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Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China (Y.D., G.-H.F., J.Z., N.L.); Department of Biomedical Sciences, Meharry Medical College, Nashville, Tennessee (G.-H.F.); Martin Luther King Jr. Magnet School, Nashville, Tennessee (M.L.); Department of Nuclear Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China (Z.X., Y.H.); and Department of Chinese Medicine, Shenzhen No. 9 Hospital, Shenzhen, People's Republic of China (S.W.)
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 the 73-kDa heat shock cognate protein (Hsc73) in human embryonic kidney 293 cells in response to ligand stimulation. Truncation of the carboxyl terminal domain of CXCR4 reduced the association with Hsc73 and a glutathione S-transferase-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 colocalization with Hsc73, but the receptor endocytosis was blocked by knockdown of Hsc73 with RNA interference. 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 and the receptor-mediated chemotaxis.
Address correspondence to: Dr. Guo-Huang Fan, Department of Biomedical Sciences, Meharry Medical College, Nashville, TN 37208. E-mail: gfan{at}mmc.edu
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