Funktion der Protein-Tyrosin-Phosphatase SHP2 und des feedback-Inhibitors SOCS3 in der IL-6-Signaltransduktion

Interleukin-6 signals through a hexameric receptor complex composed of IL-6, the IL-6 receptor a and gp130. The intracellular region of gp130 is associated with the Janus kinases Jak1, Jak2 and Tyk2. Additionally, the intracellular part of gp130 displays six tyrosine motifs. The four membrane distal tyrosine motifs are able to recruit the STAT factors STAT1 and STAT3. Once recruited, STAT factors are phosphorylated, dimerise and translocate to the nucleus where they induce the expression of acute phase genes. Tyrosine 759 of gp130 was identified as an inhibitory motif for the Jak/STAT pathway. This tyrosine residue is a recruitment site for the protein tyroinse phosphatase SHP2 and for the STAT induced feedback inhibitor SOCS3. Therefore the relative contributions of SHP2 and SOCS3 to the repression of the IL-6 signal transduction were investigated. In this work it could be shown that SHP2 inhibits the Jak/STAT pathway in a SOCS3 independent manner requiring the SHP2 phosphatase activity. SHP2(Ex3-/-) cells expressing a truncated SHP2 mutant that is unable to be recruited to the receptor were used for additional experiments. Studies in these cells revealed that the inhibitory effect of SOCS3 is independent of SHP2. Currently, it is not known how SOCS3 negatively regulates IL-6 signal transduction. It is likely that SOCS3 inhibits the Jak kinase activity. Moreover SOCS3 could deliver signalling proteins of the Jak/STAT pathway to proteasomal degradation via the interaction of the SOCS box with Elongin C which is part of a protein complex with E3 Ubiquitin ligase activity. IL-6 is a potent activator of the acute phase response. The regulation of the acute phase response is an important step in tissue homeostasis. General modulation of the Jak/STAT pathway could be achieved by SHP2 dephosphorylating signalling molecules (gp130, Jak, STAT factors). On the other hand, SOCS3 mediates an efficient downregulation of IL-6 signalling as STAT induced feedback inhibitor. SHP2 is also involved in the activation of the Ras/Raf/Erk cascade upon IL-6 stimulation. The C-terminal part of SHP2 is able to recruit the adapter protein Grb2 which links SHP2 to the signal enhancer Gab1. Interestingly, experiments with SHP2 mutants displaying dysregulated phosphatase activity all resulted in a loss of Erk activation. Furthermore, it could be shown that the activation of the Ras/Raf/Erk cascade in SHP2(Ex3-/-) cells is likely to occur via a SHP2 independent mechanism. In these cells tyrosine 759 of gp130 was also shown to be the main mediator of the IL-6 dependent Erk activation, though interaction of the truncated SHP2 protein could neither be detected with a pY759 peptide nor with Gab1. Interestingly, the loss of the p85 recruitment sites on Gab1 was found to be critical for Erk activation in SHP2(Ex3-/-) cells. The catalytic activity of PI3K was shown not to be involved in IL-6 mediated Erk activation, so it is likely that either p85 is able to link gp130 and Gab1 or that other molecules are involved in this process.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2003

Author dc:creator

• Lehmann, Ute

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/570
• Interleukin 6
• Signaltransduktion
• Inhibition
• Proteintyrosinphosphatase
• Cytokine
• Suppressorgen
• Biowissenschaften, Biologie
• Interleukin-6
• Akutphase
• SHP2
• SOCS3
• STAT
• Ras/Raf/Erk-Kaskade
• Gab1
• MAPK
• PI3K

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-114574%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A52343