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 recently identified novel proteins that interact with JAK2. Their effect on the JAK/STAT signalling pathway is currently under investigation.
Related publications:
- Lavens et al. A complex interaction pattern of CIS and SOCS2 with the leptin receptor. J. Cell Sci. (2006)
- Piessevaux et al. Functional cross-modulation between SOCS proteins can stimulate cytokine signaling. J. Biol. Chem. (2006)
- Lavens et al. The C-terminus of CIS defines its interaction pattern. Biochem. J. (2007)
- Uyttendaele et al. MAPPIT analysis of STAT5, CIS and SOCS2 interactions with the growth hormone receptor. Mol. Endocrinol. (2007)
- Piessevaux et al. Elongin B/C recruitment regulates substrate binding by CIS. J. Biol. Chem. (2008)
- Piessevaux et al. The many faces of the SOCS-box. Cytokine Growth Factor Rev. (2008)
- Dumoutier et al. New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain. J. Biol. Chem. (2009)
- Wauman et al. RNF41 (Nrdp1) controls type 1 cytokine receptor degradation and ectodomain shedding. J. Cell Sci (2011)
