Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases

Area of Science:

• Cellular signaling
• Cancer biology
• Proteomics

Background:

• Receptor tyrosine kinases (RTKs) regulate cell growth, proliferation, and survival through downstream serine-threonine kinase pathways like PI3K-Akt, Ras-MAPK-RSK, and mTOR-p70 S6.
• These kinases phosphorylate substrates on a specific RxRxxS/T motif, controlling cellular functions.

Purpose of the Study:

• To identify novel substrates of the Akt, RSK, and p70 S6 kinase family in cancer cell lines driven by specific RTKs (c-Met, EGFR, PDGFRalpha).
• To investigate the functional impact of these substrates on cell viability and their regulation by RTK inhibitors and pathway inhibitors.

Main Methods:

• A large-scale proteomic approach was employed to identify kinase substrates.
• Cancer cell lines dependent on c-Met, EGFR, or PDGFRalpha were utilized.
• The effects of RTK inhibitors, PI3K, mTOR, and MAPK pathway inhibitors on substrate phosphorylation were assessed.
• Small interfering RNA was used to determine the impact of substrate depletion on cell viability.

Main Results:

• Over 300 substrates for the Akt-RSK-S6 kinase family were identified in RTK-driven cancer cells.
• A subset of these substrates showed decreased phosphorylation upon treatment with RTK inhibitors or pathway inhibitors.
• Phosphorylation of small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) at serine-305 was critical for PDGFRalpha stabilization and cancer cell survival.

Conclusions:

• This study provides a comprehensive view of RTK and Akt-RSK-S6 kinase signaling.
• Previously unidentified substrates were revealed, offering new insights into cancer cell survival mechanisms.
• These novel substrates represent potential targets for combination therapies with RTK inhibitors in cancer treatment.