KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes

Cell Reports

Diana J. Cha¹  James G. Patton¹  Andrew J. McKenzie²  Nan Hyung Hong²  Alissa M. Weaver²  Robert J. Coffey³  Jeffrey L. Franklin³  Daisuke Hoshino⁴ 

[1] Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA;Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA;Division of Cancer Cell Research, Kanagawa Cancer Center, Yokohama 241-8515, Japan;

关键词: exosomes;    extracellular vesicles;    miRNA;    Argonaute;    extracellular RNA;    signaling;   

DOI  :  10.1016/j.celrep.2016.03.085

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown