucleotides and several lipid mediators in platelets and may thus represent a novel target to interfere with platelet function. Besides its localisation in the plasma membrane, MRP4 has been also detected in the membrane of dense granules in resting platelets. In polarised cells it is localised at the basolateral or apical plasma membrane. To date, the mechanism of MRP4 trafficking has not been elucidated; protein interactions may regulate both the localisation and function of this transporter. We approached this issue by searching for interacting proteins by in vitro binding assays, followed by immunoblotting and mass spectrometry, and by visualising their co-localisation in platelets and haematopoietic cells. We identified the PDZ domain containing scaffold proteins ezrin-binding protein 50 (EBP50/NHERF1), postsynaptic density protein 95 (PSD95), and sorting nexin 27 (SNX27), but also the adaptor protein complex 3 subunit β3A (AP3B1) and the heat shock protein HSP90 as putative interaction partners of MRP4. The knockdown of SNX27, PSD95, and AP3B1 by siRNA in megakaryoblastic leuk aemia cells led to a redistribution of MRP4 from intracellular structures to the plasma membrane. Inhibition of HSP90 led to a diminished expression and retention of MRP4 in the endoplasmic reticulum. These results indicate that MRP4 localisation and function are regulated by multiple protein interactions. Changes in the adaptor proteins can hence lead to altered localisation and function of the transporter.

Supplementary Material to this article is available at www.thrombosis-online.com.

Keywords

Protein trafficking - PDZ domain - AP3B1 - HSP90 - delta-storage pool deficiencies

Volltext

Referenzen

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