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• W4220746619 endingPage "2552" @default.
• W4220746619 startingPage "2525" @default.
• W4220746619 abstract "Cytokines are soluble factors vital for mammalian physiology. Cytokines elicit highly pleiotropic activities, characterized by their ability to induce a wide spectrum of functional responses in a diverse range of cell subsets, which makes their study very challenging. Cytokines activate signalling via receptor dimerization/oligomerization, triggering activation of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway. Given the strong crosstalk and shared usage of key components of cytokine signalling pathways, a long‐standing question in the field pertains to how functional diversity is achieved by cytokines. Here, we discuss how biophysical – for example, ligand‐receptor binding affinity and topology – and cellular – for example, receptor, JAK and STAT protein levels, endosomal compartment – parameters contribute to the modulation and diversification of cytokine responses. We review how these parameters ultimately converge into a common mechanism to fine‐tune cytokine signalling that involves the control of the number of Tyr residues phosphorylated in the receptor intracellular domain upon cytokine stimulation. This results in different kinetics of STAT activation, and induction of specific gene expression programs, ensuring the generation of functional diversity by cytokines using a limited set of signalling intermediaries. We describe how these first principles of cytokine signalling have been exploited using protein engineering to design cytokine variants with more specific and less toxic responses for immunotherapy." @default.
• W4220746619 created "2022-04-03" @default.
• W4220746619 creator A5045244900 @default.
• W4220746619 creator A5049110418 @default.
• W4220746619 creator A5061399065 @default.
• W4220746619 date "2022-03-14" @default.
• W4220746619 modified "2023-10-18" @default.
• W4220746619 title "Molecular and cellular factors determining the functional pleiotropy of cytokines" @default.
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