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A more recent version of this article appeared on September 1, 2007

Published online before print June 12, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1106678

Received for publication November 15, 2006.
Revised March 6, 2007.
Accepted for publication April 13, 2007.

Article

Pivotal Advance: Slit-2/Robo-1 modulates the CXCL12/CXCR4-induced chemotaxis of T cells

Anil Prasad *, Zahida Qamri *, Jane Wu {dagger}, and Ramesh K. Ganju *@

*Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; and {dagger}Northwestern University Feinberg Medical School, Robert H. Laurie Comprehensive Cancer Center, Center for Genetic Medicine, Chicago, Illinois, USA

@ To whom correspondence should be addressed. E-mail: rganju{at}bidmc.harvard.edu.


  Abstract

Slit, which mediates its function by binding to the Roundabout (Robo) receptor, has been shown to regulate neuronal, dendritic, and leukocyte migration. However, the molecular mechanism by which the Slit/Robo complex inhibits the migration of cells is not well defined. Here, we showed that Slit-2 can inhibit the CXCL12-induced chemotaxis and transendothelial migration of T cells and monocytes. We observed that CXCR4 associates with Robo-1 and that Slit-2 treatment enhances this association with the Robo-1 receptor. Robo-1 is a single-pass transmembrane receptor whose intracellular region contains four conserved motifs designated as CC0, CC1, CC2, and CC3. Structural and functional analyses of Robo receptors revealed that interaction of the CC3 motif with the CXCR4 receptor may regulate the CXCL12-induced chemotaxis of T cells. We further characterized Slit-2-mediated inhibition of the CXCL12/CXCR4 chemotactic pathway and found that Slit-2 can block the CXCL12-induced activation of the Src and Lck kinases but not Lyn kinase. Although Slit-2 did not inhibit the CXCL12-induced activation of MAPKs, it did inhibit the Akt phosphorylation and Rac activation induced by this chemokine. Altogether, our studies indicate a novel mechanism by which the Slit/Robo complex may inhibit the CXCR4/CXCL12-mediated chemotaxis of T cells.

Key Words: leukocytes • migration • chemokine • inflammation • signal transduction


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