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Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex

Tian Xia1, Di Chen1, Xiaolong Liu1

  • 1CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.

Cell Death & Disease
|April 29, 2022
PubMed

Insights

Midkine (MDK) protein disrupts the LKB1-AMPK signaling pathway inside cells, inhibiting energy production and promoting cancer cell growth. This discovery reveals a new mechanism for controlling AMPK activation in cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Midkine (MDK) is a secreted growth factor involved in cancer progression.
  • The intracellular functions and signaling mechanisms of MDK are not fully understood.
  • MDK can be internalized into the cytoplasm via endocytosis.

Purpose of the Study:

  • To elucidate the intracellular function of Midkine (MDK).
  • To investigate the mechanism by which MDK regulates intracellular signaling pathways.
  • To determine the role of MDK in cancer cell proliferation and AMPK activation.

Main Methods:

  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • Western blotting to assess protein levels and phosphorylation.
  • Cell proliferation assays.
  • Analysis of MDK expression in human cancer datasets.

Main Results:

  • Intracellular MDK interacts with LKB1 and STRAD, disrupting the LKB1-STRAD-Mo25 complex.
  • MDK inhibits LKB1 activity, leading to reduced activation of AMPK.
  • MDK accelerates cancer cell proliferation by suppressing the LKB1-AMPK axis.
  • MDK expression is significantly upregulated in liver, kidney, and breast cancers, correlating with poor clinical outcomes.

Conclusions:

  • Intracellular MDK inhibits AMPK activation by disrupting the LKB1-STRAD-Mo25 complex.
  • MDK promotes cancer progression through the inhibition of the LKB1-AMPK signaling pathway.
  • MDK represents a potential therapeutic target for cancers, particularly liver, kidney, and breast cancers.

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