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DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway

Liu Liu1,2, Xiaoming Dai3, Shasha Yin1,2

  • 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

Science Signaling
|January 4, 2022
PubMed

Insights

DNA-PK activates AKT, a key cell survival protein, after DNA damage. This pathway involves Sin1 and ECT2, and blocking it increases cancer cell sensitivity to DNA-damaging drugs.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The AKT (also known as protein kinase B) pathway is crucial for cell proliferation, survival, and metabolism.
  • AKT activation is triggered by growth factors and also occurs in response to DNA damage.
  • Understanding DNA damage-induced AKT activation is vital for cancer therapy development.

Purpose of the Study:

  • To elucidate the mechanism by which DNA damage activates AKT and promotes cell survival.
  • To investigate the role of DNA-PK in mediating DNA damage-induced AKT activation.

Main Methods:

  • Investigated DNA-PK-dependent phosphorylation of Sin1 in response to DNA damage (ionizing radiation, topoisomerase inhibitors).
  • Assessed the interaction between phosphorylated Sin1 and ECT2.
  • Utilized gene depletion (Sin1, ECT2) and functional disruption of ECT2 to evaluate effects on AKT activation and cell sensitivity.

Main Results:

  • DNA damage induced DNA-PK-dependent phosphorylation of Sin1, facilitating its interaction with ECT2.
  • Depletion of Sin1 or ECT2, or disruption of ECT2 function, attenuated DNA damage-induced AKT activation.
  • Impaired AKT activation enhanced cellular sensitivity to DNA-damaging agents.

Conclusions:

  • DNA-PK sustains cell survival by phosphorylating Sin1, leading to increased AKT activity via the ECT2 pathway.
  • This pathway represents a novel mechanism for DNA damage-induced AKT activation and cell survival.
  • Targeting this pathway could enhance the efficacy of DNA-damaging cancer therapies.

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