PTEN loss promotes mitochondrially dependent type II Fas-induced apoptosis via PEA-15.
Two distinct biochemical signals are delivered by the CD95/Fas death receptor. The molecular basis for the differential mitochondrially independent (type I) and mitochondrially dependent (type II) Fas apoptosis pathways is unknown. By analyzing 24 Fas-sensitive tumor lines, we now demonstrate that expression/activity of the PTEN tumor suppressor strongly correlates with the distinct Fas signals. PTEN loss-of-function and gain-of-function studies demonstrate the ability to interconvert between type I and type II Fas pathways. Importantly, from analyses of Bcl-2 transgenic Pten(+/-) mice, Pten haploinsufficiency converts Fas-induced apoptosis from a Bcl-2-independent to a Bcl-2-sensitive response in primary thymocytes and activated T lymphocytes. We further show that PTEN influences Fas signaling, at least in part, by regulating PEA-15 phosphorylation and activity that, in turn, regulate the ability of Bcl-2 to suppress Fas-induced apoptosis. Thus, PTEN is a key molecular rheostat that determines whether a cell dies by a mitochondrially independent type I versus a mitochondrially dependent type II apoptotic pathway upon Fas stimulation.
Peacock
James W
JW
The Prostate Centre at Vancouver General Hospital, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
Palmer
Jodie
J
Fink
Dieter
D
Ip
Stephen
S
Pietras
Eric M
EM
Mui
Alice L-F
AL
Chung
Stephen W
SW
Gleave
Martin E
ME
Cox
Michael E
ME
Parsons
Ramon
R
Peter
Marcus E
ME
Ong
Christopher J
CJ
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C092039:PEA15 protein, human; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse