We aim to understand how cells sense environment and transduce signals in cells under normal and pathologic conditions, using a combination of structural and biochemical studies. In particular, we are interested in molecular mechanisms of the Wnt/Norrin signaling pathway and its role in development, stem cell and cancer biology. In addition, we are investigating molecular mechanisms of cell regulation by protein poly(ADP-ribosyl)ation (PARylation) and phosphorylation. We are also designing proteins with novel functions and small-molecule antagonists/agonists that may be useful for regenerative medicine and cancer treatment.
The canonical Wnt/beta-catenin signaling pathway plays critical roles in embryonic development, stem cell/tissue regeneration and tumorigenesis. In addition to Wnt proteins, this pathway can also be activated by Norrin, a secreted retinal growth factor with angiogenic and neuroprotective properties. Norrin mutations are associated with the Norrie disease, familiar exudative vitreoretinopathy (FEVR), retinopathy of prematurity (ROP), and other retinal hypovascularization diseases. Despite its distinct structure from Wnt proteins, Norrin binds specifically to Frizzled 4 (Fz4), a Wnt receptor, and Lrp5/6, a Wnt co-receptor, and activates the canonical Wnt/beta-catenin signaling pathway inside the cell. Using a combination of biophysical and molecular biology tools including X-ray crystallography, we aim to understand how Wnt/Norrin signals are sensed and integrated on membrane by Wnt receptor/coreceptor and regulators, such as Frizzled and LRP5/6. Our study will be important not only for understanding the mechanism of Wnt signaling, but also for developing novel tools to intervene with Wnt/Norrin signaling that may be useful for the treatment of multiple diseases (e.g. retinal hypovascularization diseases) and manipulation of stem cells.
Protein PARylation regulates a myriad of biological processes, including DNA damage responses, transcriptional regulation and cell-death programs. Most recently, PARylation has been shown to control the polyubiquitination and degradation of Axin, a key regulator of the Wnt signaling pathway, among other substrates. We strive to reveal how PARylation is coupled to ubiquitination by the ubiquitin E3 ligase RNF146, how the PARylation-dependent ubiquitination (PARdU) specificity is achieved, how PARdU is regulated, and how PARdU controls various biological processes, including Wnt signaling. Furthermore, we are developing a novel inducible protein knockout system using RNF146/iso-ADPr as the template.
In addition to the above directions, we are also working on structural analysis of CIP2A and PP2A complexes, and development of PP2A agonists that may be useful for cancer treatment.
Publications [from PubMed]
- 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
- MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.Cheng TL, Wang Z, Liao Q, Zhu Y, Zhou WH, Xu W, Qiu ZDevelopmental cell. 2014 Mar; 28 5: 547-60
- 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
- Crystal structure of a Tankyrase-Axin complex and its implications for Axin turnover and Tankyrase substrate recruitment.Morrone S, Cheng Z, Moon RT, Cong F, Xu WProceedings of the National Academy of Sciences of the United States of America. 2012 Jan; 109 5: 1500-5
- Recognition of the iso-ADP-ribose moiety in poly(ADP-ribose) by WWE domains suggests a general mechanism for poly(ADP-ribosyl)ation-dependent ubiquitination.Wang Z, Michaud GA, Cheng Z, Zhang Y, Hinds TR, Fan E, Cong F, Xu WGenes & development. 2012 Feb; 26 3: 235-40
- Cheng Z, Biechele T, Wei Z, Morrone S, Moon RT, Wang L, Xu WNature structural & molecular biology. 2011 Oct; 18 11: 1204-10
- Xu Z, Cetin B, Anger M, Cho US, Helmhart W, Nasmyth K, Xu WMolecular cell. 2009 Aug; 35 4: 426-41
- Cho US, Morrone S, Sablina AA, Arroyo JD, Hahn WC, Xu WPLoS biology. 2007 Aug; 5 8: e202
- Cho US, Xu WNature. 2007 Jan; 445 7123: 53-7