Seminar: Prof. Jacob Piehler

Spatiotemporal regulation of cytokine receptor plasticity

25 February 2014 00:00 hrs.
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Spatiotemporal regulation of cytokine receptor plasticity

Prof. Jacob Piehler, Department of Biology, University of Osnabrück, Germany


Prof. Roland Brock, department of Biochemistry, Radboudumc

25-02-2014 00:00:00Europe/AmsterdamSpatiotemporal regulation of cytokine receptor plasticity Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route

Remarks / more information:

Piehler , JacobCytokine receptors are comprised by two or more receptor subunits, which are cross-linked by their ligand, leading to the activation of Janus family kinases (JAKs) associated with the cytoplasmic tails the receptor subunits. We aim to unravel cytokine receptor assembly, dynamics and effector activation as well as its regulation by plasma membrane organization and specific feedback mechanisms in a quantitative manner. To this end we have established single molecule dimerization assays, which allow visualizing assembly and dynamics of receptor complexes at physiological receptor concentrations in living cells. Thus, ligand-induced dimerization was clearly demonstrated for several cytokine receptors, which was studied in more detail for the type I interferon (IFN) receptor. Strikingly, rapid and very efficient dimerization of the sub-units IFNAR1 and IFNAR2 and the formation of a dynamic signalling complex were observed, in contrast to dimerization experiments with transmembrane receptors reconstituted into polymer-supported membrane in vitro. More detailed studies with deletions constructs of IFNAR revealed that the cytosolic receptor domains contribute to stabilizing the signalling complex, probably by interactions between the JAKs. Interestingly, dimerization of IFNAR is modulated by the negative feedback regulator USP18, which binds to the cytosolic domain of IFNAR2. We further investigated USP18 interaction with the IFNAR signaling complex by cell micropatterning. Surprisingly, USP18 docks to IFNAR2 via the signal transducer and activator of transcription 2 (STAT2) and stabilizes its constitutive interaction with IFNAR2. Thus, USP18 not only regulates IFN signaling on the level of receptor assembly but also by modulating the dynamics of effector activation.

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