Format

Send to

Choose Destination
Cell Rep. 2016 May 3;15(5):978-987. doi: 10.1016/j.celrep.2016.03.085. Epub 2016 Apr 21.

KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes.

Author information

1
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
2
Division of Cancer Cell Research, Kanagawa Cancer Center, Yokohama 241-8515, Japan.
3
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA.
4
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Veterans Affairs Medical Center, Nashville, TN 37232, USA.
5
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: alissa.weaver@vanderbilt.edu.

Abstract

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.

KEYWORDS:

Argonaute; exosomes; extracellular RNA; extracellular vesicles; miRNA; signaling

PMID:
27117408
PMCID:
PMC4857875
DOI:
10.1016/j.celrep.2016.03.085
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center