Document Detail

Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases.
MedLine Citation:
PMID:  20736484     Owner:  NLM     Status:  MEDLINE    
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.
Albrecht Moritz; Yu Li; Ailan Guo; Judit Villén; Yi Wang; Joan MacNeill; Jon Kornhauser; Kam Sprott; Jing Zhou; Anthony Possemato; Jian Min Ren; Peter Hornbeck; Lewis C Cantley; Steven P Gygi; John Rush; Michael J Comb
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Publication Detail:
Type:  Journal Article     Date:  2010-08-24
Journal Detail:
Title:  Science signaling     Volume:  3     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2010  
Date Detail:
Created Date:  2010-08-25     Completed Date:  2010-12-10     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  ra64     Citation Subset:  IM    
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MeSH Terms
Amino Acid Motifs
Carrier Proteins / chemistry,  metabolism
Cell Line
Peptides / chemistry*,  metabolism
Proto-Oncogene Proteins c-akt / chemistry*,  metabolism
Receptor, Platelet-Derived Growth Factor alpha / chemistry*,  metabolism
Ribosomal Protein S6 Kinases, 70-kDa / chemistry*,  metabolism
Substrate Specificity
TOR Serine-Threonine Kinases / chemistry*,  metabolism
Grant Support
K99 CA140789/CA/NCI NIH HHS; K99 CA140789-01/CA/NCI NIH HHS; R00 CA140789/CA/NCI NIH HHS; R01 GM041890/GM/NIGMS NIH HHS; R01 GM056203/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Carrier Proteins; 0/Peptides; 0/SGTA protein, human; EC protein, human; EC Serine-Threonine Kinases; EC, Platelet-Derived Growth Factor alpha; EC Proteins c-akt; EC Protein S6 Kinases, 70-kDa

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