Functional definition of the multi-side docking protein Gab1
Multi-site docking proteins are proteins that, after their activation (e.g. by post-translational modifications, changes in their conformation and/or localisation), serve as a platform for the binding of a variety of different proteins and thus enable the temporal and spatial co-ordination of the activation of the bound proteins. We could show that after stimulation with cytokines and growth factors, the multi-site docking protein Gab1 is recruited to the cell membrane via its PH domain. There, Gab1 enhances the activation of the MAPK and PI3K signalling pathways. Together with the research group of Prof. Feller (Halle), we were able to elucidate a previously unknown mechanism that enables the PH domain-dependent recruitment of Gab1 to the membrane. Besides the PH domain, Gab1 has a variety of binding sites for other signalling molecules (e.g. SHP2, RasGAP, Grb2, PI3K). We are investigating how Gab1 integrates IL 6-induced signals by recruiting these molecules.
Dysregulation of Gab1 function as a cellular integrator is implicated in the development of proliferative diseases. Our own studies on breast cancer and leukaemia cells show constitutive membrane association and tyrosine phosphorylation of Gab1. With the help of approaches from molecular biology and biochemistry, we want to develop innovative therapy approaches directed against Gab1 in order to block the proliferation of cancer cells in a project funded by the OvGU Innovation Fund.
Fluorescence imaging of the Gab1-GFP fusion-protein after IL-6 stimulation: Video (.avi, 0.5MB)
