Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases
| Autor: | Peter Hornbeck, John Rush, Jing Zhou, Steven P. Gygi, Michael J. Comb, Jian Min Ren, Judit Villén, Albrecht Moritz, Yu Li, Kam Sprott, Ailan Guo, Anthony Possemato, Jon M. Kornhauser, Lewis C. Cantley, Yi Wang, Joan MacNeill |
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| Rok vydání: | 2010 |
| Předmět: |
Receptor
Platelet-Derived Growth Factor alpha Amino Acid Motifs P70-S6 Kinase 1 Biochemistry Receptor tyrosine kinase Article Cell Line Substrate Specificity Ribosomal s6 kinase Humans Phosphorylation Protein kinase A Molecular Biology Protein kinase B biology TOR Serine-Threonine Kinases JAK-STAT signaling pathway Ribosomal Protein S6 Kinases 70-kDa Cell Biology biology.protein Cancer research Carrier Proteins Peptides Tyrosine kinase Proto-Oncogene Proteins c-akt Platelet-derived growth factor receptor Molecular Chaperones |
| Zdroj: | Science signaling. 3(136) |
| ISSN: | 1937-9145 |
| Popis: | 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 (PDGFRalpha) 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 PDGFRalpha stabilization and cell survival in PDGFRalpha-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. |
| Databáze: | OpenAIRE |
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