Identification of the JNK Signaling Pathway as a Functional Target of the Tumor Suppressor PTEN

Although most of the oncogenic phenotypes of PTEN loss have been 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 found that PTEN inactivation causes an enrichment of genes associated with JNK activation. Biochemically, 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. We also found that negative feedback regulation of PI3K was impaired in PTEN-null cells. These findings implicate JNK in PI3K-driven cancers and demonstrate the utility of GSEA to identify functional pathways using genetically defined systems.

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Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ, Jiao J, Rose J, Xie W, Loda M, Golub T, Mellinghoff IK, Davis RJ, Wu H, Sawyers CL