Xu, Wenqing, Ph.D.
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.
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.