Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases.
Fas/CD95/Apo-I has been shown to stimulate a variety of molecules including several members of the caspase family and the acidic sphingomyelinase (Martin and Green 1995; Gulbins et al, 1995). Here, we demonstrate that Fas receptor-triggered activation of the acidic sphingomyelinase, consumption of sphingomyelin, release of ceramide, and subsequent activation of JNK and p38-K are regulated by caspases. Inhibition of caspases by Ac-YVAD-chloromethylketone or transient CrmA transfection prevented stimulation of acidic sphingomyelinase, release of ceramide and activation of JNK and p38-K upon Fas-receptor crosslinking. Likewise, Fas triggered apoptosis was almost completely blocked by Ac-YVAD-chloromethylketone or CrmA mediated inhibition of caspases. The results suggest a new signalling cascade from the Fas receptor via caspases to acidic sphingomyelinase, ceramide and JNK/p38-K.
Brenner
B
B
Department of Physiology, University of Tuebingen, Gmelinstrasse 5, 72076 Tuebingen, Germany.
Ferlinz
K
K
Grassmé
H
H
Weller
M
M
Koppenhoefer
U
U
Dichgans
J
J
Sandhoff
K
K
Lang
F
F
Gulbins
E
E
D000143:Acids / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D019169:Jurkat Cells / Q000166:cytology* / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases; D015843:Serpins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology; D014162:Transfection; D014764:Viral Proteins; D019014:fas Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000143:Acids; D018759:Adrenergic Uptake Inhibitors; D000590:Amino Acid Chloromethyl Ketones; D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D004075:Diglycerides; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D015843:Serpins; D014764:Viral Proteins; D019014:fas Receptor; C074641:interleukin-1beta-converting enzyme inhibitor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases; D007099:Imipramine