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J. Biol. Chem., Vol. 283, Issue 1, 623-637, January 4, 2008

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Cyclophilin A Is Required for CXCR4-mediated Nuclear Export of Heterogeneous Nuclear Ribonucleoprotein A2, Activation and Nuclear Translocation of ERK1/2, and Chemotactic Cell Migration^*

Heng Pan, Cherry Luo, Runsheng Li, Aimin Qiao, Li Zhang^¶, Marjelo Mines, Alfred M. Nyanda, Jingwu Zhang, and Guo-Huang Fan¹

From the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, the Department of Veterans Affairs and Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, Tennessee 37208, and the ^¶Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37212

The chemokine receptor CXCR4-mediated signaling cascades play an important role in cell proliferation and migration, but the underlying mechanisms by which the receptor signaling is regulated remain incompletely understood. Here, we demonstrate that CXCR4 was co-immunoprecipitated with cyclophilin A (CyPA) from the lysate of HEK293 cells stably expressing CXCR4. Although both the glutathione S-transferase-CXCR4 N- and C-terminal fusion proteins were associated with the purified CyPA, truncation of the C-terminal domain of CXCR4 robustly inhibited the receptor co-immunoprecipitation with CyPA in intact cells, thereby suggesting a critical role of the receptor C terminus in this interaction. Ligand stimulation of CXCR4 induced CyPA phosphorylation and nuclear translocation, both of which were inhibited by truncation of the C-terminal domain of CXCR4. CyPA was associated with transportin 1, and knockdown of transportin 1 by RNA interference (RNAi) blocked CXCL12-induced nuclear translocation of CyPA, thereby suggesting a transportin 1-mediated nuclear import of CyPA. CyPA formed a complex with heterogeneous nuclear ribonucleoprotein (hnRNP) A2, which underwent nuclear export in response to activation of CXCR4. Interestingly, the CXCR4-mediated nuclear export of hnRNP A2 was blocked by RNAi of CyPA. Moreover, CXCR4-evoked activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was attenuated by CyPA RNAi, by overexpression of a PPIase-deficient mutant of CyPA (CyPA-R55A), and by pretreatment of the immunosuppressive drugs, cyclosporine A and sanglifehrin A. Finally, CXCL12-induced chemotaxis of HEK293 cells stably expressing CXCR4 or Jurkat T cells was inhibited by CyPA RNAi or CsA treatment.

Received for publication, June 14, 2007 , and in revised form, October 24, 2007.

^* This work was supported by Science and Technology Commission of Shanghai Municipality Project 04DZ14902, RCMI Grant RR03032-19 from the National Institutes of Health, a Merit Award from the Department of Veterans Affairs, and a Specialized Neuroscience Research Program (SNRP) grant from the National Institutes of Health. 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.

¹ To whom correspondence should be addressed. Tel.: 615-327-6363; Fax: 615-327-6757; E-mail: gfan{at}mmc.edu.

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