KRAS Engages AGO2 to Enhance Cellular Transformation

Sunita Shankar; Sethuramasundaram Pitchiaya; Rohit Malik; Vishal Kothari; Yasuyuki Hosono; Anastasia K. Yocum; Harika Gundlapalli; Yasmine White; Ari Firestone; Xuhong Cao; Saravana M. Dhanasekaran; Jeanne A. Stuckey; Gideon Bollag; Kevin Shannon; Nils G. Walter; Chandan Kumar-Sinha; Arul M. Chinnaiyan

doi:10.1016/j.celrep.2016.01.034

Cell Reports (Feb 2016)

KRAS Engages AGO2 to Enhance Cellular Transformation

Sunita Shankar,
Sethuramasundaram Pitchiaya,
Rohit Malik,
Vishal Kothari,
Yasuyuki Hosono,
Anastasia K. Yocum,
Harika Gundlapalli,
Yasmine White,
Ari Firestone,
Xuhong Cao,
Saravana M. Dhanasekaran,
Jeanne A. Stuckey,
Gideon Bollag,
Kevin Shannon,
Nils G. Walter,
Chandan Kumar-Sinha,
Arul M. Chinnaiyan

Affiliations

Sunita Shankar: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Sethuramasundaram Pitchiaya: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Rohit Malik: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Vishal Kothari: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Yasuyuki Hosono: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Anastasia K. Yocum: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Harika Gundlapalli: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Yasmine White: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Ari Firestone: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Xuhong Cao: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Saravana M. Dhanasekaran: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Jeanne A. Stuckey: Life Science Institute, University of Michigan, Ann Arbor, MI 48109, USA
Gideon Bollag: Plexxikon Inc., Berkeley, CA 94710, USA
Kevin Shannon: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
Nils G. Walter: Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
Chandan Kumar-Sinha: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Arul M. Chinnaiyan: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA

DOI: https://doi.org/10.1016/j.celrep.2016.01.034
Journal volume & issue: Vol. 14, no. 6
pp. 1448 – 1461

Abstract

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Oncogenic mutations in RAS provide a compelling yet intractable therapeutic target. Using co-immunoprecipitation mass spectrometry, we uncovered an interaction between RAS and Argonaute 2 (AGO2). Endogenously, RAS and AGO2 co-sediment and co-localize in the endoplasmic reticulum. The AGO2 N-terminal domain directly binds the Switch II region of KRAS, agnostic of nucleotide (GDP/GTP) binding. Functionally, AGO2 knockdown attenuates cell proliferation in mutant KRAS-dependent cells and AGO2 overexpression enhances KRASG12V-mediated transformation. Using AGO2−/− cells, we demonstrate that the RAS-AGO2 interaction is required for maximal mutant KRAS expression and cellular transformation. Mechanistically, oncogenic KRAS attenuates AGO2-mediated gene silencing. Overall, the functional interaction with AGO2 extends KRAS function beyond its canonical role in signaling.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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