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Automated Detection and Analysis of Exocytosis
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Automated Detection and Analysis of Exocytosis

Published on: September 11, 2021

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KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes

Andrew J McKenzie1, Daisuke Hoshino2, Nan Hyung Hong1

  • 1Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Cell Reports
|April 28, 2016
PubMed

Insights

Mutant KRAS disrupts Argonaute 2 (Ago2) secretion in exosomes, a key process in cell communication. Inhibiting MEK restores Ago2 exosome release, impacting microRNA levels.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Extracellular vesicles, including exosomes, mediate intercellular communication through RNA transfer.
  • Argonaute 2 (Ago2), a core component of the RNA-induced silencing complex (RISC), is implicated in microRNA (miRNA) secretion.
  • Aberrant KRAS signaling is common in colon cancer and may influence cellular communication pathways.

Purpose of the Study:

  • To investigate the role of KRAS mutation in regulating Ago2 secretion in exosomes.
  • To elucidate the molecular mechanisms by which KRAS affects Ago2 localization and exosomal release.
  • To determine the impact of Ago2 exosomal sorting on miRNA levels.

Main Methods:

  • Utilized isogenic colon cancer cell lines with and without KRAS mutations.
  • Employed techniques to assess Ago2 localization to multivesicular endosomes (MVEs) and its secretion in exosomes.
  • Investigated the effects of MEK and Akt inhibition on Ago2 trafficking and secretion.
  • Analyzed Ago2 phosphorylation status and its impact on MVE interaction using mutant Ago2 constructs.

Main Results:

  • Activating KRAS mutations inhibited Ago2 localization to MVEs and reduced its exosomal secretion.
  • Inhibition of MEK signaling, but not Akt, reversed the KRAS-mediated inhibition of Ago2-MVE association and exosomal secretion.
  • Phosphorylation of Ago2 at serine 387 was identified as a key event preventing MVE interaction and exosome release.
  • Regulation of Ago2 exosomal sorting influenced the levels of specific candidate miRNAs within exosomes.

Conclusions:

  • KRAS signaling, through MEK-dependent pathways, critically regulates Ago2 exosomal secretion in colon cancer cells.
  • Ago2 phosphorylation at S387 is a key determinant of its sorting into exosomes.
  • This pathway represents a novel mechanism controlling intercellular communication via miRNA-containing exosomes in cancer.
Keywords:
Argonauteexosomesextracellular RNAextracellular vesiclesmiRNAsignaling

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