Research ArticlePhosphoproteomics

Akt–RSK–S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases

Sci. Signal.  24 Aug 2010:
Vol. 3, Issue 136, pp. ra64
DOI: 10.1126/scisignal.2000998

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Breaking a Deadly Addiction

Most carcinomas are driven by aberrant signaling from receptor tyrosine kinases (RTKs) and, indeed, may become so dependent on these signals that they rely on them for survival. The enormous complexity of the downstream pathways, however, and the sheer numbers of potential targets, have made determining the substrates that mediate this “oncogene addiction” a daunting task. Moritz et al. developed a phosphoproteomic approach to identify targets of three core signaling pathways—all of which involve activation of AGC family kinases—downstream of oncogenic RTKs. They identified more than 300 phosphorylation targets of these signaling pathways, including a set of proteins downstream of three different oncogenic RTKs [c-Met, epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor α (PDGFRα)]. Moreover, they identified six targets of RTK signaling whose knockdown affected cell viability. A detailed analysis of one of these proteins—the chaperone SGTA—revealed a role for it in stabilization of PDGFRα and survival of cancer cells addicted to PDGFRα signaling.

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