KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes
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 sho...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2016-05-01
|
Series: | Cell Reports |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716303874 |
id |
doaj-ba25df87581a4849b49879ca02acc089 |
---|---|
record_format |
Article |
spelling |
doaj-ba25df87581a4849b49879ca02acc0892020-11-25T01:02:28ZengElsevierCell Reports2211-12472016-05-0115597898710.1016/j.celrep.2016.03.085KRAS-MEK Signaling Controls Ago2 Sorting into ExosomesAndrew J. McKenzie0Daisuke Hoshino1Nan Hyung Hong2Diana J. Cha3Jeffrey L. Franklin4Robert J. Coffey5James G. Patton6Alissa M. Weaver7Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADivision of Cancer Cell Research, Kanagawa Cancer Center, Yokohama 241-8515, JapanDepartment of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USADepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USADepartment of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USASecretion 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.http://www.sciencedirect.com/science/article/pii/S2211124716303874exosomesextracellular vesiclesmiRNAArgonauteextracellular RNAsignaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrew J. McKenzie Daisuke Hoshino Nan Hyung Hong Diana J. Cha Jeffrey L. Franklin Robert J. Coffey James G. Patton Alissa M. Weaver |
spellingShingle |
Andrew J. McKenzie Daisuke Hoshino Nan Hyung Hong Diana J. Cha Jeffrey L. Franklin Robert J. Coffey James G. Patton Alissa M. Weaver KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes Cell Reports exosomes extracellular vesicles miRNA Argonaute extracellular RNA signaling |
author_facet |
Andrew J. McKenzie Daisuke Hoshino Nan Hyung Hong Diana J. Cha Jeffrey L. Franklin Robert J. Coffey James G. Patton Alissa M. Weaver |
author_sort |
Andrew J. McKenzie |
title |
KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes |
title_short |
KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes |
title_full |
KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes |
title_fullStr |
KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes |
title_full_unstemmed |
KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes |
title_sort |
kras-mek signaling controls ago2 sorting into exosomes |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2016-05-01 |
description |
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. |
topic |
exosomes extracellular vesicles miRNA Argonaute extracellular RNA signaling |
url |
http://www.sciencedirect.com/science/article/pii/S2211124716303874 |
work_keys_str_mv |
AT andrewjmckenzie krasmeksignalingcontrolsago2sortingintoexosomes AT daisukehoshino krasmeksignalingcontrolsago2sortingintoexosomes AT nanhyunghong krasmeksignalingcontrolsago2sortingintoexosomes AT dianajcha krasmeksignalingcontrolsago2sortingintoexosomes AT jeffreylfranklin krasmeksignalingcontrolsago2sortingintoexosomes AT robertjcoffey krasmeksignalingcontrolsago2sortingintoexosomes AT jamesgpatton krasmeksignalingcontrolsago2sortingintoexosomes AT alissamweaver krasmeksignalingcontrolsago2sortingintoexosomes |
_version_ |
1725204824105943040 |