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p70S6K is regulated by focal adhesion kinase and is required for Src-selective autophagy

Emma Sandilands1, Christina Schoenherr1, Margaret C Frame1

  • 1Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, United Kingdom.

Cellular Signalling
|June 14, 2015
PubMed

Insights

Focal adhesion kinase (FAK) is crucial for the Akt-p70S6K-S6 pathway in squamous cell carcinoma (SCC). FAK deficiency impairs this pathway and Src-selective autophagy, impacting cancer cell signaling and trafficking.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Signaling

Background:

  • Focal adhesion kinase (FAK) plays a role in cell signaling pathways.
  • The Akt-p70S6K-S6 pathway is implicated in cancer progression.
  • Autophagy is a cellular process involved in degradation and recycling.

Purpose of the Study:

  • To investigate the role of FAK in the Akt-p70S6K-S6 signaling pathway in squamous cell carcinoma (SCC).
  • To determine the impact of FAK deficiency on Src-selective autophagy.
  • To elucidate the relationship between FAK, the Akt-p70S6K-S6 pathway, and autophagy in SCC cells.

Main Methods:

  • Genetic deficiency of FAK in SCC cells.
  • Assessment of protein phosphorylation (Akt, p70S6K, S6).
  • Pharmacological inhibition of signaling pathways (Akt-p70S6K-S6, PDK1).
  • Analysis of c-Src (p-Src) targeting to autophagosomes and complex formation with LC3.
  • siRNA-mediated knockdown of p70S6K.
  • Co-localization studies of signaling pathway components with p-Src at autophagosomes.

Main Results:

  • FAK deficiency in SCC cells leads to reduced phosphorylation of Akt, p70S6K, and S6.
  • Signaling to the Akt-p70S6K-S6 pathway is more sensitive to inhibition in FAK-deficient SCCs.
  • FAK deficiency impairs the autophagic targeting of activated c-Src (p-Src) and disrupts the p-Src-LC3 complex.
  • Inhibition of p70S6K also impairs Src-selective autophagy.
  • Components of the PDK1-Akt-p70S6K pathway co-localize with p-Src at autophagosomes.

Conclusions:

  • FAK is essential for optimal Akt-p70S6K-S6 pathway signaling in SCC.
  • FAK regulates Src-selective autophagy, potentially through the PDK1-Akt-p70S6K signaling module.
  • The FAK-regulated PDK1-Akt-p70S6K module controls Src intracellular trafficking at Src-containing autophagosomes.
Keywords:
AktAutophagosomesFAKPDK1S6p70S6K

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