Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/37286
Title: The multi-site docking protein Grb2-associated binder 1 (Gab1) enhances interleukin-6-induced MAPK-pathway activation in an SHP2-, Grb2-, and time-dependent manner
Author(s): Bongartz, Hannes
Gille, Karen
Hessenkemper, Wiebke
Mandel, KatharinaLook up in the Integrated Authority File of the German National Library
Lewitzky, Marc
Feller, Stephan M.
Schaper, FredLook up in the Integrated Authority File of the German National Library
Issue Date: 2019
Type: Article
Language: English
URN: urn:nbn:de:gbv:ma9:1-1981185920-375202
Subjects: Interleukin-6
Janus kinase
Signal transduction
Signal orchestration
Cytokines
Abstract: Background: Cytokine-dependent activation of signalling pathways is tightly orchestrated. The spatiotemporal activation of signalling pathways dictates the specific physiological responses to cytokines. Dysregulated signalling accounts for neoplastic, developmental, and inflammatory diseases. Grb2-associated binder (Gab) family proteins are multisite docking proteins, which expand cytokine-induced signal transduction in a spatial- and time-dependent manner by coordinating the recruitment of proteins involved in mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) and phosphatidyl-inositol-3-kinase (PI3K) signalling. Interaction of Gab family proteins with these signalling proteins determines strength, duration and localization of active signalling cascades. However, the underlying molecular mechanisms of signal orchestration by Gab family proteins in IL-6-induced signalling are only scarcely understood. Methods: We performed kinetic analyses of interleukin-6 (IL-6)-induced MAPK activation and analysed downstream responses. We compared signalling in wild-type cells, Gab1 knock-out cells, those reconstituted to express Gab1 mutants, and cells expressing gp130 receptors or receptor mutants. Results: Interleukin-6-induced MAPK pathway activation can be sub-divided into an early Gab1-independent and a subsequent Gab1-dependent phase. Early Gab1-independent MAPK activation is critical for the subsequent initiation of Gab1-dependent amplification of MAPK pathway activation and requires binding of SH2 domain-containing phosphatase 2 (SHP2) to the interleukin-6 receptor complex. Subsequent and coordinated recruitment of Grb2 and SHP2 to Gab1 is essential for Gab1-dependent amplification of IL-6-induced late MAPK pathway activation and subsequent gene expression. Conclusions: Overall, we elaborated the molecular requirements for Gab1-dependent, spatiotemporal orchestration of interleukin-6-dependent MAPK signalling. We discriminated IL-6-induced Gab1-independent, early activation of MAPK signalling and Gab1-dependent, sustained activation of MAPK signalling.
URI: https://opendata.uni-halle.de//handle/1981185920/37520
http://dx.doi.org/10.25673/37286
Open Access: Open access publication
License: (CC BY-SA 4.0) Creative Commons Attribution ShareAlike 4.0(CC BY-SA 4.0) Creative Commons Attribution ShareAlike 4.0
Sponsor/Funder: OVGU-Publikationsfonds 2019
Journal Title: Cell communication and signaling
Publisher: Biomed Central
Publisher Place: London
Volume: 17
Issue: 2019
Original Publication: 10.1186/s12964-019-0451-2
Page Start: 1
Page End: 23
Appears in Collections:Fakultät für Naturwissenschaften (OA)

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