Das Adapterprotein Gab1 in der Regulation der IL-6 Signaltransduktion

Adapterproteins connect cell surface receptors to intracellular signaling pathways. These adapters are able to bind different proteins and thereby represent a platform from which diverse signaling pathways are initiated. One of these adapters is Gab1. It is ubiquitously expressed and mediates the activation of the MAPK and PI3K signaling pathways after stimulation with growth factors and cytokines. It was described that Gab1 is involved in the IL-6 mediated ERK-activation. However, the mechanisms of the activation of the MAPK-cascade after activation of the IL-6 receptor gp130 are still unclear. Therefore, in the study presented here, these mechanisms were investigated in molecular detail. It turned out that Gab1 interaction with SHP2 and Grb2 is required for the ERK-activation after IL-6 stimulation. Additionally, Gab1 has to bind with its PH-domain to the phospholipid PtdIns(3,4,5)P3 to activate the MAPK-cascade. The interactions with SHP2, Grb2 and PtdIns(3,4,5)P3 are also important for tyrosine 627 phosphorylation of Gab1. This phosphorylation reflects the activation of Gab1. In the course of this study the involvement of the PI3K-product PtdIns(3,4,5)P3 for the Gab1-activation became obvious, thus the intracellular localisation of Gab1 was investigated. The localisation is important due to the fact that the substrates of the binding partners of Gab1 are at or in the plasma membrane. It turned out that Gab1 translocates from the cytoplasma to the plasma membrane after IL6-stimulation. This translocation is independent of the binding of Gab1 to SHP2, Grb2 and PI3K, respectively. However, the phospholipid PtdIns(3,4,5)P3 in the plasma membrane is required as a binding partner for the PH-domain of Gab1. In other proteins the localisation is solely dependent on the binding partner of the PH-domain, whereas this is not sufficient for the localisation of Gab1. Additionally to the presence of the phospholipid, a stimulation of the cell is necessary for the translocation of Gab1. The activation of the MAPK-cascade was identified as the additional stimulus. Without activation of the MAPKs Gab1 remains in the cytoplasma after IL6-stimulation. The region in Gab1 that mediates the MAPK-dependent translocation was identified: ERK-phosphorylation at serine 551 determines whether Gab1 is recruited to the plasmamembrane after stimulation. Hence, a new mechanism was found, which regulates the recruitment of a protein with a PtdIns(3,4,5)P3-binding PH-domain to the plasmamembrane.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2008

Author dc:creator

• Eulenfeld, René

Contributors dc:contributor

• Schaper, Fred

• info:eu-repo/classification/ddc/570
• Signaltransduktion
• Interleukin 6
• Cytologie
• Konfokale Mikroskopie
• Lokalisation
• Biowissenschaften, Biologie
• MAPK
• PH-Domäne
• Gab1
• PIP3
• PH-domain

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-112787%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A50234