The Journal of Experimental Medicine
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Published online 31 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/313/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 313-324

Original Article

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

Bettina Tiltona, Liza Hoa, Estelle Oberlina, Pius Loetschera, Françoise Baleuxb, Ian Clark-Lewisc, and Marcus Thelend
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

Correspondence to: Marcus Thelen, Istituto di Ricerca in Biomedicina, Via Vela 6, CH-6500 Bellinzona, Switzerland. Tel:41-91-820-0317 Fax:41-91-820-0305 E-mail: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 1ß (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


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