FIGURE 5.

CXCR7 expression enhances chemotaxis. A, chemotaxis of MDA-MB-231 breast cancer cells induced by 0, 1, 10, and 100 nm of SDF-1 in the presence of increasing amounts of transfected CXCR7. Cells become more chemotactic to SDF-1 when increasing amounts of CXCR7 are expressed. B, chemotaxis of U87-CD4 cells stably expressing CXCR4 (U87-CD4-CXCR4) induced by 12.5 nm SDF-1 is enhanced in the presence of CXCR7 in a dose-dependent manner (0, 0.5, and 2 μg of CXCR7). Pretreatment of cells with 100 nm ITAC results in decreased SDF-1-stimulated migration of CXCR7 co-expressing cells. C, U87-CD4-CXCR4 cells were transfected with nontargeting (N.T.) siRNA, βArr2 siRNA, or βArr DN along with 1 μg of CXCR7. Potentiation of SDF-1-stimulated migration of U87-CD4-CXCR4 cells by CXCR7 is reverted in the presence of βArr2 siRNA and βArr DN. Data are expressed as means ± S.E. (n = 3). D, proposed model showing that in cells treated with SDF-1, CXCR4 triggers inhibition of intracellular cAMP production and Ca²⁺ mobilization, and both CXCR4 and CXCR7 stimulate ERK 1/2 activation (left panel). Co-expression of CXCR4 and CXCR7 leads to apparent heterodimerization of CXCR4 and CXCR7, and the heteromeric CXCR4·CXCR7 complex demonstrates a dramatically altered signaling profile. The CXCR4·CXCR7 heteromer is unable to trigger inhibition of cellular cAMP production. The constitutive recruitment of β-arrestin couples CXCR4 stimulation in the CXCR4·CXCR7 complex to proliferative pathways (ERK1/2, p38 MAPK, and SAPK).