Death-Associated Protein Kinase Controls STAT3 Activity in Intestinal Epithelial Cells.

Death-Associated Protein Kinase Controls STAT3 Activity in Intestinal Epithelial Cells. Am J Pathol. 2013 Mar;182(3):1005-20 Authors: Chakilam S, Gandesiri M, Rau TT, Agaimy A, Vijayalakshmi M, Ivanovska J, Wirtz RM, Schulze-Luehrmann J, Benderska N, Wittkopf N, Chellappan A, Ruemmele P, Vieth M, Rave-Fränk M, Christiansen H, Hartmann A, Neufert C, Atreya R, Becker C, Steinberg P, Schneider-Stock R Abstract The TNF-IL-6-STAT3 pathway plays a crucial role in promoting ulcerative colitis-associated carcinoma (UCC). To date, the negative regulation of STAT3 is poorly understood. Interestingly, intestinal epithelial cells of UCC in comparison to ulcerative colitis show high expression levels of anti-inflammatory death-associated protein kinase (DAPK) and low levels of pSTAT3. Accordingly, epithelial DAPK expression was enhanced in STAT3(IEC-KO) mice. To unravel a possible regulatory mechanism, we used an in vitro TNF-treated intestinal epithelial cell model. We identified a new function of DAPK in suppressing TNF-induced STAT3 activation as DAPK siRNA knockdown and treatment with a DAPK inhibitor potentiated STAT3 activation, IL-6 mRNA expression, and secretion. DAPK attenuated STAT3 activity directly by physical interaction shown in three-dimensional structural modeling. This model suggests that DAPK-induced conformational changes in the STAT3 dimer masked its nuclear localization signal. Alternatively, pharmacological inactivation of STAT3 led...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research