Many receptors coupled to the pertussis toxin-sensitive G i/o proteins stimulate the mitogenactivated protein kinase (MAPK) pathway. The role of the ␣ chains of these G proteins in MAPK activation is poorly understood. We investigated the ability of G␣ o to regulate MAPK activity by transient expression of the activated mutant G␣ o -Q205L in Chinese hamster ovary cells. G␣ o -Q205L was not sufficient to activate MAPK but greatly enhanced the response to the epidermal growth factor (EGF) receptor. This effect was not associated with changes in the state of tyrosine phosphorylation of the EGF receptor. G␣ o -Q205L also potentiated MAPK stimulation by activated Ras. In Chinese hamster ovary cells, EGF receptors activate B-Raf but not Raf-1 or A-Raf. We found that expression of activated G␣ o stimulated B-Raf activity independently of the activation of the EGF receptor or Ras. Inactivation of protein kinase C and inhibition of phosphatidylinositol-3 kinase abolished both B-Raf activation and EGF receptor-dependent MAPK stimulation by G␣ o . Moreover, G␣ o -Q205L failed to affect MAPK activation by fibroblast growth factor receptors, which stimulate Raf-1 and A-Raf but not B-Raf activity. These results suggest that G␣ o can regulate the MAPK pathway by activating B-Raf through a mechanism that requires a concomitant signal from tyrosine kinase receptors or Ras to efficiently stimulate MAPK activity. Further experiments showed that receptor-mediated activation of G␣ o caused a B-Raf response similar to that observed after expression of the mutant subunit. The finding that G␣ o induces Ras-independent and protein kinase C-and phosphatidylinositol-3 kinase-dependent activation of B-Raf and conditionally stimulates MAPK activity provides direct evidence for intracellular signals connecting this G protein subunit to the MAPK pathway. INTRODUCTIONThe mitogen-activated protein kinase (MAPK) pathway plays a central role in the stimulation of cell growth by cell surface receptors (Marshall, 1994;Cobb and Goldsmith, 1995). Both tyrosine kinase receptors and G protein-coupled receptors lead to the activation of the serine/threonine kinases known as p44 MAPK and p42 MAPK or extracellular signal-regulated kinases 1 and 2, which phosphorylate and regulate a large array of substrates, including nuclear transcription factors that control genes essential for cell proliferation (Davis, 1993). A well-characterized signaling pathway links tyrosine kinase receptors to MAPK activation. Growth factor-induced tyrosine phosphorylation of these receptors, and the subsequent recruitment of the adaptor molecules Shc and Grb2 bring to the plasma membrane the Sos protein, which acts as a guanine nucleotide exchange factor for Ras (Boguski and McCormick, 1993;Schlessinger, 1994). Ras activation is followed by a kinase cascade in which one or more of the proteins referred as Raf-1, A-Raf, and B-Raf phosphorylate and activate the MAPK/extracellular signal-regulated kinase kinases (MEK), which in turn phosphorylate and activate p44 and p42 MAPK (Mars...

The Wide Field Imager (WFI) is one of two focal plane instruments of the Advanced Telescope for High-Energy Astrophysics (Athena), ESA's next large x-ray observatory, planned for launch in the early 2030s. The current baseline halo orbit is around L2, and the second Lagrangian point of the Sun-Earth system L1 is under consideration. For both potential halo orbits, the radiation environment, solar and cosmic protons, electrons, and He-ions will affect the performance of the instruments. A further critical contribution to the instrument background arises from the unfocused cosmic hard x-ray background. It is important to understand and estimate the expected instrumental background and to investigate measures, such as design modifications or analysis methods, which could improve the expected background level to achieve the challenging scientific requirement (<5 × 10 −3 counts∕cm 2 ∕keV∕s at 2 to 7 keV). Previous WFI background simulations done in Geant4 have been improved by taking into account new information about the proton flux at L2. In addition, the simulation model of the WFI instrument and its surroundings employed in Geant4 simulations has been refined to follow the technological development of the WFI camera. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

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