title: KRAS Engages AGO2 to Enhance Cellular Transformation.
abstract: 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 KRAS(G12V)-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.
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Sunita
authors: S
authors: Shankar
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Sethuramasundaram
authors: S
authors: Pitchiaya
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Rohit
authors: R
authors: Malik
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Vishal
authors: V
authors: Kothari
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Yasuyuki
authors: Y
authors: Hosono
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Anastasia K
authors: AK
authors: Yocum
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Harika
authors: H
authors: Gundlapalli
authors: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Yasmine
authors: Y
authors: White
authors: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Ari
authors: A
authors: Firestone
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Xuhong
authors: X
authors: Cao
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Saravana M
authors: SM
authors: Dhanasekaran
authors: Life Science Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Jeanne A
authors: JA
authors: Stuckey
authors: Plexxikon Inc., Berkeley, CA 94710, USA.
authors: Gideon
authors: G
authors: Bollag
authors: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Kevin
authors: K
authors: Shannon
authors: Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Nils G
authors: NG
authors: Walter
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Chandan
authors: C
authors: Kumar-Sinha
authors: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: arul@umich.edu.
authors: Arul M
authors: AM
authors: Chinnaiyan
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C117307:KRAS protein, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D002268:Carboxypeptidases; C436327:SCPEP1 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Argonaute 2; EIF2C2; KRAS; RNA silencing; cancer