Shifting Signals with CXCR7

Sci. Signal.  20 Sep 2011:
Vol. 4, Issue 191, pp. ec259
DOI: 10.1126/scisignal.4191ec259

Signaling mediated by the chemokine SDF-1 (stromal cell–derived factor 1, also known as CXCL12) and its receptor CXCR4, a G protein–coupled receptor (GPCR), directs trafficking of hematopoietic stem cells and leukocytes in the body and has been implicated in cancer cell metastasis. SDF-1 binds to another chemokine receptor, CXCR7; unlike its association with CXCR4, SDF-1 binding to CXCR7 fails to activate Gi signaling. Noting that CXCR7 has been implicated in tumor cell survival and growth, can form heterodimers with CXCR4, and can signal through β-arrestins, Décaillot et al. explored signaling through the CXCR4-CXCR7 complex. Tagged forms of CXCR4 and CXCR7 coimmunoprecipitated when coexpressed in human embryonic kidney (HEK) 293 cells and colocalized with each other in Neuro2A cells, indicating that the two receptors formed a complex. Coexpression of CXCR7 attenuated CXCR4 signaling through Gi in HEK293 cells (assessed by SDF-dependent inhibition of forskolin-induced cAMP production), whereas coexpression of CXCR4 enhanced β-arrestin recruitment to CXCR7 even in the absence of SDF-1. Coexpression of the two receptors enhanced SDF-1–dependent phosphorylation of the mitogen-activated protein kinase (MAPK) ERK1/2 over that seen with either receptor alone and potentiated both basal and SDF-1–stimulated phosphorylation of two other members of the MAPK family, p38 and SAPK. Moreover, CXCR7 enhanced SDF-1–dependent migration in cells with functional CXCR4. β-arrestin knockdown with siRNA decreased SDF-1–dependent ERK1/2 phosphorylation, as well as basal and SDF-1–stimulated p38 and SAPK phosphorylation in cells coexpressing CXCR4 and CXCR7, and β-arrestin knockdown or a dominant-negative β-arrestin mutant inhibited CXCR7’s potentiation of cell migration. Thus, the authors propose that, by forming a complex with CXCR4, CXCR7 shifts the downstream response of CXCR4 to SDF-1 from activation of Gi-mediated pathways to the activation of those mediated through β-arrestin.

F. M. Décaillot, M. A. Kazmi, Y. Lin, S. Ray-Saha, T. P. Sakmar, P. Sachdev, CXCR7/CXCR4 heterodimer constitutively recruits β-arrestin to enhance cell migration. J. Biol. Chem. 286, 32188–32197 (2011). [Abstract] [Full Text]