A single amino acid substitution (Trp666→Ala) in the interbox1/2 region of the interleukin-6 signal transducer gp130 abrogates binding of JAK1, and dominantly impairs signal transduction

HAAN, Claude; Hermanns, Heike M.; Heinrich, Peter C.; Behrmann, Iris

doi:10.1042/bj3490261

Cited by 13 publications

(1 citation statement)

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“…This interdependence between JAKs and cytokine-receptors surface expression ensures that only receptors binding JAKs can interact with cytokines, guaranteeing that every cytokine-receptor binding event can be translated into signalling. In the absence of this quality control mechanism, cytokine-receptors not bound to JAKs could act as dominant negatives, behaving as cytokine 'sinks' and preventing effective responses [177]. Indeed, there is evidence supporting competition between cytokine-receptors for limiting JAKs, highlighting the biological significance of this JAK chaperone role [178,179].…”

Section: Jaks and Cytokine-receptor Surface Densitymentioning

confidence: 99%

Molecular and cellular factors determining the functional pleiotropy of cytokines

2022

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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 biophysicalfor example, ligand-receptor binding affinity and topologyand cellularfor example, receptor, JAK and STAT protein levels, endosomal compartmentparameters 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.

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Section: Jaks and Cytokine-receptor Surface Densitymentioning

confidence: 99%