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XulargeXu, Wenqing, Ph.D.
Professor

K-452a
(206) 221-5609
wxu@u.washington.edu

 

 

 

Research Interests

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 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-ribosylation (PARylation) and other posttranslational modifications. We are also designing proteins with novel functions and small molecule antagonists and 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. Using a combination of biophysical and molecular biology tools including X-ray crystallography, we aim to understand: (1) how Wnt signals are sensed and integrated on membrane by Wnt receptor/coreceptor and regulators, such as Frizzled and LRP5/6; (2) structural and mechanistic analysis of the beta-catenin destruction complex, the central regulatory complex in the Wnt/beta-catenin pathway; (3) structural analysis of the transcriptional assembly nucleated by the beta -catenin/Tcf complex. This assembly controls the transcription of Wnt-target genes and is a critical target for designing Wnt pathway inhibitors. Our study will be important not only for understanding the mechanism of Wnt signaling, but also for developing tools to intervene with Wnt signaling that may be useful for the treatment of multiple diseases and manipulation of stem cells.

Protein ubiquitination regulates diverse biological processes. In many cases, proteins are earmarked for ubiquitination via their phosphorylation. Most recently, PARylation has been shown to control the polyubiquitination and degradation of a number of cell regulators, including Axin, a key regulator of the Wnt signaling pathway. Protein PARylation, catalyzed by PAR polymerases (PARPs), regulates a myriad of biological processes, including DNA damage responses, transcriptional regulation, energy metabolism, circadian rhythm, cell survival and cell-death programs. We strive to reveal how PARylation is coupled to ubiquitination by a specific 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. 

In addition to the above directions, we are also working on: (1) structural analysis of PP2A and PP2A complexes, and development of PP2A agonists that may be useful for cancer treatment; (2) structural and functional analysis of the TSC1-TSC2 complex; and (3) development of an inducible protein knockout system.

Selected publications

Cheng, T., Wang, Z., Liao, Q., Zhu, Y., Xu, W., Qiu, Z.  (2014). MeCP2 suppresses microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.  Developmental Cell. 28, 547-560.

Sun, W., Zhu, Y., Wang, Z., Zhong, Q., Gao, F., Lou, J., Gong, W., Xu, W. (2013). Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathogenic mutations. Nature Communications, 4, 2135.

Wang, Z, Michaud, G.A., Cheng, Z., Zhang, Y., Hinds, T.R. Fan, E., Cong, F., Xu, W. (2012).  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.  Genes & Development, 26, 235-240.

Morrone, S., Cheng, Z., Moon, R.T., Cong, F., Xu, W.  (2012). Crystal structure of a Tankyrase-Axin complex and its implications for Axin turnover and Tankyrase substrate recruitment.  PNAS, 109, 1500-1505.

Cheng, Z., Biechele, T., Wei, Z., Morrone, S., Moon, R.T., Wang, L., Xu, W. (2011). Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nature Structural & Molecular Biology, 18, 1204-1210.

Xu, Z., Cetin, B., Anger, M., Cho, U., Helmhart, W., Nasmyth, K. and Xu, W. (2009). Structure and function of the PP2A-shugoshin interaction. Molecular Cell, 35, 426-441.

Liu, J., Philips, B., Amaya, M., Kimble, J., and Xu , W. (2008). The C. elegans SYS-1 protein is a bona fide beta-catenin. Developmental Cell, 14, 751-761.

Xing, Y.,  Takemaru, K.I., Liu, J., Jason D. Berndt, J.D., Zheng, J., Moon, R.T. and Xu, W. (2007).  Crystal structure of a full-length beta-catenin. Structure, 16, 478-487.

Cho, U., Morrone, S., Sablina, A.A., Arroyo, J.D., Hahn, W.C. and Xu, W. (2007). Structural basis of PP2A inhibition by small t antigen. PLoS Biology 5, 1810-1819.

Cho, U., and Xu, W. (2007). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature , 445, 53-57 (Article).

Sampietro, S., Dahlberg, C.L., Cho, U.S., Hinds, T.R., Kimelman, D., and Xu, W. (2006). Crystal Structure of a beta-catenin/BCL9/Tcf4 Complex. Molecular Cell, 24, 293-300.

Kimelman, D., and Xu, W. (2006). The beta-catenin destruction complex: insights and questions from a structural perspective (review). Oncogene, 25, 7482-7491.

Zhu, Y., Huang, W., Lee, S.K. and Xu, W. (2005). Crystal structure of a polyphosphate kinase and its implications for polyphosphate synthesis. EMBO Reports, 6, 681-687.

Bader, M. W., Sanowar, S., Daley, M. E., Schneider, A. R., Cho, U., Xu, W., Klevit, R. E., Le Moual, H., Miller, S. I. (2005). Recognition of Antimicrobial Peptides by a Bacterial Sensor Kinase. Cell, 122, 461-472.

Xing, Y., Clements, W.K., Le Trong, I., Hinds, T.R., Stenkamp, R., Kimelman, D. and Xu, W. (2004). Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. Molecular Cell . 15, 523-533. (cover story)

Xing, Y., Clements, W., Kimelman, D. and Xu, W.  (2003). Crystal structure of a beta-catenin/Axin complex suggests a mechanism for the beta-catenin destruction complex. Genes & Development, 17, 2753-2764. (cover story)

Graham, T., Clements, W., Kimelman, D., Xu, W. (2002). Crystal structure of the beta-catenin/ICAT complex reveals a inhibitory mechanism of Wnt signaling pathway. Molecular Cell, 10, 563-571.

Graham, T., Ferkey, D. M., Mao, F., Kimelman, D., Xu, W. (2001). Structure basis of beta-catenin/Tcf-4 interactions. Nature Structure Biology , 8, 1048-1052.

Graham, T., Weaver, C., Mao, F., Kimelman, D., Xu, W. (2000). Crystal structure of a beta-catenin/Tcf complex .  Cell , 103, 885-896.

 

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