Joint Division of Cancer – CRUK Convergence Seminar Series, Thursday 26.01.23 @ 13.30, hosted by Professor Iain McNeish. This seminar will be hybrid.
We are delighted to have Anastasia Mylona, Advanced Research Fellow at Cancer Division at Imperial College. Please see her abstract below: –
Phosphorylation at multiple sites of a protein by a kinase is a major regulatory mechanism in cellular signalling. Deregulation of phosphorylation pathways commonly underlies cancer aetiology. The c-JUN proto-oncoprotein is phosphorylated at four residues within its N-terminal transactivation domain (TAD) by the JNK family of MAP kinases. c-Jun N-terminal phosphorylation has numerous physiological functions and plays a crucial role in colon cancer formation. The JNK kinase has been a desirable drug target for years, but so far JNK inhibitors have not been translated into clinical use due to undesirable side effects. Key downstream signalling events offer opportunities to therapeutically target the JNK pathway, but these novel approaches require a detailed mechanistic understanding of the c-Jun phosphorylation dependent interactome and function.
This seminar will discuss the elucidation of temporal dimension of c-JUN multisite phosphorylation by JNK using time-resolved NMR and a combination of in vivo techniques. This work revealed that c-JUN multisite phosphorylation by JNK occurs with a range of rates, leading to intrinsic temporal phosphorylation states which directly orchestrate protein co-activator and repressor binding binding (Waudby et al.; Nature Communications, 2022). The progressive phosphorylation of c-JUN by JNK phosphorylation encodes a complex signalling response from a single JNK input, which serves as self-limiting safety mechanism to attenuate excessive JNK signalling activation, without the need of phosphatases. This mechanism contrasts the dogma of the classic ‘on and off switch’ of the transcriptional response via the dual role of kinases and phosphatases in MAPK signalling and perhaps more general in signalling pathways, revealing that the temporal dimension of multisite phosphorylation of a protein domain allows for more elaborate signalling responses. Finally, future approaches how these temporal functional c-JUN phosphorylation states can be therapeutically targeted will be discussed.