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14-3-3 interacts with LKB1 via recognizing phosphorylated threonine 336 residue and suppresses LKB1 kinase function

Yu Bai1, Tao Zhou, Haian Fu

  • 1School of Life Sciences, Anhui University, Hefei, Anhui 230039, China.

FEBS Letters
|May 12, 2012
PubMed

Insights

14-3-3 proteins regulate LKB1 activity by phosphorylating Thr336. This phosphorylation by 14-3-3 zeta inhibits LKB1

Area of Science:

  • Cellular signaling and regulation
  • Molecular mechanisms of protein activity control

Background:

  • Liver kinase B1 (LKB1) is a crucial tumor suppressor kinase.
  • LKB1 regulates cellular metabolism and energy balance through AMP-activated protein kinase (AMPK) and other substrates.
  • Understanding LKB1 regulation is vital for cancer research and metabolic disease studies.

Purpose of the Study:

  • To elucidate the regulatory mechanism of LKB1 by 14-3-3 proteins.
  • To investigate the role of LKB1 phosphorylation at Thr336 in its activity and substrate interactions.

Main Methods:

  • Investigated the interaction between LKB1 and 14-3-3 proteins.
  • Assessed the impact of 14-3-3 binding on LKB1's ability to phosphorylate its substrates, including AMPK.
  • Examined the effects of LKB1 phosphorylation on cell cycle progression and apoptosis.
  • Studied the influence of serum starvation on LKB1 activity and Thr336 phosphorylation.

Main Results:

  • 14-3-3 proteins, specifically 14-3-3 zeta, bind to phosphorylated LKB1 at Thr336.
  • This interaction inhibits LKB1's phosphorylation of AMPK and attenuates LKB1-mediated G1 cell cycle arrest and apoptosis.
  • Regulation occurs without altering LKB1's catalytic activity or subcellular localization.
  • Serum starvation enhances LKB1 activity and promotes Thr336 phosphorylation.

Conclusions:

  • Autophosphorylation of LKB1 at Thr336 serves as an activating signal.
  • Activated LKB1 recruits 14-3-3 proteins, which then act as negative regulators, attenuating LKB1 activity.
  • This feedback loop maintains LKB1 activity within a controlled range, preventing excessive signaling.

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