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J. Biol. Chem., Vol. 278, Issue 11, 9536-9543, March 14, 2003
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From the Division of Experimental Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Massachusetts
02115
The chemokine receptor CXCR4
and its cognate ligand, stromal cell-derived factor-1
Differential Regulation of CXCR4-mediated T-cell Chemotaxis
and Mitogen-activated Protein Kinase Activation by the Membrane
Tyrosine Phosphatase, CD45*
,, and
(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 mitogen-activated
protein kinase (MAPK) activation in T-cells. We observed a
significant reduction in CXCL12-induced chemotaxis in the CD45-negative
Jurkat cell line (J45.01) as compared with the CD45-positive control
(JE6.1) cells. Expression of a chimeric protein containing the
intracellular phosphatase domain of CD45 was able to partially restore
CXCL12-induced chemotaxis in the J45.01 cells. However, reconstitution
of CD45 into the J45.01 cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant effect on CXCL12 or human
immunodeficiency virus gp120-induced internalization of the
CXCR4 receptor. Furthermore, J45.01 cells showed a slight enhancement
in CXCL12-induced MAP kinase activity as compared with the JE6.1 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-
-cyclodextrin, blocked the association between CXCR4 and CD45
and markedly abolished CXCL12-induced chemotaxis. Comparisons of
signaling pathways induced by CXCL12 in JE6.1 and J45.01 cells revealed
that CD45 might moderately regulate the tyrosine phosphorylation of the
focal adhesion components the related adhesion focal tyrosine
kinase/Pyk2, focal adhesion kinase, 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. Our results show that CD45 differentially regulates
CXCR4-mediated chemotactic activity and MAPK activation by
modulating the activities of focal adhesion components and the
downstream effectors of the T-cell receptor.
*
This work was supported in part by National Institutes of
Health Grants AI49140 and CA76950 and by a grant from the American Foundation for AIDS Research (to R. K. G).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to this work.
§
To whom correspondence should be addressed: Harvard Inst. of
Medicine-BIDMC, 4 Blackfan Circle, Rm. 343, Boston, MA 02115. Tel.:
617-667-0060; Fax: 617-975-5243; E-mail: rganju@caregroup.harvard.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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