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My research focuses on the role of IKK/NF-κB and JNK signaling in B and T lymphocyte development, inflammation, auto-immunity and lymphomagenesis. I aim to dissect these signaling pathways during normal physiology and disease using targeted loss and gain of function mutagenesis in the mouse. Inhibition of NF-κB leads to immuno-deficiency in human patients whereas constitutive activation of NF-κB or JNK are implicated in tumor development. Therefore an important aim of my research is to create and analyze mouse models for human disease. In addition, I want to identify new components involved in regulating or executing IKK/NF-κB and JNK-related signal transduction.
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Fig. 1 Cartoons of the NF-κB and JNK signaling pathways. Stress, inflammatory stimuli and antigen, amongst other stimuli, activate the NF-κB and JNK signaling cascades. The activation of NFκB transcription factors occurs through two main pathways: the canonical and the alternative NF-κB activation pathway. During canonical signaling upstream mediators activate the IκB kinase (IKK) complex, composed of the two catalytic subunits IKK1 and IKK2 and the regulatory protein NF-κBessential Modulator (NEMO), to phosphorylate inhibitory IκB proteins, leading to their ubiquitination and degradation. NF-κBdimers are then free to bind to DNA and activate gene transcription. Alternative NF-κB signaling is mediated by NF-κB Inducing Kinase (NIK) and IKK1, which induce the partial proteolytical degradation of p100 to p52, which together with RelB transactivates their target genes. Activation of the c-Jun N-terminal Kinase (JNK) proteins via upstream mitogen activated protein kinases leads to activation of transcription factors of the AP-1 family. In addition, JNK proteins regulate protein turnover via the E3 ubiquitin ligase Itch and apoptosis by phosphorylating members of the Bcl2 family of anti-apoptotic proteins. |
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