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Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression

Giada Dogliotti1, Lars Kullmann1,2, Pratibha Dhumale3,4

  • 1Molecular and Cellular Anatomy, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.

Nature Communications
|June 27, 2017
PubMed

Insights

The serine/threonine kinase LKB1 requires membrane binding to phosphatidic acid for full activation. This mechanism is crucial for LKB1

Area of Science:

  • Cell Biology
  • Molecular Oncology

Background:

  • The serine/threonine kinase LKB1 regulates cell proliferation, energy, and polarity.
  • Upstream regulatory mechanisms of LKB1 are largely unknown.
  • LKB1 is frequently downregulated in tumors.

Purpose of the Study:

  • To elucidate the upstream regulatory mechanisms of LKB1 activation.
  • To investigate the role of membrane targeting in LKB1 function.
  • To explore LKB1's role in development and carcinogenesis.

Main Methods:

  • Investigated LKB1 binding to phosphatidic acid.
  • Utilized LKB1 mutants deficient in membrane binding.
  • Assessed LKB1 function in Drosophila development.
  • Examined LKB1 expression in malignant melanoma.

Main Results:

  • Direct binding of LKB1 to phosphatidic acid is essential for full kinase activation.
  • LKB1 mutants lacking membrane binding fail to activate AMPK and control mTOR signaling.
  • In vivo LKB1 function in Drosophila development requires membrane association.
  • LKB1 is downregulated in malignant melanoma with aberrant Akt activation and Phospholipase D overexpression.

Conclusions:

  • Membrane targeting via phosphatidic acid binding is a fundamental mechanism for LKB1 activation.
  • This mechanism is critical for LKB1's in vivo functions and implications in carcinogenesis.
  • Findings provide insights into LKB1 regulation and its role in cancer development.

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