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Inhibition of PTEN and activation of Akt by menadione

Kyoko Yoshikawa1, Kiyomi Nigorikawa, Mariko Tsukamoto

  • 1Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.

Biochimica Et Biophysica Acta
|February 6, 2007
PubMed

Insights

Menadione (vitamin K3) activates Akt signaling independently of EGFR. It inhibits PTEN phosphatase activity and also decelerates Akt dephosphorylation by inhibiting tyrosine phosphatases.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Menadione (vitamin K3) is known to activate Erk signaling pathways.
  • EGFR activation, resulting from protein tyrosine phosphatase inhibition, mediates menadione's effect on Erk.
  • The impact of menadione on Akt signaling remains less understood.

Purpose of the Study:

  • To investigate the effects of menadione on Akt phosphorylation in Chinese hamster ovary (CHO) cells.
  • To elucidate the mechanisms underlying menadione-induced Akt activation, particularly its independence from EGFR signaling.

Main Methods:

  • Utilized cell-free and intact cell systems to study menadione's effects on Akt.
  • Employed AG1478, an EGFR inhibitor, to assess the role of EGFR in menadione's action.
  • Investigated menadione's impact on PTEN lipid phosphatase activity and its effect on Akt in PTEN-null cells.

Main Results:

  • Menadione-induced Akt phosphorylation was not inhibited by AG1478, indicating EGFR independence.
  • Menadione directly inhibited PTEN lipid phosphatase activity in a cell-free system.
  • Menadione impaired PTEN's inhibitory effect on Akt in intact cells, suggesting PTEN inhibition as a mechanism.
  • Menadione also slowed Akt dephosphorylation in PTEN-null cells, pointing to tyrosine phosphatase inhibition.

Conclusions:

  • Menadione activates Akt through PTEN inhibition, leading to accelerated Akt activation.
  • Menadione also contributes to sustained Akt activation by decelerating its inactivation via tyrosine phosphatase inhibition.
  • These findings reveal dual mechanisms of EGFR-independent Akt activation by menadione.

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