In all life forms, cells must be able to perceive and correctly respond to their environment. In humans, dysregulation of cell signaling pathways can lead to many diseases including cancers. We aim to understand how cells sense their environment and transduce signals in cells under normal and pathologic conditions, using a combination of structural (X-ray crystallographic and cryo-EM) and biochemical studies. Our work helps to lay the foundation for developing novel therapeutic approaches for disease treatment.
In particular, we are interested in molecular mechanisms of the Wnt/Norrin signaling pathway, which plays a critical role in embryonic development, stem cell homeostasis and tumorigenesis. In this pathway, we aim to understand: (1) how porcupine, a membrane-bound O-acyltransferase (MBOAT), catalyzes essential palmitoylation of Wnt proteins; (2) how Wnt/Norrin signals are sensed and integrated on the membrane by Wnt receptor/coreceptor and regulators, such as Frizzled and LRP5/6; (3) how Wnt/Norrin-receptor interactions promote turnover of cytosolic beta-catenin; and (4) how nuclear beta-catenin activates transcription of Wnt target genes, and how we may develop Wnt pathway inhibitors for potential therapeutic uses.
In addition to Wnt signaling, we investigate molecular mechanisms of cell regulation by protein phosphorylation, polyubiquitination and poly(ADP-ribosyl)ation (PARylation). We are working on structural analysis of CIP2A and PP2A complexes, and development of PP2A agonists that may be useful for cancer treatment. We are also developing a novel inducible protein knockout system using RNF146/iso-ADPr as the template, which may become a powerful tool for biomedical research.
Publications [from PubMed]
- Ma D, Wang Z, Merrikh CN, Lang KS, Lu P, Li X, Merrikh H, Rao Z, Xu WNature. 2018 Oct; 562 7726: 286-290
- Identification of ICAT as an APC Inhibitor, Revealing Wnt-Dependent Inhibition of APC-Axin Interaction.Ji L, Lu B, Wang Z, Yang Z, Reece-Hoyes J, Russ C, Xu W, Cong FMolecular cell. 2018 Oct; 72 1: 37-47.e4
- Lu P, Min D, DiMaio F, Wei KY, Vahey MD, Boyken SE, Chen Z, Fallas JA, Ueda G, Sheffler W, Mulligan VK, Xu W, Bowie JU, Baker DScience (New York, N.Y.). 2018 03; 359 6379: 1042-1046
- Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome.Sun W, Kuang XL, Liu YP, Tian LF, Yan XX, Xu WScientific reports. 2017 Nov; 7 1: 15638
- The SIAH E3 ubiquitin ligases promote Wnt/β-catenin signaling through mediating Wnt-induced Axin degradation.Ji L, Jiang B, Jiang X, Charlat O, Chen A, Mickanin C, Bauer A, Xu W, Yan X, Cong FGenes & development. 2017 05; 31 9: 904-915
- Wang J, Okkeri J, Pavic K, Wang Z, Kauko O, Halonen T, Sarek G, Ojala PM, Rao Z, Xu W, Westermarck JEMBO reports. 2017 03; 18 3: 437-450
- Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7).Qin J, Wang Z, Hoogeveen-Westerveld M, Shen G, Gong W, Nellist M, Xu WThe Journal of biological chemistry. 2016 Apr; 291 16: 8591-601
- Shen G, Ke J, Wang Z, Cheng Z, Gu X, Wei Y, Melcher K, Xu HE, Xu WCell research. 2015 Sep; 25 9: 1078-81
- DaRosa PA, Wang Z, Jiang X, Pruneda JN, Cong F, Klevit RE, Xu WNature. 2015 Jan; 517 7533: 223-6
- Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.Sun W, Zhu YJ, Wang Z, Zhong Q, Gao F, Lou J, Gong W, Xu WNature communications. 2013 ; 4 : 2135