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PTK6 mediates intestinal endothelial barrier dysfunction in response to TNFα (695.1)
Author(s) -
Haines Ricci,
Beard Richard,
Yuan Sarah,
Wu Mack
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.695.1
Subject(s) - endothelium , barrier function , inflammation , endothelial dysfunction , microbiology and biotechnology , endothelial stem cell , tumor necrosis factor alpha , cancer research , immunology , biology , endocrinology , in vitro , biochemistry
A key event in the progression of systemic inflammation resulting from severe trauma or shock involves hyperpermeability of the intestinal endothelium. The signaling events leading to increased endothelial permeability in these disease states are incompletely understood. Although the role of protein tyrosine kinase 6 (PTK6, also known as breast tumor kinase BRK) has been primarily studied in mechanisms underlying metastasis and cancer, it has also been shown that PTK6 participates in mediating colonic epithelial barrier dysfunction. In this study, we hypothesized that PTK6 is 1‐ expressed in intestinal endothelial cells, and 2‐ contributes to endothelial hyperpermeability in response to inflammation. To this end, we investigated the role of PTK6 in mediating the disruption of intestinal endothelial barrier function. Results showed that PTK6 was detected in intestinal endothelial cells at the level of protein and mRNA. In addition, PTK6 knockdown attenuated decrease in transendothelial electric resistance (TER) as measured by electric cell‐substrate impedance sensing (ECIS) of intestinal endothelial monolayers in response to inflammatory factors including TNFα. Furthermore, we showed that TNFα increased activity of PTK6 as evidenced by increased phosphorylation at Y342, supporting the hypothesis that this kinase plays a role in endothelial inflammation. We further studied the potential targets of PTK6 including junctional structure proteins to determine the molecular mechanism of its role in regulating endothelial barrier function. Our study explores a potential implication that targeting PTK6 may serve as a novel therapeutic strategy in treating diseases characterized by hyperpermeability of the intestinal endothelium. Grant Funding Source : Supported by VA Merit Review 5101BX000799, the NIH grants HL96640, HL61507 and HL70752