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G Protein-Coupled Receptor Kinase 5 Phosphorylation of Hip Regulates Internalization of the Chemokine Receptor CXCR4

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Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States
Tel: 215-503-4607. Fax: 215-503-5393. E-mail: [email protected]
Cite this: Biochemistry 2011, 50, 32, 6933–6941
Publication Date (Web):July 6, 2011
https://doi.org/10.1021/bi2005202
Copyright © 2011 American Chemical Society

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    Abstract

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    Regulation of the magnitude, duration, and localization of G protein-coupled receptor (GPCR) signaling responses is controlled by desensitization, internalization, and downregulation of the activated receptor. Desensitization is initiated by the phosphorylation of the activated receptor by GPCR kinases (GRKs) and the binding of the adaptor protein arrestin. In addition to phosphorylating activated GPCRs, GRKs have been shown to phosphorylate a variety of additional substrates. An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303–319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells. While Hip was previously implicated in chemokine receptor trafficking, we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4. Taken together, Hip has been identified as a novel substrate of GRK5 in vitro and in cells, and phosphorylation of Hip by GRK5 plays a role in modulating CXCR4 internalization.

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    7. Amos Fumagalli, Aurélien Zarca, Maria Neves, Birgit Caspar, Stephen J. Hill, Federico Mayor, Martine J. Smit, Philippe Marin. CXCR4/ACKR3 Phosphorylation and Recruitment of Interacting Proteins: Key Mechanisms Regulating Their Functional Status. Molecular Pharmacology 2019, 96 (6) , 794-808. https://doi.org/10.1124/mol.118.115360
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    9. John M. Streicher. The Role of Heat Shock Proteins in Regulating Receptor Signal Transduction. Molecular Pharmacology 2019, 95 (5) , 468-474. https://doi.org/10.1124/mol.118.114652
    10. Antonella Rigo, Isacco Ferrarini, Giulio Innamorati, Fabrizio Vinante. A single amino acid substitution in CXCL12 confers functional selectivity at the beta-arrestin level. Oncotarget 2018, 9 (48) , 28830-28841. https://doi.org/10.18632/oncotarget.25533
    11. Zhenhai Shang, Feifei Han, Xueyan Zhou, Zejun Bao, Jing Zhu, Tao Wang, Qian Lu, Lei Du, Wei Li, Dongmei Lv, Xiaoxing Yin. A variant of GRK5 is associated with the therapeutic efficacy of repaglinide in Chinese Han patients with type 2 diabetes mellitus. Drug Development Research 2018, 79 (3) , 129-135. https://doi.org/10.1002/ddr.21426
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    29. Sandeep K. Raghuwanshi, Yingjun Su, Vandana Singh, Katherine Haynes, Ann Richmond, Ricardo M. Richardson. The Chemokine Receptors CXCR1 and CXCR2 Couple to Distinct G Protein-Coupled Receptor Kinases To Mediate and Regulate Leukocyte Functions. The Journal of Immunology 2012, 189 (6) , 2824-2832. https://doi.org/10.4049/jimmunol.1201114
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