Two new mechanisms of suppression of inflammatory responses, mediated by the Toll-like receptor, TLRS and the transcription factor, lRF-3, will be studied at the cellular and organismal levels. TLRS is a sensor of double-stranded RNA and has been studied in the context of immediate innate responses to virus infection. But TLRS can also mediate response to endogenous cellular dsRNAs generated during a vahety of tissue injuries. One ofthe major findings in the current funding period was that the phosphorylation of tyrosine residues in TLRS is essential for its ability to initiate signaling.
In specific aim 1, the regulation of Tyr phosphorylation of TLRS will be investigated with emphasis upon the role of the tyrosine-kinase activity of EGF receptors, which were found by us to interact with TLRS. A unique property of TLRS is its exclusive use of the adaptor protein TRIF for the activation of transcription factors IRFS and NFKB. Surprisingly, we have discovered a TRIF-independent activity of TLRS that requires the recruitment and activation of the proto?? oncogene Src and causes inhibition of cell migration. In the second specific aim, the requirements for and consequences of Src activation by TLRS will be defined and the cellular and physiologic consequences will be evaluated. Finally, we have recently observed that IRFS has a significant suppressive effect on the pro?? inflammatory transcription factor, NFKB. The third specific aim will identify the structural features of the two proteins that mediate their physical interaction, and determine the biochemical, cellular and physiologic consequences ofthis interaction. The proposed experiments will test the hypothesis that TLRS and its associated components are coupled with both stimulus (dsRNA) dependent and independent functions that collectively impact upon pro-inflammatory gene expression and trafficking of pro-inflammatory leukocytes. These functions are likely to operate in a cell type and tissue restricted fashion and have significant impact on inflammatory disease and the associated effect on tumorigenesis. Interactions with projects 2, S, 4 and core B will be essential to assess how these functions and their control will impact inflammation related tumongenesis.

Public Health Relevance

Results from the proposed studies will shed light on the anti-inflammatory role of TLRS signaling by inhibiting inflammatory cell migration and that of IRF-S by inhibiting inflammatory gene induction by NFkB. They will also connect the actions of two oncoproteins, Src and EGF receptor, to TLRS signaling, thus revealing a new aspect of interplay between inflammation and cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Chattopadhyay, Saurabh; Sen, Ganes C (2014) Meet the terminator: The phosphatase PP2A puts brakes on IRF-3 activation. Mol Cell 54:210-1
Dermawan, Josephine Kam Tai; Gurova, Katerina; Pink, John et al. (2014) Quinacrine overcomes resistance to erlotinib by inhibiting FACT, NF-?B, and cell-cycle progression in non-small cell lung cancer. Mol Cancer Ther 13:2203-14
Zhao, Chenyang; Pavicic Jr, Paul G; Datta, Shyamasree et al. (2014) Cellular stress amplifies TLR3/4-induced CXCL1/2 gene transcription in mononuclear phagocytes via RIPK1. J Immunol 193:879-88
De, Sarmishtha; Dermawan, Josephine Kam Tai; Stark, George R (2014) EGF receptor uses SOS1 to drive constitutive activation of NF?B in cancer cells. Proc Natl Acad Sci U S A 111:11721-6
Yu, Minjia; Zhou, Hao; Zhao, Junjie et al. (2014) MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases. J Exp Med 211:887-907
Chattopadhyay, Saurabh; Sen, Ganes C (2014) dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interferon Cytokine Res 34:427-36
Chattopadhyay, Saurabh; Sen, Ganes C (2014) Tyrosine phosphorylation in Toll-like receptor signaling. Cytokine Growth Factor Rev 25:533-41
Stahl, Martin; Ries, Jenna; Vermeulen, Jenny et al. (2014) A novel mouse model of Campylobacter jejuni gastroenteritis reveals key pro-inflammatory and tissue protective roles for Toll-like receptor signaling during infection. PLoS Pathog 10:e1004264
Lin, Keng-Mean; Hu, Wei; Troutman, Ty Dale et al. (2014) IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proc Natl Acad Sci U S A 111:775-80
Dasgupta, Maupali; Unal, Hamiyet; Willard, Belinda et al. (2014) Critical role for lysine 685 in gene expression mediated by transcription factor unphosphorylated STAT3. J Biol Chem 289:30763-71

Showing the most recent 10 out of 210 publications