title: Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/β-catenin signaling through blocking autophagic degradation of dishevelled2.
abstract: Wnt signaling plays a pivotal role in cell proliferation, tissue homeostasis, and tumorigenesis. Dishevelled (Dvl) is a central node of Wnt signaling. Insulin receptor substrates (IRSs), as a critical component of insulin signaling, are involved in cell proliferation, metabolism, and cancer development. In this study, we report that IRS1/2 promotes Wnt/β-catenin signaling by stabilizing Dvl2. We found that IRS1/2 interacts with Dvl2. Overexpression of IRS1/2 increased the protein level of Dvl2 and promoted canonical Wnt signaling, as evidenced by the increased T cell-specific factor 4 transcriptional activity and the up-regulation of expression of CYCLIN D1 and c-MYC, two Wnt target genes critical for cell growth, whereas depletion of IRS1/2 reduced the level of Dvl2 and attenuated Wnt/β-catenin signaling. Biochemical analyses revealed that IRS1/2 decreased Lys-63-linked ubiquitination of Dvl2 and stabilized Dvl2 protein via suppressing its autophagy-mediated degradation. We further revealed that IRS1/2 blocks autophagy-induced formation of the Dvl2-p62/SQSTM1 complex, resulting in disabled association of Dvl2 to autophagosomes. We demonstrated that IRS1/2 promoted the induction of epithelial-mesenchymal transition (EMT) and cell proliferation in response to Wnt stimulation, whereas depletion of Dvl2 impaired the IRS1/2-mediated EMT and cell growth. Our findings revealed that IRS1/2 promotes EMT and cell proliferation through stabilizing Dvl2.
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China,; State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Geng
authors.affiliation: the Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, China, and.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Fangli
authors.initials: F
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tomoeda
authors.affiliation: the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
authors.forename: Mioka
authors.initials: M
authors.lastname: Kishida
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Fuqin
authors.initials: F
authors.lastname: Su
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Wei
authors.affiliation: the Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, China, and.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Jia
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China,. Electronic address: liyi@pku.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China,. Electronic address: zhijiec@tsinghua.edu.cn.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D000072261:Dishevelled Proteins; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C530104:CCND1 protein, human; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; C489427:MYC protein, human; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1
keywords: Autophagy; Cell Proliferation; Dishevelled2; EMT; IRS; Wnt Signaling; β-Catenin