Negative Regulation der Oncostatin M-vermittelten Signaltransduktion

To avoid overshooting cytokine signalling with possible pathological consequences, the duration as well as the intensity of the activated signal transduction pathways are tightly regulated. The importance of the feedback inhibitor suppressor of cytokine signalling 3 (SOCS3) in inhibition of the interleukin (IL)-6 type cytokine signal transduction is well documented. Expression of SOCS3 is induced via the STAT transcription factors, and it exerts its inhibitory effect via interaction with the phosphorylated Y759 motif within the cytoplasmic region of the common receptor chain of all IL-6 type cytokines, gp130. Thereby SOCS3 colocalizes with the receptor associated Janus kinases, which is a prerequisite for the inhibition of the kinase activity. In this study, the role of the specific Oncostatin M receptor (OSMR) in the SOCS3 mediated inhibition of the OSM pathway is analyzed. The obtained results point to a new mechanism of the inhibitory action of SOCS3. We could show that OSM induces the expression of SOCS3 much more efficiently than IL-6 due to a strong activation of the mitogen activated protein kinases ERK1 and 2 which act together with the STAT factors to induce the feedback inhibitor. The negative regulatory role on OSM mediated signal transduction is independent of the gp130 Y759 motif. However, a direct interaction of SOCS3 with the OSMR – analogous to gp130 and all receptors so far described to be SOCS3 sensitive – could be excluded. Rather, the inhibitory function of SOCS3 depends on a direct interaction with JAK1. So far such a direct interaction has only been shown with overexpressed proteins and thought to be physiologically irrelevant due to the weak affinity of SOCS3 to the phosphorylated kinase activation loop. The second part of this study deals with the inhibitory effect of the arsenic compound phenylarsine oxide (PAO) on the signal transduction of IL-6 type cytokines. It is shown, that PAO influences this pathway in two ways. On the one hand, it induces the endocytosis of gp130 via activation of p38 and phosphorylation of serine 782 within the receptor internalization motif. This contradicts its postulated function as internalization inhibitor. Second, PAO inhibits the activation of JAK1 and TYK2, probably due to the oxidation of vicinal thiol groups. Thereby, the activation of the STATs is inhibited. Although in many studies PAO is used as a phosphatase inhibitor, comparative studies with pervanadate do not support this function in our experimental system. Interestingly, a selective influence of PAO on STAT activation via the IL-6 type cytokines was found. While the IFN-gamma mediated JAK1 and JAK2 phosphorylation are inhibited by preincubation with PAO, nearly no effect is seen on the resulting STAT1 activation. This points to a different regulation of the IL-6, LIF and OSM induced STAT activation compared to the one by IFN-gamma. Besides, PAO was used in studies with parental and JAK1 deficient fibrosarcoma cells additionally to other JAK inhibitors to get further insights into the relative importance of the different kinases JAK1, JAK2 and TYK2 in IL-6 and OSM mediated signalling pathways. Thereby, an important role of JAK1 in the IL-6 dependent STAT3 phosphorylation could be confirmed. Additionally, it was shown that the presence of JAK1 is necessary for the OSM induced JAK2 but not TYK2 phosphorylation and that TYK2 is sufficient for a normal STAT3 phosphorylation even in the absence of JAK1 and JAK2 activation.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2006

Author dc:creator

• Stroß, Claudia

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/570
• Biowissenschaften, Biologie
• Signaltransduktion
• Inhibition
• Interleukin 6
• Phenylarsenoxid
• Interferon
• Oncostatin M
• suppressor of cytokine signalling 3

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-122542%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:60855