PMID- 24616100
OWN - NLM
STAT- MEDLINE
DCOM- 20140604
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 16
DP  - 2014 Apr 18
TI  - Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/beta-catenin signaling through 
      blocking autophagic degradation of dishevelled2.
PG  - 11230-11241
LID - S0021-9258(20)48340-1 [pii]
LID - 10.1074/jbc.M113.544999 [doi]
AB  - 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/beta-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/beta-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.
FAU - Geng, Yongtao
AU  - Geng Y
AD  - 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.
FAU - Ju, Yanfang
AU  - Ju Y
AD  - the Department of Oncology, Chinese People's Liberation Army General Hospital, 
      Beijing 100853, China, and.
FAU - Ren, Fangli
AU  - Ren F
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, School of 
      Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua 
      University, Beijing 100084, China.
FAU - Qiu, Ying
AU  - Qiu Y
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, School of 
      Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua 
      University, Beijing 100084, China.
FAU - Tomita, Yasuhiko
AU  - Tomita Y
AD  - the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular 
      Diseases, Osaka 537-8511, Japan.
FAU - Tomoeda, Miki
AU  - Tomoeda M
AD  - the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular 
      Diseases, Osaka 537-8511, Japan.
FAU - Kishida, Mioka
AU  - Kishida M
AD  - the Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular 
      Diseases, Osaka 537-8511, Japan.
FAU - Wang, Yinyin
AU  - Wang Y
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, School of 
      Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua 
      University, Beijing 100084, China.
FAU - Jin, Lian
AU  - Jin L
AD  - School of Life Sciences, Peking University, Beijing 100871, China.
FAU - Su, Fuqin
AU  - Su F
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, School of 
      Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua 
      University, Beijing 100084, China.
FAU - Wei, Chunhong
AU  - Wei C
AD  - School of Life Sciences, Peking University, Beijing 100871, China.
FAU - Jia, Baoqing
AU  - Jia B
AD  - the Department of Oncology, Chinese People's Liberation Army General Hospital, 
      Beijing 100853, China, and.
FAU - Li, Yi
AU  - Li Y
AD  - School of Life Sciences, Peking University, Beijing 100871, China,. Electronic 
      address: liyi@pku.edu.cn.
FAU - Chang, Zhijie
AU  - Chang Z
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140310
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CCND1 protein, human)
RN  - 0 (DVL2 protein, human)
RN  - 0 (Dishevelled Proteins)
RN  - 0 (IRS1 protein, human)
RN  - 0 (IRS2 protein, human)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (MYC protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (SQSTM1 protein, human)
RN  - 0 (Sequestosome-1 Protein)
RN  - 0 (Transcription Factor 7-Like 2 Protein)
RN  - 0 (Wnt Proteins)
RN  - 0 (beta Catenin)
RN  - 136601-57-5 (Cyclin D1)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Autophagy/*physiology
MH  - Cell Proliferation
MH  - Cyclin D1/genetics/metabolism
MH  - Dishevelled Proteins
MH  - Epithelial-Mesenchymal Transition/*physiology
MH  - HEK293 Cells
MH  - Humans
MH  - Insulin Receptor Substrate Proteins/genetics/*metabolism
MH  - Multiprotein Complexes/genetics/metabolism
MH  - Phosphoproteins/genetics/*metabolism
MH  - Protein Stability
MH  - Proto-Oncogene Proteins c-myc/genetics/metabolism
MH  - Sequestosome-1 Protein
MH  - Transcription Factor 7-Like 2 Protein/genetics/metabolism
MH  - Ubiquitination/physiology
MH  - Wnt Proteins/genetics/metabolism
MH  - Wnt Signaling Pathway/*physiology
MH  - beta Catenin/genetics/metabolism
PMC - PMC4036261
OTO - NOTNLM
OT  - Autophagy
OT  - Cell Proliferation
OT  - Dishevelled2
OT  - EMT
OT  - IRS
OT  - Wnt Signaling
OT  - beta-Catenin
EDAT- 2014/03/13 06:00
MHDA- 2014/06/05 06:00
PMCR- 2015/04/18
CRDT- 2014/03/12 06:00
PHST- 2014/03/12 06:00 [entrez]
PHST- 2014/03/13 06:00 [pubmed]
PHST- 2014/06/05 06:00 [medline]
PHST- 2015/04/18 00:00 [pmc-release]
AID - S0021-9258(20)48340-1 [pii]
AID - M113.544999 [pii]
AID - 10.1074/jbc.M113.544999 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Apr 18;289(16):11230-11241. doi: 10.1074/jbc.M113.544999. Epub 
      2014 Mar 10.