Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/β-catenin signaling through blocking autophagic degradation of dishevelled2
- J Biol Chem. 2014 Apr 18;289(16):11230-11241. doi: 10.1074/jbc.M113.544999.
- 1. 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.
- 2. the Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, China, and.
- 3. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
- 4. the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
- 5. School of Life Sciences, Peking University, Beijing 100871, China.
- 6. School of Life Sciences, Peking University, Beijing 100871, China,. Electronic address: [email protected].
- 7. 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: [email protected].
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.