Targeting the interaction between p38α and TAB1

Abstract

p38α, a member of the mitogen activated protein kinase family, is a stress activated serine/threonine kinase which plays an important role in signalling pathways mediating fundamental processes such as inflammation, apoptosis, autophagy, and cell division, differentiation and death. Over the last two decades, its prominence in ischaemic heart disease has risen rapidly with several studies providing overwhelming evidence that p38α activation aggravates lethal injury during myocardial ischaemia. Several inhibitors have been tested to prevent p38α activation and although they have performed well in the laboratory; unfortunately the results have not translated to clinical trials in patients. This has mainly been due to toxicity such as liver injury, skin rashes, gastrointestinal disorders, and flares-ups of rheumatoid arthritis. These adverse effects are shared by different inhibitors, the majority of which belong to the ATP-mimetic, type I group, suggesting they result from an on-target effect of inhibiting ubiquitously expressed p38α. As a result, an alternative therapeutic strategy, other than the blanket inhibition of p38, is required. TAB1 mediated p38α activation appears to be the culprit behind the detrimental p38α signalling during myocardial ischaemia and selectively targeting this branch of p38α activation, without affecting prototypical p38α activation, is highly desirable. In this thesis I studied the structural features of p38α and TAB1 which contribute to the TAB1-mediated p38α autoactivation mechanism. Using various biochemical and biophysical tools in in-vitro and ex-vivo systems, I have identified the key residue in p38α, and TAB1, which contribute to the auto-activation of p38α by TAB1. The results from my investigations suggest that targeting these residues impairs the autoactivation process and these structural features may be exploited to elucidate p38α’s role in myocardial ischaemia. Ischaemic heart disease continues to be the biggest killer in the world, and the search for p38α inhibitors still continues without any fruitful outcomes. A new direction and strategy focusing on circumstance selective inhibition is required in p38α therapeutics, and hopefully the results in my thesis will contribute to that search.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Michael Marber (Supervisor)