IKK is the major signaling hub for inflammatory and innate immune responses. It is an enzyme complex that receives signals from a large number of cellular receptors regulates that activity of the NF-kB family of transcription factors. Misregulation of IKK is associated with many chronic diseases, such as chronic inflammatory pathologies (arthritis, atherosclerosis, etc) and many different types of cancer. Genetic evidence strongly supports IKK's critical and central role in many functions in physiology and pathology, but its potential as a drug target has not been realized. Mechanistic and biophysical studies have been lacking, and we have neither a kinetic understanding of IKK regulation nor structural information. However, what is clear is that IKK mediates signaling specificity by tight dynamic control that is stimulus-specific and induces the expression of specific sets of genes. Recent studies have reported on a tightly coupled activation and inactivation mechanism that can only be described by a multi-state activation-inactivation cycle that involves the function of several enzymes with different functions, such as ubiquitin ligases, kinases, phosphatases, and foldases. Through regulation of these activities, we hypothesize that the IKK cycle is driven in a stimulus- and cell type-specific manner, and that understanding the kinetic relationships will reveal opportunities for rationally targeted pharmacological intervention that discriminate between disease associated misregulation and stimulus-responsive regulation in healthy cells. In this proposal, we will construct a mathematical model of the IKK cycle to explore the dynamic regulation of IKK activity. We will then focus biochemical and biophysical studies on specific control mechanisms. In particular, we test the roles of IKK oligomerization, conformational changes, and upstream kinases in IKK activation and inhibition of IKK. Computational simulations will guide genetic and pharmacological manipulation of IKK dynamics. Finally, we will focus our study on how TNF and IL-1 produce differential dynamic control of IKK;how differential dose response and temporal control determine the efficacy of cytokine traps.
The IkappaB kinase (IKK) complex is large protein kinase that specifically receives signals from cell surface receptors and transmits the signal to down stream effector transcription factor NF-kB. IKK must remain at a low activity state under resting state of the cell and transits into a high activity state upon receiving signals. Any alteration of this tight regulatory mode of IKK results to abnormal cellular outcomes including inflammatory diseases and cancer. The precise mechanism of how IKK-intrinsic and extrinsic cellular mechanisms control IKK activity is poorly understood. This proposal will integrate diverse methodologies that include mathematical modeling, biophysics, biochemistry and genetics to probe IKK regulation.
|Wang, Vivien Ya-Fan; Li, Yidan; Kim, Daniel et al. (2017) Bcl3 Phosphorylation by Akt, Erk2, and IKK Is Required for Its Transcriptional Activity. Mol Cell 67:484-497.e5|
|Polley, Smarajit; Passos, Dario Oliveira; Huang, De-Bin et al. (2016) Structural Basis for the Activation of IKK1/?. Cell Rep 17:1907-1914|
|Fusco, Amanda J; Mazumder, Anup; Wang, Vivien Ya-Fan et al. (2016) The NF-?B subunit RelB controls p100 processing by competing with the kinases NIK and IKK1 for binding to p100. Sci Signal 9:ra96|
|Almaden, Jonathan V; Liu, Yi C; Yang, Edward et al. (2016) B-cell survival and development controlled by the coordination of NF-?B family members RelB and cRel. Blood 127:1276-86|
|Fortmann, Karen T; Lewis, Russell D; Ngo, Kim A et al. (2015) A Regulated, Ubiquitin-Independent Degron in I?B?. J Mol Biol 427:2748-56|
|Cheng, Zhang; Taylor, Brooks; Ourthiague, Diana R et al. (2015) Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation. Sci Signal 8:ra69|
|Almaden, Jonathan V; Tsui, Rachel; Liu, Yi C et al. (2014) A pathway switch directs BAFF signaling to distinct NF?B transcription factors in maturing and proliferating B cells. Cell Rep 9:2098-111|
|Hauenstein, Arthur V; Rogers, W Eric; Shaul, Jacob D et al. (2014) Probing kinase activation and substrate specificity with an engineered monomeric IKK2. Biochemistry 53:2064-73|
|Shinohara, Hisaaki; Behar, Marcelo; Inoue, Kentaro et al. (2014) Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-?B activation. Science 344:760-4|
|Behar, Marcelo; Barken, Derren; Werner, Shannon L et al. (2013) The dynamics of signaling as a pharmacological target. Cell 155:448-61|
Showing the most recent 10 out of 18 publications