NewBnrBlue

[Home]
[Denis Baskin]
[Olivia Bermingham-McDonogh]
[James Brinkley]
[Margaret Byers]
[John Clark]
[Daniel Cook]
[Dennis Dacey]
[Ajay Dhaka]
[Anita Hendrickson]
[Wim Hol]
[Weiqing Li]
[Andy Farr]
[Anitha Pasupathy]
[Dave Raible]
[Thomas Reh]
[Farrel Robinson]
[Ronald Stenkamp]
[Helen  Sherk]
[Wang]
[Rachel Wong]
[Wenqing Xu]
[Zipora Yablonka-Reuveni]

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 during 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 biology and cancer biology. In addition, we are investigating molecular mechanisms of cell regulation by protein phosphorylation and poly-ADP-ribosylation (PARylation). We are also developing small molecule antagonists and/or agonists of protein complexes and enzyme systems, which may be useful for treatment of cancer, osteoporosis and other diseases.

Wnt signaling pathway

The canonical Wnt/beta-catenin signaling pathway plays critical roles in embryonic development, stem cell/tissue regeneration and tumorigenesis. Central to the pathway is the turnover of beta-catenin, a protein that functions in both cell adhesion and gene transcription. In the absence of a Wnt signal, free cytosolic beta-catenin is phopshorylated by a large protein complex called the "beta-catenin destruction complex" that labels beta-catenin for degradation by an ubiquitin ligase/proteasome system. In the presence of a Wnt signal, the binding of Wnt to its receptors leads to beta-catenin phosphorylation in the beta-catenin destruction complex. Inhibition of the beta-catenin destruction complex results in the accumulation of nuclear beta-catenin, which is essential for the transcriptional activation of Wnt target genes.

Using a combination of biophysical and molecular biology tools including X-ray crystallography, our laboratory is working on: (1) how Wnt signals are processed and integrated near membrane by Wnt receptor/coreceptor and regulators, such as LRP5/6 and DKK; (2) structural and mechanistic analysis of the beta-catenin destruction complex, the central regulatory complex in the Wnt/beta-catenin pathway, in particular the mechanism of its inhibition by Wnt signals; (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 the design of Wnt pathway inhibitors for cancer treatment. In addition to the canonical Wnt/beta-catenin pathway, we have also started working on the molecular mechanisms of non-canonical Wnt signaling pathways. 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.

PP2A and PP2A complexes

Reversible protein Ser/Thr phosphorylation is a fundamental mechanism for cell regulation. While more than 400 Ser/Thr kinases have been identified in the human genome, there are only a few catalytic subunits for Ser/Thr phosphatases. In contrast to the previous assumption that phosphatases are constitutively active , recent work has shown that many phosphatases are highly regulated. One of the main regulatory mechanisms is the formation of specific complexes between the Ser/Thr phosphatase catalytic subunits and different regulatory or targeting subunits. We focus on the structural analysis of protein phosphatase 2A (PP2A), a major human phosphatase that regulates many, if not most, aspects of cellular activities and is a critical tumor suppressor. Deregulation of PP2A is associated with breast, lung, and colorectal cancers as well as Alzheimer's Disease. We aim to provide the structural basis for understanding the assembly and regulation of PP2A complexes, through structural determination by X-ray crystallography and related biochemical analysis. Our study will be important not only for understanding the regulation of protein Ser/Thr dephosphorylation, but also for designing PP2A activators that either stabilize functional PP2A assembly or disrupt PP2A-inhibitory protein interactions. Such compounds can be useful for cancer treatment.

Protein PARylation and PARylation-dependent ubiquitination

Protein ubiquitination regulates diverse biological processes. However, the mechanism by which proteins are earmarked for ubiquitination remains incompletely understood. Other than phosphorylation that is a general mechanism for many cases, hydroxylation of a substrate (i.e. HIF1-alpha) and the binding of small molecules (e.g. the plant hormones auxin) to E3 ligases have been shown to control protein ubiquitination in sporadic cases. Protein poly(ADP-ribosyl)ation (PARylation), catalyzed by PAR polymerases (PARPs), also regulates a myriad of biological processes, including DNA damage responses, transcriptional regulation, intracellular trafficking, energy metabolism, circadian rhythm, cell survival and cell-death programs, among others. How PARylation affects so many biological functions remains largely mysterious. Most recently, PARylation has been shown to control the polyubiquitination and degradation of Axin, a key regulator of the Wnt signaling pathway.  We are interested in understanding whether protein PARylation is a general signal for subsequent ubiquitination and if this is true, how this may happen and how this process may be regulated in the cell.

In addition to the general signaling mechanism, we are particularly interested in the turnover of Axin and Axin2, the key negative regulator of the Wnt signaling pathway, which are also attractive therapeutic targets for cancers and brain damages.

Selected  publications

Wang, Z, Michaud, G.A., Cheng, Z., Zhang, Y., Hinds, T.R. Fan, E., Cong, F., Xu, W.   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, in press.

Morrone, S., Cheng, Z., Moon, R.T., Cong, F., Xu, W.   Crystal structure of a Tankyrase-Axin complex and its implications for Axin turnover and Tankyrase substrate recruitment. PNAS, in press.

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. (2008). 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.

Liu, J., Xing, Y., Hinds, T.R., Zheng. J., Xu, W. (2006). The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin. Journal of Molecular Biology. 360, 133-144.

Cho, U., Bader, M., Amaya, M. F., Delay, M. E., Klevit, K., Miller, S., and Xu, W. (2006). Metal Bridges between the PhoQ Sensor Domain and the Membrane Regulate Transmembrane Signaling. Journal of Molecular Biology. 356, 1193-1206.

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., Liu, D., Zhang, R., Joachimiak, A., Songyang, Z. and Xu, W. (2004). Structural basis of membrane targeting by the phox homology domain of cytokine-independent survival kinase (CISK-PX). Journal of Biological Chemistry. 279, 30662-30669.

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.

 

Terms and Conditions of Use for university websites: http://www.washington.edu/online/terms/   Online Privacy Statement:  http://www.washington.edu/online/privacy/