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activation of wnt signaling by chemically induced dimerization of lrp5 disrupts cellular homeostasis激活wnt信号的化学诱导二聚lrp5破坏细胞内稳态
Activation of Wnt Signaling by Chemically Induced
Dimerization of LRP5 Disrupts Cellular Homeostasis
1. 1.¤ 2 1 1
Payam Shahi , Dongsu Park , Adam C. Pond , Mamatha Seethammagari , Shin-Heng Chiou ,
3 1 1 3 1
Kyucheol Cho , Julienne L. Carstens , William K. Decker , Pierre D. McCrea , Michael M. Ittmann ,
2 1
Jeffrey M. Rosen , David M. Spencer *
1 Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America, 2 Department of Molecular and Cellular Biology,
Baylor College of Medicine, Houston, Texas, United States of America, 3 Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer
Center, Houston, Texas, United States of America
Abstract
Wnt signaling is crucial for a variety of biological processes, including body axis formation, planar polarity, stem cell
maintenance and cellular differentiation. Therefore, targeted manipulation of Wnt signaling in vivo would be extremely
useful. By applying chemical inducer of dimerization (CID) technology, we were able to modify the Wnt co-receptor, low-
density lipoprotein (LDL)-receptor-related protein 5 (LRP5), to generate the synthetic ligand inducible Wnt switch, iLRP5. We
show that iLRP5 oligomerization results in its localization to disheveled-containing punctate structures and sequestration of
scaffold protein Axin, leading to robust b-catenin-mediated signaling. Moreover, we identify a novel LRP5 cytoplasmic
domain critical for its intracellular localization and casein k
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