PMID- 28804910
OWN - NLM
STAT- MEDLINE
DCOM- 20171019
LR  - 20181113
IS  - 1749-6632 (Electronic)
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 1405
IP  - 1
DP  - 2017 Oct
TI  - T cell protein tyrosine phosphatase prevents STAT1 induction of claudin-2 
      expression in intestinal epithelial cells.
PG  - 116-130
LID - 10.1111/nyas.13439 [doi]
AB  - T cell protein tyrosine phosphatase (TCPTP) dephosphorylates a number of 
      substrates, including JAK-STAT (signal transducer and activator of transcription) 
      signaling proteins, which are activated by interferon (IFN)-gamma, a major 
      proinflammatory cytokine involved in conditions such as inflammatory bowel 
      disease. A critical function of the intestinal epithelium is formation of a 
      selective barrier to luminal contents. The structural units of the epithelium 
      that regulate barrier function are the tight junctions (TJs), and the protein 
      composition of the TJ determines the tightness of the barrier. Claudin-2 is a TJ 
      protein that increases permeability to cations and reduces transepithelial 
      electrical resistance (TER). We previously showed that transient knockdown (KD) 
      of TCPTP permits increased expression of claudin-2 by IFN-gamma. Here, we demonstrate 
      that the decreased TER in TCPTP-deficient epithelial cells is alleviated by STAT1 
      KD. Moreover, increased claudin-2 in TCPTP-deficient cells requires enhanced 
      STAT1 activation and STAT1 binding to the CLDN2 promoter. We also show that 
      mutation of this STAT-binding site prevents elevated CLDN2 promoter activity in 
      TCPTP-deficient epithelial cells. In summary, we demonstrate that TCPTP protects 
      the intestinal epithelial barrier by restricting STAT-induced claudin-2 
      expression. This is a potential mechanism by which loss-of-function mutations in 
      the gene encoding TCPTP may contribute to barrier defects in chronic intestinal 
      inflammatory disease.
CI  - (c) 2017 New York Academy of Sciences.
FAU - Krishnan, Moorthy
AU  - Krishnan M
AD  - Division of Biomedical Sciences, University of California, Riverside, California.
FAU - McCole, Declan F
AU  - McCole DF
AUID- ORCID: 0000-0002-6286-0802
AD  - Division of Biomedical Sciences, University of California, Riverside, California.
LA  - eng
GR  - R01 DK091281/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170814
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (Claudin-2)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 2)
SB  - IM
MH  - Cell Line
MH  - Claudin-2/genetics/*metabolism
MH  - Epithelial Cells/cytology/metabolism
MH  - Humans
MH  - Intestinal Mucosa/cytology/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics/*metabolism
MH  - STAT1 Transcription Factor/genetics/*metabolism
MH  - Tight Junctions/*metabolism
PMC - PMC5768570
MID - NIHMS889626
OTO - NOTNLM
OT  - barrier function
OT  - inflammatory bowel disease
OT  - interferon-gamma
OT  - protein tyrosine phosphatase
OT  - tight junction
COIS- Competing interests D.F.M. has a 2016 ASPIRE-Pfizer IBD Research Award 
      investigator-initiated research grant from Pfizer Inc. M.K. has no conflict of 
      interest to disclose.
EDAT- 2017/08/15 06:00
MHDA- 2017/10/20 06:00
PMCR- 2018/10/01
CRDT- 2017/08/15 06:00
PHST- 2017/01/20 00:00 [received]
PHST- 2017/06/21 00:00 [revised]
PHST- 2017/06/26 00:00 [accepted]
PHST- 2017/08/15 06:00 [pubmed]
PHST- 2017/10/20 06:00 [medline]
PHST- 2017/08/15 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - 10.1111/nyas.13439 [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2017 Oct;1405(1):116-130. doi: 10.1111/nyas.13439. Epub 2017 
      Aug 14.