title: RIG-I modulates Src-mediated AKT activation to restrain leukemic stemness.
abstract: Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: Xian-Yang
authors.initials: XY
authors.lastname: Li
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: Lin-Jia
authors.initials: LJ
authors.lastname: Jiang
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: Meng-Lei
authors.initials: ML
authors.lastname: Ding
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: He-Zhou
authors.initials: HZ
authors.lastname: Guo
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China.
authors.forename: Hong-Xin
authors.initials: HX
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Ma
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Xiang-Zhen
authors.initials: XZ
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Xi
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, People's Republic of China; Shanghai E-Institute for Model Organisms, Shanghai 200025, People's Republic of China. Electronic address: zhujiang@shsmu.edu.cn.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D011971:Receptors, Immunologic; C546842:MTOR protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases