A new mechanism for the regulation of Gab1 recruitment to the plasma membrane.
Adaptor 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, adaptor proteins represent a molecular platform from which different signalling pathways are initiated. Gab1 is an adaptor protein that recruits the p85 subunit of the phosphatidylinositol 3-kinase, the adaptor Grb2, the adaptor and phosphatase SHP2 and the GTPase-activating protein Ras-GAP. Gab1 thus contributes to the activation of the PI3K cascade and the MAPK cascade through many growth factors and cytokines. The recruitment of Gab1 to phosphatidylinositol (3,4,5)-trisphosphate within the plasma membrane by its pleckstrin-homology domain is regarded as a major regulatory step for the activation of Gab1. Here, we present a new more complex mechanism for Gab1 translocation that involves and depends on the activation of ERK. We demonstrate that the presence of PI3K activity in the cell is not sufficient for binding Gab1 to the plasma membrane. Instead, additional MAPK-dependent phosphorylation of Ser551 in Gab1 is crucial for the recruitment of Gab1 to the plasma membrane. This mechanism represents a new mode of regulation for the function of PH domains.
Eulenfeld
René
R
Department of Biochemistry, RWTH Aachen University, Aachen, Germany.
Schaper
Fred
F
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases