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Papers In Press, published online ahead of print January 8, 2003
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115
Corresponding Author: rganju{at}caregroup.harvard.edu
The chemokine receptor CXCR4 and its cognate ligand, stromal cell derived factor-1alpha (CXCL12) regulate lymphocyte trafficking and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and MAP kinase activation in T-cells. We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat cell line J45.01 as compared to the CD45-positive control JE6.1 cells. Expression of a chimeric protein containing the intracellular phosphatase domain of CD45, with the extracellular and transmembrane domains of HLA-A2, was able to partially restore CXCL12-induced chemotaxis in the CD45-negative cells. However, reconstitution of CD45 into the CD45 negative cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant effect on CXCL12 or HIV gp120-induced internalization of the CXCR4 receptor. Furthermore, CD45-negative cells showed a slight enhancement in CXCL12-induced MAP kinase activity as compared to the CD45-positive cells. We also observed that CXCL12 treatment enhanced the tyrosine phosphorylation of CD45 and induced its association with the CXCR4 receptor. Pretreatment of T-cells with the lipid raft inhibitor, methyl-beta-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly abolished CXCL12-induced chemotaxis. Comparisons of signaling pathways induced by CXCL12 in CD45-positive and CD45-negative cells revealed that CD45 might moderately regulate the tyrosine phosphorylation of focal adhesion components, RAFTK/Pyk2, FAK, p130Cas and paxillin. CD45 has also been shown to regulate CXCR4-mediated activation and phosphorylation of T-cell receptor downstream effectors Lck, ZAP-70 and SLP-76. Taken together, our results show that CD45 differentially regulates CXCR4-mediated chemotactic activity and MAP kinase activation by modulating the activities of focal adhesion components and the downstream effectors of the T-cell receptor.
J. Biol. Chem, 10.1074/jbc.M211803200
Submitted on November 20, 2002
Revised on January 8, 2003
Accepted on January 7, 2003
Differential regulation of CXCR4-mediated T-cell chemotaxis and MAP kinase activation by the membrane tyrosine phosphatase, CD45
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