Visit our Expo - Redox and Inflammation signaling 2012

Jaks and cytokine receptors – an intimate relationship
Claude Haan 1 , Simone Radtke 2 , Bernd Giese 2 , Christiane Margue-Wurth 1 , Andreas
Herrmann 2 , Gerhard Müller-Newen 2 , Serge Haan 2 , Peter C. Heinrich 2 , Iris Behrmann 1
1 Laboratoire de Biologie et Physiologie Intégrée, University of Luxembourg, 162a, av. de
la Faïencerie, 1511 Luxembourg, Grand-Duchy of Luxemburg,
2 Institute of Biochemistry, RWTH-Aachen Medical School, 52074 Aachen, Germany
E-mail: iris.behrmann@uni.lu
Many cytokines signal via Janus kinases (Jaks). These tyrosine kinases are associated with
cytokine receptor subunits, they become activated upon receptor triggering and subsequently
activate downstream signalling events, e. g. the phosphorylation of STAT transcription
factors.
Using gp130 (the common receptor subunit for IL-6-type cytokines) and Jak1 as an example,
we analysed the structural requirements for association between Jaks and cytokine receptors,
as well as the dynamics of this interaction. Subdomains F1 and F2 of the N-terminal FERM
domain of Jak1 are crucially involved in binding to gp130 as well as to other cytokine
receptors. On the receptor side, the conserved box1 and box2 regions as well as the
intervening sequences are crucial for Jak association. The receptor plays an active role in
activation of the bound Jaks, as shown by the mutant gp130-W652A that does not elicit
signalling in spite of associating Jaks (1,2).
Jaks are found exclusively in membrane fractions. The plasma membrane localization of Jaks
is dependent on their ability to associate with cytokine receptors since the non-receptor
binding Jak1 mutant L80A/Y81A is only found within the cytoplasm. Using FRAP analysis
with fluorescent gp130 and Jak1 proteins we show that Jak1 has the same diffusion behaviour
as the transmembrane protein gp130, and that there is no rapid exchange of Jaks between
different receptors. Thus, this cytokine receptor/Jak complex can be regarded to be equivalent
to a receptor tyrosine kinase (3,4).
To assess the role of the predicted SH2 domain in Jak1 we exchanged the conserved arginine
residue by lysine, a mutation known to abrogate the phosphotyrosine binding. This R466K
mutation did not affect the signal transducing capacities of the kinase, nor its localization,
indicating that the Jak1-SH2 domain does not fulfil the “classical” SH2 domain function.
However, it may play a structural role for association with the oncostatin M receptor
(OSMR)(5).
Jaks are not only crucial for signal transduction of cytokines, but they are also involved in the
regulation of the surface expression of at least some cytokine receptors, including the OSMR.
We identified three dileucine motifs within the interbox1/2 region that prevent efficient
OSMR surface expression in the absence of associated Jaks, possibly by lysosomal targeting
and destabilization of the receptor. This may provide a quality control ensuring that
signalling-competent receptors (i. e. those with an associated Jak) would be enriched at the
cell surface (6).
Refs.:
(1) Haan et al., 2001, JBC 276: 37451
(2) Haan et al., 2002, Biochem. J. 361: 105
(3) Behrmann et al., 2004, JBC 279: 35486
(4) Giese et al., 2003, JBC 278: 39205
(5) Radtke et al., 2005, JBC 280: 25760
(6) Radtke et al., 2005, JBC online.
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