Charakterisierung der Oncostatin-M-vermittelten STAT5-Aktivierung : Beitrag des Rezeptorkomplexes und der Januskinasen

Most cytokines and growth factors act on their target cells by binding specific receptors on the cell surface and activation of an intracellular signal cascade. OSM, a pleiotropic cytokine, belongs to the IL-6 family of cytokines and signals through a receptor complex containing the subunits gp130 and OSMR. This leads to activation of the JAK/STAT pathway. Our study shows that OSM is characterized by a strong activation of STAT5 in different cell lines; this is not the case for IL-6 or LIF. Recruitment of STAT5 is mediated by the specific OSMR subunit and does not require gp130. Different chimeric IL-5/OSMR mutants with a shortened intracellular part were used to further determine the STAT5 activation. Additionally the role of the janus kinases in OSM-mediated STAT5 activation was investigated. In summary, the results show the following:- The STAT3 binding tyrosines Y917 and Y944 as well as the more distal localized tyrosines Y901 and Y861 are not required for STAT5 activation.- The tyrosines Y837 and Y839 in the YLYLLP motif are able to recruit STAT5. Furthermore, we observed a STAT5 activation independent of receptor tyrosine docking sites, but only in the presence of an intact box1/2 region for the association with the janus kinases.- JAK1 and JAK2, which bind to the OSMR, are both involved in STAT5-phosphorylation: JAK1 is mandatory, whereas JAK2 further enhances STAT5 activation.- If JAK2 lacks its kinase activity or the OSMR its YLYLLP-motif, STAT5 activation is reduced to approximately 50\%. Maximal activation of STAT5 requires tyrosines Y837 and Y839 as well as an intact kinase function of JAK2.Our study shows that STAT5 activation through the OSMR subunit does not require receptor tyrosine docking sites. This new finding is different from the previously described STAT activation mechanism of IL-6-type cytokines, which is based on recruitment of STAT5 to receptor-tyrosine motifs. Our results indicate a direct JAK/STAT interaction similar to that found for other cytokine receptors. The present data suggests that the STAT5 activation is mediated by receptor phosphotyrosines of the OSMR YLYLLP-motif as well as by a JAK2/STAT interaction. The responsible interactions between JAK2 and STAT5 at the OSMR should be examined in further studies.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2007

Author dc:creator

• Evers, Christina

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/610
• Signaltransduktion
• Medizin
• Oncostatin M
• OSM
• STAT5
• Januskinasen
• JAK

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124133%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62569