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Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM

Juan Guinea Viniegra1, Natalia Martínez, Pegah Modirassari

  • 1CRIB/Facultad de Medicina, Universidad de Castilla la Mancha, 02071 Albacete, Spain.

The Journal of Biological Chemistry
|November 18, 2004
PubMed

Insights

Ataxia telangiectasia (ATM) is crucial for activating PKB/Akt, impacting cell cycle control and DNA damage response. This discovery sheds light on AT patient radiosensitivity and insulin intolerance.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Ataxia telangiectasia (AT) is a genetic disorder linked to ATM gene mutations.
  • ATM and PKB/Akt are involved in cell cycle control, DNA damage response, and insulin signaling.
  • Phenotypic abnormalities in AT patients resemble those seen with impaired PKB/Akt function.

Purpose of the Study:

  • To investigate the role of ATM in PKB/Akt activation.
  • To elucidate the mechanism by which ATM influences PKB/Akt activity.
  • To explore the implications for AT-related cellular responses.

Main Methods:

  • Transient transfection assays using PKB/Akt and ATM in Cos cells.
  • Utilizing ATM inhibitors and small interfering RNA (siRNA).
  • Analyzing transcription factor activity and phosphorylation in AT patient cell lines and ATM knockout mice.

Main Results:

  • ATM is a key regulator of PKB/Akt activation by insulin and gamma-radiation.
  • ATM's phosphatidylinositol 3-kinase domain mediates Akt serine 473 phosphorylation.
  • Impaired Akt phosphorylation at serine 473 was observed in ATM-deficient cells, affecting downstream responses.

Conclusions:

  • ATM plays a critical role in PKB/Akt activation, particularly in response to insulin and DNA damage.
  • This finding offers insights into the molecular mechanisms underlying AT.
  • The study provides potential explanations for radiosensitivity and insulin intolerance in AT patients and suggests ATM's role in identifying PDK2.

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