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Inhibition of Chk1 by activated PKB/Akt

Frank W King1, Jennifer Skeen, Nissim Hay

  • 1Cancer Research Institute, University of California San Francisco, 94115, USA.

Cell Cycle (Georgetown, Tex.)
|April 27, 2004
PubMed

Insights

Protein kinase B (PKB/Akt) phosphorylates Chk1 at serine 280, impairing its activation by DNA damage. This prevents Chk1 from forming complexes and undergoing essential activating phosphorylations, thus attenuating the DNA damage response.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • DNA Damage Response

Background:

  • Checkpoint kinase 1 (Chk1) is crucial for the DNA damage response.
  • Protein kinase B/Akt (PKB/Akt) is known to phosphorylate Chk1 in vitro.
  • Activated PKB/Akt has been observed to suppress Chk1 activation by DNA damage in vivo.

Purpose of the Study:

  • To investigate the in vivo phosphorylation of Chk1 by PKB/Akt.
  • To elucidate the mechanism by which PKB/Akt-mediated phosphorylation impairs Chk1 activation.
  • To determine the functional consequences of Chk1 serine 280 phosphorylation by PKB/Akt.

Main Methods:

  • In vivo studies to assess Chk1 phosphorylation by PKB/Akt.
  • Analysis of Chk1 complex formation after replication arrest.
  • Assessment of Chk1 activating phosphorylation by ATM/ATR in the presence of PKB/Akt.

Main Results:

  • Chk1 is phosphorylated by PKB/Akt in vivo on serine 280.
  • Increased serine 280 phosphorylation correlates with impaired Chk1 activation by DNA damage.
  • PKB/Akt-phosphorylated Chk1 fails to form protein complexes and undergo ATM/ATR-mediated activating phosphorylation.

Conclusions:

  • PKB/Akt-mediated phosphorylation of Chk1 at serine 280 inhibits its activation by DNA damage.
  • This inhibition occurs because phosphorylated Chk1 cannot form essential protein complexes or be activated by ATM/ATR.
  • These findings provide a mechanism for how PKB/Akt attenuates the Chk1-dependent DNA damage response.

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