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Sci. Signal., 24 August 2010
Vol. 3, Issue 136, p. ra64
[DOI: 10.1126/scisignal.2000998]

RESEARCH ARTICLES

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

Albrecht Moritz1*, Yu Li1*, Ailan Guo1*, Judit Villén2*{dagger}, Yi Wang1, Joan MacNeill1, Jon Kornhauser1, Kam Sprott1, Jing Zhou1, Anthony Possemato1, Jian Min Ren1, Peter Hornbeck1, Lewis C. Cantley3,4, Steven P. Gygi2, John Rush1, and Michael J. Comb1{ddagger}

1 Cell Signaling Technology Inc., 3 Trask Lane, Danvers, MA 01923, USA.
2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
4 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} Present address: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

Abstract: Receptor tyrosine kinases (RTKs) activate pathways mediated by serine-threonine kinases, such as the PI3K (phosphatidylinositol 3-kinase)–Akt pathway, the Ras–MAPK (mitogen-activated protein kinase)–RSK (ribosomal S6 kinase) pathway, and the mTOR (mammalian target of rapamycin)–p70 S6 pathway, that control important aspects of cell growth, proliferation, and survival. The Akt, RSK, and p70 S6 family of protein kinases transmits signals by phosphorylating substrates on an RxRxxS/T motif (R, arginine; S, serine; T, threonine; and x, any amino acid). We developed a large-scale proteomic approach to identify more than 300 substrates of this kinase family in cancer cell lines driven by the c-Met, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor {alpha} (PDGFR{alpha}) RTKs. We identified a subset of proteins with RxRxxS/T sites for which phosphorylation was decreased by RTK inhibitors (RTKIs), as well as by inhibitors of the PI3K, mTOR, and MAPK pathways, and we determined the effects of small interfering RNA directed against these substrates on cell viability. Phosphorylation of the protein chaperone SGTA (small glutamine-rich tetratricopeptide repeat–containing protein {alpha}) at serine-305 was essential for PDGFR{alpha} stabilization and cell survival in PDGFR{alpha}-dependent cancer cells. Our approach provides a new view of RTK and Akt–RSK–S6 kinase signaling, revealing previously unidentified Akt–RSK–S6 kinase substrates that merit further consideration as targets for combination therapy with RTKIs.

{ddagger} To whom correspondence should be addressed. E-mail: mcomb{at}cellsignal.com

Citation: A. Moritz, Y. Li, A. Guo, J. Villén, Y. Wang, J. MacNeill, J. Kornhauser, K. Sprott, J. Zhou, A. Possemato, J. M. Ren, P. Hornbeck, L. C. Cantley, S. P. Gygi, J. Rush, M. J. Comb, Akt–RSK–S6 Kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases. Sci. Signal. 3, ra64 (2010).

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