Published online before print July 24, 2008

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(Journal of Leukocyte Biology. 2008;84:1130-1140.)
© 2008 by Society for Leukocyte Biology

A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34⁺ cells

Tanja Nicole Hartmann^*,, Valentin Grabovsky^*, Ronit Pasvolsky^*, Ziv Shulman^*, Eike C. Buss^*,, Asaf Spiegel^*, Arnon Nagler, Tsvee Lapidot^*, Marcus Thelen^|| and Ronen Alon^*,1

^* Department of Immunology, Weizmann Institute of Science, Rehovot, Israel;
Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel;
^|| Institute for Research in Biomedicine, Bellinzona, Switzerland;
Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology of the Paracelsus Medical University Salzburg, Salzburg, Austria; and
Department of Internal Medicine V, University of Heidelberg, Germany

¹ Correspondence: Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel. E-mail: ronen.alon{at}weizmann.ac.il

The chemokine CXCL12 promotes migration of human leukocytes, hematopoietic progenitors, and tumor cells. The binding of CXCL12 to its receptor CXCR4 triggers Gi protein signals for motility and integrin activation in many cell types. CXCR7 is a second, recently identified receptor for CXCL12, but its role as an intrinsic G-protein-coupled receptor (GPCR) has been debated. We report that CXCR7 fails to support on its own any CXCL12-triggered integrin activation or motility in human T lymphocytes or CD34⁺ progenitors. CXCR7 is also scarcely expressed on the surface of both cell types and concentrates right underneath the plasma membrane with partial colocalization in early endosomes. Nevertheless, various specific CXCR7 blockers get access to this pool and attenuate the ability of CXCR4 to properly rearrange by surface-bound CXCL12, a critical step in the ability of the GPCR to trigger optimal CXCL12-mediated stimulation of integrin activation in T lymphocytes as well as in CD34⁺ cells. In contrast, CXCL12-triggered CXCR4 signaling to early targets, such as Akt as well as CXCR4-mediated chemotaxis, is insensitive to identical CXCR7 blocking. Our findings suggest that although CXCR7 is not an intrinsic signaling receptor for CXCL12 on lymphocytes or CD34⁺ cells, its blocking can be useful for therapeutic interference with CXCR4-mediated activation of integrins.

Key Words: adhesion molecules • cell trafficking • shear • endothelium • migration

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