GABARAPL1 negatively regulates Wnt/β-catenin signaling by mediating Dvl2 degradation through the autophagy pathway

Yanquan Zhang; Fang Wang; Liang Han; Yinyuan Wu; Shan Li; Xi Yang; Yinyin Wang; Fangli Ren; Yonggong Zhai; Dianjun Wang; Baoqing Jia; Yongjing Xia; Zhijie Chang

doi:10.1159/000329952

GABARAPL1 negatively regulates Wnt/β-catenin signaling by mediating Dvl2 degradation through the autophagy pathway

Cell Physiol Biochem. 2011;27(5):503-12. doi: 10.1159/000329952. Epub 2011 Jun 15.

Authors

Yanquan Zhang¹, Fang Wang, Liang Han, Yinyuan Wu, Shan Li, Xi Yang, Yinyin Wang, Fangli Ren, Yonggong Zhai, Dianjun Wang, Baoqing Jia, Yongjing Xia, Zhijie Chang

Affiliation

¹ State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, R.P. China.

PMID: 21691068
DOI: 10.1159/000329952

Abstract

Wnt signaling is critical for many biological processes and is tightly regulated. In this study, we found that GABARAPL1 (GABA(A) receptor-associated protein like 1, GABARAPL1) interacts with Dvl2 by both yeast two-hybrid screening and immunoprecipitation experiments. Furthermore, we observed that p62 is required for the interaction of Dvl2 and GABARAPL1. Luciferase assays indicated that GABARAPL1 represses Wnt/β-catenin signaling stimulated by Wnt1, Dvl2 and β-catenin. We further demonstrated that GABARAPL1 mediates degradation of Dvl2 and the effect is blocked by addition of 3-MA, a specific inhibitor of autophagy. Finally, we provided evidence that over-expression of GABARAPL1 inhibits proliferation and tumor growth of MCF7 cells in vitro and in nude mice. Taken together, our results suggested that GABARAPL1 as a tumor repressor inhibits Wnt signaling via mediating Dvl2 degradation through the autophagy pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Autophagy*
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation
Cloning, Molecular
Dishevelled Proteins
Female
Gene Expression
HEK293 Cells
Humans
Immunoprecipitation
Luciferases / analysis
Mice
Mice, Nude
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / metabolism*
Neoplasm Transplantation
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Plasmids
Protein Binding
Signal Transduction*
Transfection
Two-Hybrid System Techniques
Up-Regulation
Uterine Cervical Neoplasms / metabolism*
Uterine Cervical Neoplasms / pathology
Wnt1 Protein / antagonists & inhibitors
Wnt1 Protein / genetics
Wnt1 Protein / metabolism*
beta Catenin / antagonists & inhibitors
beta Catenin / genetics
beta Catenin / metabolism*

Substances

Adaptor Proteins, Signal Transducing
DVL2 protein, human
Dishevelled Proteins
Dvl2 protein, mouse
Gabarapl1 protein, mouse
Microtubule-Associated Proteins
Phosphoproteins
WNT1 protein, human
Wnt1 Protein
beta Catenin
Luciferases