IMMUNOLOGY Chemokine Receptor Pairs

Abstract:

The complexity of chemokine response biology has just increased. Mellado et al. report that chemokine receptors can heterodimerize, broadening a cell's sensitivity and response to these proinflammatory cytokines. In both transfected cells and human peripheral blood mononuclear cells, the chemokine receptors CCR2 and CCR5 formed homodimers and heterodimers when their cognate ligands, monocyte chemotactic protein-1 (MCP-1) and RANTES (regulated upon activation, normal T cell-expressed and secreted), respectively, were added simultaneously to cells. Surprisingly, activation of the heterodimers occurred at ligand concentrations as small as 1/100th those that activated homodimers. CCR2-CCR5 complexes also recruited the downstream signaling molecules associated with each of the receptors when cells were treated with both chemokines, and expression of either a CCR2 or CCR5 mutant receptor impaired such recruitment to the heterodimer partner. Although each receptor homodimer signals through the Gi heterotrimeric GTPase during chemotaxis, the heterodimer appears to associate with Gq/11. The signal pathways governed by heterodimers also appears to control cell adhesion rather than chemotaxis.

M. Mellado, J. M. Rodríguez-Frade, A. J. Vila-Coro, S. Fernandez, A. Martín de Ana, D. R. Jones, J. L. Torán, C. Martínez-A., Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J. 20, 2497-2507 (2001). [Abstract] [Full Text]