KRAS Engages AGO2 to Enhance Cellular Transformation

被引：34

作者：

Shankar, Sunita ^{[1
,2
]}

Pitchiaya, Sethuramasundaram ^{[1
,2
,3
]}

Malik, Rohit ^{[1
,2
]}

Kothari, Vishal ^{[1
,2
]}

Hosono, Yasuyuki ^{[1
,2
]}

Yocum, Anastasia K. ^{[1
,2
]}

Gundlapalli, Harika ^{[1
,2
]}

White, Yasmine ^{[4
,5
]}

Firestone, Ari ^{[4
,5
]}

Cao, Xuhong ^{[1
,6
]}

Dhanasekaran, Saravana M. ^{[1
,2
]}

Stuckey, Jeanne A. ^{[7
,8
]}

Bollag, Gideon ^{[9
]}

Shannon, Kevin ^{[4
,5
]}

Walter, Nils G. ^{[3
]}

Kumar-Sinha, Chandan ^{[1
,2
]}

Chinnaiyan, Arul M. ^{[1
,2
,6
,10
,11
]}

机构：

[1] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Chem, Single Mol Anal Grp, Ann Arbor, MI 48109 USA

[4] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[6] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA

[9] Plexxikon Inc, Berkeley, CA 94710 USA

[10] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA

[11] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA

来源：

CELL REPORTS | 2016年 / 14卷 / 06期

关键词：

HUMAN ARGONAUTE PROTEINS; RAS SIGNALING PATHWAYS; K-RAS; NUCLEOTIDE EXCHANGE; MICRORNA EXPRESSION; RNA INTERFERENCE; HYPERACTIVE RAS; SMALL MOLECULES; TARGETING RAS; ONCOGENIC RAS;

D O I：

10.1016/j.celrep.2016.01.034

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 KRASdependent 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.

引用

页码：1448 / 1461

页数：14

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