Signal transduction by CXC chemokine receptor 4: Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes

We report that stromal cell-derived factor (SDF)-1 has the remarkable capac ity to induce sustained signaling through CXC chemokine receptor 4 (CXCR4). In contrast to other chemokines, such as monocyte chemotactic protein 1 (C C chemokine receptor 2 [CCR2]), macrophage inflammatory protein 1 beta (CCR 5), liver and activation-regulated chemokine (LARC [CCR6]), Epstein-Barr vi rus-induced molecule 1 ligand chemokine (ELC [CCR7]), and IP10 (CXCR3), SDF -1 stimulates the prolonged activation of protein kinase B and extracellula r signal-regulated kinase (ERK)-2. Activation of protein kinase B is revers ed by displacement of SDF-1 from CXCR4 or inhibition of phosphatidylinosito l 3-kinase. Although increasing concentrations of SDF-1 enhance CXCR4 inter nalization, kinase activation is prolonged. In addition, restimulation yiel ds >60% of initial protein kinase B activity, indicating that the remaining receptors are not desensitized. Furthermore, activation is prolonged by in hibiting SDF-1 degradation. The sustained activation of cell survival and m itogenic pathways may account for the unique role of SDF-1 and CXCR4 in emb ryogenesis and lymphopoiesis.