Glycosphingolipid-induced relocation of Lyn and Syk into detergent-resistant membranes results in mast cell activation.
Sphingosine, sphingosine-1-phosphate, and the more complex sphingolipid ceramide exert strong immunomodulatory effects on a variety of leukocytes. However, little is known regarding such a potential of glycosphingolipids, a class of sugar derivatives of sphingosine. Here we demonstrate that galactosylsphingosine, one of the smallest representatives of this group, accumulates in the detergent-resistant membranes resulting in the relocation of the tyrosine kinases Lyn and Syk into this compartment. The result of this is an enhanced tyrosine phosphorylation and kinase activity leading to priming and activation of mast cells by conveying a weak yet significant activation of the mitogen-activated protein kinase pathway(s). In comparison to IgE/Ag triggering, galactosylsphingosine stimulates the mitogen-activated protein kinase pathway more rapidly and favors c-Jun NH2-terminal kinase 1 activation over extracellular signal-regulatory kinase 1 and 2. At the transcription factor level, this "ultratransient signaling event" results in an activation of JunD as the predominant AP-1 component. In this respect, the effects of galactosylsphingosine are clearly distinct from the signaling elicited by other sphingolipids without the sugar moiety, such as sphingosine-1-phosphate.
Prieschl
E E
EE
Department of Immunology, Novartis Research Institute, Vienna, Austria. eva.prieschl@pharma.novartis.com
Csonga
R
R
Novotny
V
V
Kikuchi
G E
GE
Baumruker
T
T
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000276:immunology; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002458:Cell Fractionation; D002460:Cell Line; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004792:Enzyme Precursors / Q000378:metabolism* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D015759:Ionomycin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism*; D051379:Mice; D017830:Octoxynol / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011609:Psychosine / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism* / Q000502:physiology
D000276:Adjuvants, Immunologic; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids; D016755:Proto-Oncogene Proteins c-jun; D011609:Psychosine; D014443:Tyrosine; D015759:Ionomycin; D017830:Octoxynol; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases