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First published on December 19, 2005; DOI: 10.1124/mol.105.020271

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Received for publication October 25, 2005.
Revised December 15, 2005.
Accepted for publication December 16, 2005.

The heat shock cognate protein 73 is a CXCR4 binding protein that regulates the receptor endocytosis and the receptor-mediated chemotaxis

Yun Ding 1, Mika Li 2, Jinwu Zhang 3, Ningli Li 3, Zongqin Xia 4, Yare Hu 4, Sunxin Wang 5, Guo-Huang Fan 2*

1 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Scienc 2 Department of Biomedical Sciences, Meharry Medical College 3 Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Sh 4 Shanghai Jiaotong University School of Medicine 5 shenzhen No.9 hospital

* Address correspondence to: E-mail: gfan{at}mmc.edu

Abstract

The CXCR4 chemokine receptor is a G protein coupled receptor that plays an important role in leukocyte homing, cancer metastasis, and human immunodeficiency virus infection. In response to ligand stimulation, chemokine receptors undergo endocytosis through clathrin-coated vesicle (CCV). Uncoating of CCV, a process involving heat shock cognate protein and several other proteins, is critical for fusion of CCV to endosomal compartments. The present study demonstrated that CXCR4 was associated with heat shock cognate protein 73 (Hsc73) in human embryonic kidney (HEK293) cells in response to ligand stimulation. Truncation of the carboxyl terminal domain of CXCR4 reduced the association with Hsc73, and a glutathione-S-transferase (GST)-CXCR4 carboxyl terminal fusion protein associated with Hsc73 in vitro, suggesting involvement of the carboxyl terminal domain of the receptor in the interaction. In response to ligand stimulation, CXCR4 underwent internalization and co-localization with Hsc73, but the receptor endocytosis was blocked by knockdown of Hsc73 with RNA interference (RNAi). Moreover, Hsc73 knockdown significantly reduced the CXCR4-mediated chemotaxis of U87 glioma cell lines. These findings suggest that Hsc73 plays a role in chemokine receptor trafficking as well as the receptor-mediated chemotaxis.


Key words: Gi family, Sequestration/Internalization, Fluorescence techniques, Mass Spectroscopy, Receptor binding studies, RNA/siRNA, Metastasis


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