The chemokine stromal cell–derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell α chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.

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The highly conserved transmembrane sequences of surface Igs (sIgs) suggest that these molecules may associate with other integral membrane proteins to execute their dual functions ofligand binding and signal transduction (1, 2). T cell studies suggest that such lineage-specific functions are most likely mediated by lineage-specific antigens (3-5). While four additional B cell-specific surface antigens have been identified (CD19, CD20, CD22, and CD72) (6-9), their functions are unknown.Since sIg is one of N30% of B cell surface antigens that modulate, we used a comodulation assay to search for sIg-associated B cell antigens. Antibody-induced antigenic modulation is the rapid, specific, and reversible loss of surface antigens caused by incubating cells at 370C with an excess of specific antibody (10). Occasionally, chemically distinct antigens comodulate, indicating that they are physically associated. For example, anti-CD3 mAbs comodulate the TCR (Ti) (3, 5). Similarly, modulation of CD3Ti by antigen or specific antibody comodulates CD4/CD8 (11, 12); confirming the close physical and functional association between CD3Ti and CD4/CD8 (4). Our studies indicate that the B cell-specific and pan-B sIg and CD19 surface antigens are functionally and physically associated.

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