JAK/STAT signalling

A key signalling route used by many cytokines is the JAK/STAT pathway. Receptor binding leads to rapid activation of receptor-associated members of the Janus family of kinases (JAKs). Subsequent phosphorylation of tyrosine residues in the receptor tails enables recruitment of downstream signalling molecules, whereby the signal transducers and activators of transcription (STATs) play a prominent role. Activated STATs translocate to the nucleus where they control gene transcription.

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The cellular response to receptor activation involves fine-tuning at several levels using various mechanisms. These include the control of receptor cell surface expression level and various types of post-activation signal attenuation. In addition, such attenuating mechanisms must be eliminated to prevent a prolonged cellular refractory state.

Abnormalities at the level of cytokine receptor signalling and responsiveness can contribute to several human pathologies. It is in this context that the mechanisms controlling JAK/STAT signalling are being investigated. For example, detailed structure/function analysis of SOCS proteins (Suppressors Of Cytokine Signalling) is revealing the different operational modes of the distinct members of this regulatory family. We have also identified novel proteins that interact with JAK2. Their effect on the JAK/STAT signalling pathway is currently under investigation. Finally, we are also investigating novel modes of regulation of STAT3 via post-translational modifications like acetylation and tyrosine phosphorylation.

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