KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes.

McKenzie AJ, Hoshino D, Hong NH, Cha DJ, Franklin JL, Coffey RJ, Patton JG, Weaver AM
Cell Rep. 2016 15 (5): 978-987

PMID: 27117408 · PMCID: PMC4857875 · DOI:10.1016/j.celrep.2016.03.085

Secretion of RNAs in extracellular vesicles is a newly recognized form of intercellular communication. A potential regulatory protein for microRNA (miRNA) secretion is the critical RNA-induced silencing complex (RISC) component Argonaute 2 (Ago2). Here, we use isogenic colon cancer cell lines to show that overactivity of KRAS due to mutation inhibits localization of Ago2 to multivesicular endosomes (MVEs) and decreases Ago2 secretion in exosomes. Mechanistically, inhibition of mitogen-activated protein kinase kinases (MEKs) I and II, but not Akt, reverses the effect of the activating KRAS mutation and leads to increased Ago2-MVE association and increased exosomal secretion of Ago2. Analysis of cells expressing mutant Ago2 constructs revealed that phosphorylation of Ago2 on serine 387 prevents Ago2-MVE interactions and reduces Ago2 secretion into exosomes. Furthermore, regulation of Ago2 exosomal sorting controls the levels of three candidate miRNAs in exosomes. These data identify a key regulatory signaling event that controls Ago2 secretion in exosomes.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (14)

Argonaute Proteins Cell Line, Tumor Exosomes Humans MicroRNAs Mitogen-Activated Protein Kinase Kinases Multivesicular Bodies Mutant Proteins Phosphorylation Phosphoserine Protein Transport Proto-Oncogene Proteins p21(ras) Signal Transduction Subcellular Fractions

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