Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades.
The mitogen-activated protein kinase (MAPK) signalling pathway serves to translocate information from activated plasma-membrane receptors to initiate nuclear transcriptional events. This cascade has recently been subdivided into two analogous pathways: the extracellular signal-regulated kinase (ERK) cascade, which preferentially signals mitogenesis, and the stress-activated protein kinase (SAPK) cascade, which is linked to growth arrest and/or cellular inflammation. In concurrent experiments utilizing rat glomerular mesangial cells (MCs), we demonstrate that growth factors or sphingosine activate ERK but not SAPK. In contrast, inflammatory cytokines or cell-permeable ceramide analogues activate SAPK but not ERK. Ceramide, but not sphingosine, induces interleukin-6 secretion, a marker of an inflamed phenotype. Moreover, ceramide can suppress growth factor- or sphingosine-induced ERK activation as well as proliferation. These studies implicate sphingolipid metabolites as opposing regulators of cell proliferation and inflammation through activation of separate kinase cascades.
Coroneos
E
E
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Wang
Y
Y
Panuska
J R
JR
Templeton
D J
DJ
Kester
M
M
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019000:Phosphotyrosine / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013107:Sphingolipids / Q000494:pharmacology*; D013110:Sphingosine / Q000494:pharmacology; D013312:Stress, Physiological; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D002518:Ceramides; D016207:Cytokines; D006133:Growth Substances; D015850:Interleukin-6; D010982:Platelet-Derived Growth Factor; D013107:Sphingolipids; D019000:Phosphotyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine