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PMID: 10934220 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

The Journal of experimental medicine ·Vol. 192 ·No. 3 ·2000-08-07 ·Pages 313-24

Tilton B, Ho L, Oberlin E, Loetscher P, Baleux F, Clark-Lewis I, Thelen M

Abstract

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 1beta (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.

MeSH Terms
Androstadienes/pharmacology Animals Cells, Cultured Chemokine CXCL12 Chemokines, CXC/antagonists & inhibitors,metabolism,pharmacology Dose-Response Relationship, Drug Down-Regulation Enzyme Activation Enzyme Inhibitors/pharmacology Humans Mice Mitogen-Activated Protein Kinase 1/metabolism Phosphoinositide-3 Kinase Inhibitors Protein Serine-Threonine Kinases Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Receptors, CXCR4/metabolism Signal Transduction T-Lymphocytes/cytology,metabolism Time Factors Wortmannin
Chemicals
Androstadienes CXCL12 protein, human Chemokine CXCL12 Chemokines, CXC Cxcl12 protein, mouse Enzyme Inhibitors Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins Receptors, CXCR4 Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Mitogen-Activated Protein Kinase 1 Wortmannin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Tilton B
Theodor Kocher-Institute, University of Bern, CH-3000 Bern 9, Switzerland.
Ho L
Oberlin E
Loetscher P
Baleux F
Clark-Lewis I
Thelen M
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.3.313
Published
2000-08-07
Pages
313-24
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193218
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.192.3.313 PMC Full Text View journal details
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