Die Regulation der Expression des humanen Oncostatin-M-Rezeptors durch Januskinasen

The oncostatin M receptor (OSMR) is part of a heterodimeric receptor complex which mediates signal transduction of the pleiotropic cytokine OSM. Like other cytokine receptors, the OSMR does not contain intrinsic kinase activity and therefore signalling events are mediated by members of the family of Janus kinases (Jaks) which are constitutively associated with cytokine receptors at their membrane proximal region. In case of the OSMR, activation of Jak1, Jak2 and Tyk2 have been reported. Apart from their function in OSM signal transduction, a novel role of Jaks could be established in the present study: Upon heterologous expression of the OSMR in several cell lines, its surface expression was significantly enhanced by coexpression of the Janus kinases Jak1, Jak2 and Tyk2 but not Jak3. This effect was not an overexpression artefact, as the endogenous OSMR was also downregulated in Jak1-deficient cells. In order to study this effect in more detail, chimeric receptors consisting of the extracellular region of the IL-5Rb chain and the transmembrane and intracellular part of the OSMR were used. These receptors were similarly upregulated on the plasma membrane when Jak1 was coexpressed. The overall expression level of these constructs did not change significantly but Jak1 coexpression increased the amount of EndoH-resistant, fully processed OSMR chimeras. Using mutated receptor and Jak1 constructs, it could be demonstrated that association of Jak1 with the membrane proximal region of the receptor but not its kinase activity is necessary for this effect. Moreover, deletion of the OSMR-box1/2 region also resulted in an improved surface expression indicating that this region may contain a signal preventing efficient receptor surface expression in the absence of associated Jaks. Further mutational analysis revealed that this signal is most likely consists of three dileucine-like signals in the interbox1/2-region. Even though one of this signals resembles a lysosomal targeting motif, no lysosomal localization of the OSMR was detected. Both immunofluorescence data and biochemcal studies rather point to an ER retention mechanism mediated by this signal. In this scenario, Jak binding to the membrane proximal receptor region would lead to masking of this signal and therefore increase the portion of fully processed receptors. Finally it was shown that the murine OSMR, although it also contains a similar motif consisting of three dileucine-like signals in its interbox1/2-region, is only slightly upregulated at the cell surface by Jak1 coexpression. Mutational analysis revealed that this difference might be due to the fact that in the human receptor, an additional isoleucine is present which is missing in the murine receptor.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2003

Author dc:creator

• Radtke, Simone

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/570
• Biowissenschaften, Biologie
• Zytokine
• Jak
• STAT
• Oberflächenexpression
• Oncostatin M
• Dileucin-Signale
• Qualitätskontrolle

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-119229%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:57164