Adapter proteins as a central regulator of the dynamics of cytokine signaling

Adapter proteins involved in signal transduction fulfil their cellular functions by bringing signalling molecules together and by targeting these signalling components to defined compartments within the cell. Furthermore, adapter proteins represent a molecular platform from which different signalling pathways are initiated. Gab1 is an adapter which recruits the p85 subunit of the phosphatidylinositol 3-kinase, the adapter Grb2, the adapter and phosphatase SHP2 and the GTPase-activating protein Ras-GAP. By this, Gab1 contributes to the activation of the PI3K cascade and the MAPK cascade by growth factors and cytokines. A contribution of Gab1 to the signal transduction of EGF, PDGF, HGF and IL-6 has been demonstrated. The recruitment of Gab1 to phosphatidylinositol-3,4,5-tris-phosphate within the plasma membrane by its pleckstrin homology domain is regarded as a major crucial step for the regulation of Gab1. We identified a novel and more complex mechanism for Gab1 translocation induced by IL-6, which involves and depends on the activation of ERK. This mechanism represents a new mode of regulation for the function of PH domains. Although the proposed mechanism suggests a positive feedback regulation, a detailed analysis of the influence of Gab1 on the kinetics and mutual regulation of the Gab1-dependent but STAT-independent signalling pathways initiated by IL-6 remains to be determined. Qualitative and quantitative differences are expected for the individual cytokines and growth factors utilizing Gab1 for signal transduction. The long term aim of the our activities at the newly established chair for system biology at the OvGU is to gain detailed knowledge on the regulatory function of adapter proteins in cytokine signalling and its impact on the balance and dynamics of signal transduction and consequently on gene expression, cell proliferation and other biological responses. Here, we will focus on the regulatory circuits of Gab1-regulated signal transduction pathway and their impact for the dynamics of signal transduction.