The α-chemokine, stromal cell-derived factor-1α, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways

Abstract

The α-chemokine stromal cell-derived factor (SDF)-1α binds to the seven transmembrane G-protein-coupled CXCR-4 receptor and acts to modulate cell migration and proliferation. The signaling pathways that mediate the effects of SDF-1α are not well characterized. We studied events following SDF-1α binding to CXCR-4 in a model murine pre-B cell line transfected with human CXCR-4. There was enhanced tyrosine phosphorylation and association of components of focal adhesion complexes such as the related adhesion focal tyrosine kinase, paxillin, and Crk. We also observed activation of phosphatidylinositol 3-kinase. Wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase, partially inhibited the SDF-1α-induced migration and tyrosine phosphorylation of paxillin. SDF-1α treatment selectively activated p44/42 mitogen-activated protein kinase (Erk 1 and Erk 2) and its upstream kinase mitogen-activated protein kinase kinase but not p38 mitogen-activated protein kinase, c-Jun amino-terminal kinase or mitogen activated protein kinase kinase. We also observed that SDF-1α treatment increased NF-κB activity in nuclear extracts from the CXCR-4 transfectants. Taken together, these studies revealed that SDF-1α activates distinct signaling pathways that may mediate cell growth, migration, and transcriptional activation.