TAILIEUCHUNG - Báo cáo khoa học: Synergistic activation of signalling to extracellular signal-regulated kinases 1 and 2 by epidermal growth factor and 4b-phorbol 12-myristate 13-acetate

Signal transduction pathways are often embedded in com-plex networks, which result from interactions between pathways and feedback circuitry. In order to understand such networks, qualitative information on which inter-actions take place and quantitative data on their strength become essential. Here, we have investigated how the mul-tiple interactions between the mitogen-activated protein kinase cascade and protein kinase C (PKC) affect the time profile of extracellular signal-regulated kinase (ERK) phos-phorylation upon epidermal growth factor (EGF) stimula-tion in normal rat kidney fibroblasts | Eur. J. Biochem. 271 3905-3913 2004 FEBS 2004 doi Synergistic activation of signalling to extracellular signal-regulated kinases 1 and 2 by epidermal growth factor and 40-phorbol 12-myristate 13-acetate Jorrit J. Hornberg1 Marloes R. Tijssen1 and Jan Lankelma1 2 1 Department of Molecular Cell Physiology Institute of Molecular Cell Biology Faculty of Earth and Life Sciences Vrije Universiteit Amsterdam the Netherlands department of Medical Oncology VU Medical Center Amsterdam the Netherlands Signal transduction pathways are often embedded in complex networks which result from interactions between pathways and feedback circuitry. In order to understand such networks qualitative information on which interactions take place and quantitative data on their strength become essential. Here we have investigated how the multiple interactions between the mitogen-activated protein kinase cascade and protein kinase C PKC affect the time profile of extracellular signal-regulated kinase ERK phosphorylation upon epidermal growth factor EGF stimulation in normal rat kidney fibroblasts. This profile is a major determinant for the cellular response that is evoked. We found that EGF stimulation leads to a biphasic ERK-PP pattern consisting of an initial peak and a relaxation to a low quasi-steady state-phase. Costimulation with the EGF and PKC activator 4ịl-phorbol 12-myristate 13-acetate PMA resulted in a similar pattern but the ERK-PP concentration in the quasi-steady state-phase was synergistically higher than after stimulation with either EGF or PMA only. This resulted in prolonged signalling to ERK. PMA increased the EGF concentration sufficient to obtain half-maximum ERK phosphorylation. These data suggest that PKC amplifies EGF-induced signalling to ERK without increasing its sensitivity to low EGF concentrations. Furthermore PKC inhibition did not affect the ERK-PP time profile upon EGF stimulation and a cellular phospholipase A2 cPLA2 .

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