Protein-Tyrosine Phosphatase Sigma Is Associated with Ulcerative Colitis

Aleixo M. Muise, Thomas Walters, Eytan Wine, Anne M. Griffiths, Dan Turner, Richard H. Duerr, Miguel D. Regueiro, Bo Yee Ngan, Wei Xu, Philip M. Sherman, Mark S. Silverberg, Daniela Rotin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Inflammatory bowel disease (IBD), a relatively common chronic debilitating intestinal illness, is composed of two broadly defined groups, Crohn's disease (CD) and ulcerative colitis (UC). Although several susceptibility genes for CD have been recently described, susceptibility genes exclusive for UC have not been forthcoming. Here, we show that receptor protein-tyrosine phosphatase sigma (PTPRS-encoding PTPσ) knockout mice spontaneously develop mild colitis that becomes severe when challenged with two known inducers of colitis. We also demonstrate that E-cadherin and β-catenin, two important adherens junction proteins involved in maintenance of barrier defense in the colon, act as colonic substrates for PTPσ. Furthermore, we show that three SNPs (rs886936, rs17130, and rs8100586) that flank exon 8 in the human PTPRS gene are associated with UC. The presence of these SNPs is associated with novel splicing that removes the third immunoglobulin-like domain (exon 9) from the extracellular portion of PTPσ, possibly altering dimerization or ligand recognition. We propose that polymorphisms in the human PTPRS gene lead to ulcerative colitis.

Original languageAmerican English
Pages (from-to)1212-1218
Number of pages7
JournalCurrent Biology
Volume17
Issue number14
DOIs
StatePublished - 17 Jul 2007
Externally publishedYes

Bibliographical note

Funding Information:
Thanks to Joanne Stempak, Chen Lu, and Angela Griffin for technical support. This work was supported by the Canadian Institute of Health Research (CIHR) to D.R., the Crohn's Colitis Foundation of Canada (CCFC) to A.M.G. and D.R., and a Thrasher Research Fund New Investigators Grant to A.M.M. A.M.M. is supported by a fellowship from the Canadian Child Health Clinician Scientist Program (Strategic Training Initiatives in Health Research Program—CIHR). T.W., E.W., and D.T. are supported by fellowships from the Canadian Gastroenterology Association/CIHR (E.W., Astra-Zeneca Partnered; T.W. and D.T., CCFC Partnered). A.M.M., E.W., and D.T. are supported by Post-Graduate Medical Education Awards, Faculty of Medicine, University of Toronto. D.R. and P.M.S. hold a Canada Research Chair (Tier I) from the CFI/CIHR.

Keywords

  • CELLIMMUNO
  • HUMDISEASE
  • SIGNALING

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