title: 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.
abstract: 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.
authors.affiliation: The Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Tanja Nicole
authors.initials: TN
authors.lastname: Hartmann
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Ronit
authors.initials: R
authors.lastname: Pasvolsky
authors.forename: Ziv
authors.initials: Z
authors.lastname: Shulman
authors.forename: Eike C
authors.initials: EC
authors.lastname: Buss
authors.forename: Asaf
authors.initials: A
authors.lastname: Spiegel
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D018952:Antigens, CD34 / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000502:physiology*; D020239:Receptor Cross-Talk; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: C501896:ACKR3 protein, human; D018952:Antigens, CD34; D054377:Chemokine CXCL12; D016023:Integrins; D054387:Receptors, CXCR; D019718:Receptors, CXCR4