Mechanisms of L-selectin-induced activation of the nuclear factor of activated T lymphocytes (NFAT).
Selectins are mediating transient contacts of leukocytes with endothelium during inflammatory processes and in the development of the immune system. L-selectin expressed on almost all leukocytes also functions as a signaling receptor. Recently, we have identified different signaling pathways in T lymphocytes by L-selectin. One signaling cascade leads via the tyrosine kinase p56lck to the small G-proteins Ras and Rac and to MAP-kinases. A second independent pathway results in ceramide release. In this study, an L-selectin-induced translocation of the transcription factor NFAT to the nucleus was identified. Using genetically modified JCaM1.6 cells, pharmacological inhibitors, and antisense molecules, it was shown that L-selectin-induced NFAT activation depends on src-tyrosine kinases, calcineurin and small G-proteins. MAP-kinases and actin filaments were identified as Ras effectors involved in NFAT translocation. We conclude that L-selectin cross-linking results in activation of NFAT by different signaling pathways. The activation of NFAT might modulate the immune response of leukocytes interacting with endothelial cells.
Brenner
Birgit C
BC
Department of Cardiology, Children's Hospital, Moorenstrasse 5, Düsseldorf, Germany. Brenner@med.uni-duesseldorf.de
Kadel
Stephanie
S
Grigorovich
Sergei
S
Linderkamp
Otwin
O
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000906:Antibodies / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003599:Cytoskeleton / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D019041:L-Selectin / Q000276:immunology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011134:Polysaccharides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D000906:Antibodies; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011134:Polysaccharides; D014157:Transcription Factors; D019041:L-Selectin; D016572:Cyclosporine; C007789:fucoidan; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins; D016559:Tacrolimus