Regulation of inflammation by MAP kinases and NF-kB

Lead Research Organisation: The Francis Crick Institute

Abstract

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Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

Acute inflammatory responses are critical for protective immunity and tissue repair following injury, but chronic inflammation can lead to autoimmunity and cancer. Increased knowledge about the control of inflammation may inform novel approaches for treatment of inflammatory diseases. My research programme focuses on two key signalling proteins that regulate inflammation in health and disease, TPL-2 kinase and the adaptor CARD14.
TPL-2 complex signalling in inflammation and cancer
Toll-like receptors (TLRs) play a central role in the initiation of innate immune responses to pathogens. TPL-2 is a MKK1/2 kinase that mediates TLR activation of ERK1/2 MAP kinases in myeloid cells, and is critical for regulation of immune responses to bacteria and viruses. My laboratory has shown that TPL-2 forms a complex with NF-?B1 p105 and the ubiquitin-binding protein ABIN-2. TLR activation of TPL-2 MEK kinase activity requires its release from p105-mediated inhibition, triggered by IKK2 (I?B kinase 2)-induced p105 proteolysis. We have also demonstrated that IKK2 phosphorylation of the TPL-2 C-terminus promotes interaction with 14-3-3, which is essential for TPL-2 activation of ERK1/2. We are strongly positioned to make significant discoveries on the control and functions of the TPL-2 complex in inflammation and cancer, which may facilitate further development of TPL-2 as a drug target.
TPL-2 signalling in inflammation We will investigate how TPL-2 regulates transcription in TLR-stimulated macrophages to modulate inflammation.
ABIN-2 regulation of allergy Our recent experiments indicate that TPL-2 limits airway allergic responses to house dust mites independently of its kinase activity by maintaining levels of ABIN-2, the function of which is unknown. We will investigate the specific role of ABIN-2 in allergy using Abin2 knock-in mice in which ABIN-2 binding to ubiquitin or the NF-?B inhibitor A20 are ablated by point mutation without affecting TPL-2 expression.
Roles of TPL-2 and ABIN-2 in cancer TPL-2 promotes the survival and proliferation of several human cancer cell types, but experiments with Tpl2-/- mice suggest that TPL-2 inhibits lung and gut cancer development. The cancer phenotypes of Tpl2-/- mice may actually be due to the absence of ABIN-2, which depends on TPL-2 for stability and is a putative tumour suppressor. We will use Tpl2 and Abin2 knock-in mice to investigate the distinct roles of TPL-2 and ABIN-2 in lung and gut cancer.
CARD14 regulation of NF-?B in psoriasis
Rare inherited and de novo mutations in the Card14 gene promote development of psoriasis, a chronic inflammatory skin disease. Genome wide association studies also indicate a role for CARD14 in common psoriasis, which affects 2-3% of adults in the UK.
We have shown that psoriasis-associated Card14 mutations induce constitutive formation of a CARD14/BCL10/MALT1 complex, triggering BCL10 and MALT1 dependent activation of NF-?B in keratinocytes. We aim next to determine how dysregulated signaling by mutant CARD14 induces skin inflammation and the physiological roles of CARD14 in normal skin.
Induction of inflammation by mutant CARD14 Using novel Card14[E138A] conditional knock-in mice, we will determine the inflammatory effects of global/tissue-specific expression of Card14[E138A] (a severe psoriasis mutant).
Physiological regulation and functions of CARD14 We will identify receptors that activate the CARD14-NF-?B signalling pathway in keratinocytes. Using novel Card14[fl] mice, we will determine the effects of CARD14 deficiency in the skin and other tissues.

Publications

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