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 Xu, Wenqing, Ph.D.
Associate Professor
K-452a
(206) 221-5609
wxu@u.washington.edu
Dr. Xu's lab website
Research Interests
Wnt signaling pathway
The canonical Wnt/-catenin signaling pathway plays critical roles in embryonic development, stem cell
regulation and tumorigenesis. Central to the pathway is the turnover of -catenin, a protein that functions
in both cell adhesion and transcription. In the absence of a Wnt signal, free cytosolic -catenin is
phopshorylated by a large protein complex called the "-catenin destruction complex" that labels -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 -catenin phosphorylation in the -catenin destruction complex through an
unknown mechanism. Inhibition of the -catenin destruction complex results in the accumulation of nuclear
-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, my laboratory is working on: (1)
structural analysis of the transcriptional assembly nucleated by the -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; (2) structural and mechanistic analysis of the -catenin destruction
complex, the central regulatory complex in the Wnt/-catenin pathway. Our study will be important not only
for understanding the mechanism of Wnt signaling, but also for developing tools to intervene with the
canonical Wnt signaling that may be useful for the treatment of multiple diseases and manipulation of stem cells.
For more information about the Wnt pathway, please visit:
http://www.stanford.edu/~rnusse/wntwindow.html
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 and susceptibility to viral and parasitic infection. A typical PP2A holoenzyme
contains a scaffold A subunit, a catalytic C subunit and one of many regulatory B subunits, which are
divided into B, B' and B" families. Despite the functional importance, it is still largely unknown how PP2A
forms a functional complex and how the complex assembly is regulated. We aim to provide the structural
basis for understanding the assembly and regulation of PP2A heterotrimeric 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.
Selected publications
Xing, Y., Takemaru, K.I., Liu, J., Jason D. Berndt, J.D., Zheng, J., Moon, R.T. and Xu, W. Crystal
structure of a full-length -catenin. Structure, in press.
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 (Article), 445, 53-57.
Sampietro, S., Dahlberg, C.L., Cho, U.S., Hinds, T.R., Kimelman, D., and Xu, W. (2006). Crystal Structure
of a -catenin/BCL9/Tcf4 Complex. Molecular Cell, 24, 293-300.
Kimelman, D., and Xu, W. (2006). The -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 -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 -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 -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 -catenin/Tcf complex
. Cell, 103, 885-896.
Xu, W., Doshi, A., Lei, M., Eck, M. J., and Harrison, S. C. (1999). Crystal structures of c-Src reveal
features of its autoinhibitory mechanism. Molecular Cell 3, 629-638.
Xu, W., Harrison, S. C., and Eck, M. J. (1997). Three-dimensional structure of the tyrosine kinase c-Src. Nature 385, 595-602.
Xu, W., Rould, M. A., Jun, S., Desplan, C., and Pabo, C. O. (1995). Crystal structure of a paired domain
-DNA complex at 2.5Å resolution reveals structural basis for Pax developmental mutations. Cell 80, 639-650.
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