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Original Article

Bettina Tilton^a, Liza Ho^a, Estelle Oberlin^a, Pius Loetscher^a, Françoise Baleux^b, Ian Clark-Lewis^c, and Marcus Thelen^d

^a Theodor Kocher-Institute, University of Bern, CH-3000 Bern 9, Switzerland
^b Institut Pasteur, 75724 Paris Cedex 15, France
^c Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
^d Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
Istituto di Ricerca in Biomedicina, Via Vela 6, CH-6500 Bellinzona, Switzerland.41-91-820-030541-91-820-0317

marcus.thelen{at}irb.unisi.ch

We report that stromal cell–derived factor (SDF)-1 has the remarkable capacity to induce sustained signaling through CXC chemokine receptor 4 (CXCR4). In contrast to other chemokines, such as monocyte chemotactic protein 1 (CC chemokine receptor 2 [CCR2]), macrophage inflammatory protein 1β (CCR5), liver and activation-regulated chemokine (LARC [CCR6]), Epstein-Barr virus–induced molecule 1 ligand chemokine (ELC [CCR7]), and IP10 (CXCR3), SDF-1 stimulates the prolonged activation of protein kinase B and extracellular signal–regulated kinase (ERK)-2. Activation of protein kinase B is reversed by displacement of SDF-1 from CXCR4 or inhibition of phosphatidylinositol 3-kinase. Although increasing concentrations of SDF-1 enhance CXCR4 internalization, kinase activation is prolonged. In addition, restimulation yields >60% of initial protein kinase B activity, indicating that the remaining receptors are not desensitized. Furthermore, activation is prolonged by inhibiting SDF-1 degradation. The sustained activation of cell survival and mitogenic pathways may account for the unique role of SDF-1 and CXCR4 in embryogenesis and lymphopoiesis.

Key Words: CXCR4 • SDF-1 • signal transduction • protein kinase B • PI 3-kinase

© 2000 The Rockefeller University Press

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