THE ALPHA-CHEMOKINE, STROMAL CELL-DERIVED FACTOR-1-ALPHA, BINDS TO THE TRANSMEMBRANE G-PROTEIN-COUPLED CXCR-4 RECEPTOR AND ACTIVATES MULTIPLE SIGNAL-TRANSDUCTION PATHWAYS

The alpha-chemokine stromal cell-derived factor (SDF)-1 alpha binds to the seven transmembrane G-protein-coupled CXCR-4 receptor and acts to modulate cell migration and proliferation. The signaling pathways tha t mediate the effects of SDF-1 alpha are not well. characterized. We s tudied events following SDF-1 alpha binding to CXCR-4 in a model murin e pre-B cell line transfected with human CXCR-4. There was enhanced ty rosine phosphorylation and association of components of focal adhesion complexes such as the related adhesion focal tyrosine kinase, paxilli n, and Crk. We also observed activation of phosphatidylinositol 3-kina se. Wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase , partially in hibited the SDF-1 alpha-induced migration and tyrosine phosphorylation of paxillin. SDF-1 alpha treatment selectively activat ed p44/42 mitogen-activated protein kinase (Erk 1 and Erk 2) and its u pstream kinase mitogen-activated protein kinase kinase but not p38 mit ogen-activated protein kinase, c-Jun amino-terminal kinase or mitogen activated protein kinase kinase. We also observed that SDF-1 alpha tre atment increased NF-kappa B activity in nuclear extracts from the CXCR -4 transfectants. Taken together, these studies revealed that SDF-1 al pha activates distinct signaling pathways that may mediate cell growth , migration, and transcriptional activation.