Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN.
Although most oncogenic phenotypes of PTEN loss are attributed to AKT activation, AKT alone is not sufficient to induce all of the biological activities associated with PTEN inactivation. We searched for additional PTEN-regulated pathways through gene set enrichment analysis (GSEA) and identified genes associated with JNK activation. PTEN null cells exhibit higher JNK activity, and genetic studies demonstrate that JNK functions parallel to and independently of AKT. Furthermore, PTEN deficiency sensitizes cells to JNK inhibition and negative feedback regulation of PI3K was impaired in PTEN null cells. Akt and JNK activation are highly correlated in human prostate cancer. These findings implicate JNK in PI3K-driven cancers and demonstrate the utility of GSEA to identify functional pathways using genetically defined systems.
Vivanco
Igor
I
Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Palaskas
Nicolaos
N
Tran
Chris
C
Finn
Stephen P
SP
Getz
Gad
G
Kennedy
Norman J
NJ
Jiao
Jing
J
Rose
Joshua
J
Xie
Wanling
W
Loda
Massimo
M
Golub
Todd
T
Mellinghoff
Ingo K
IK
Davis
Roger J
RJ
Wu
Hong
H
Sawyers
Charles L
CL
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human