Processive phosphorylation of ERK MAP kinase in mammalian cells
The mitogen-activated protein (MAP) kinase pathway is comprised of a three-tiered kinase cascade. The distributive kinetic mechanism of two-site MAP kinase phosphorylation inherently generates a nonlinear switch-like response. However, a linear graded response of MAP kinase has also been observed in...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (31), p.12675-12680 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Aoki, Kazuhiro Yamada, Masashi Kunida, Katsuyuki Yasuda, Shuhei Matsuda, Michiyuki |
| description | The mitogen-activated protein (MAP) kinase pathway is comprised of a three-tiered kinase cascade. The distributive kinetic mechanism of two-site MAP kinase phosphorylation inherently generates a nonlinear switch-like response. However, a linear graded response of MAP kinase has also been observed in mammalian cells, and its molecular mechanism remains unclear. To dissect these input-output behaviors, we quantitatively measured the kinetic parameters involved in the MEK (MAPK/ERK kinase)-ERK MAP kinase signaling module in HeLa cells. Using a numerical analysis based on experimentally determined parameters, we predicted in silico and validated in vivo that ERK is processively phosphorylated in HeLa cells. Finally, we identified molecular crowding as a critical factor that converts distributive phosphorylation into processive phosphorylation. We proposed the term quasi-processive phosphorylation to describe this mode of ERK phosphorylation that is operated under the physiological condition of molecular crowding. The generality of this phenomenon may provide a new paradigm for a diverse set of biochemical reactions including multiple posttranslational modifications. |
| doi_str_mv | 10.1073/pnas.1104030108 |
| format | Article |
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The distributive kinetic mechanism of two-site MAP kinase phosphorylation inherently generates a nonlinear switch-like response. However, a linear graded response of MAP kinase has also been observed in mammalian cells, and its molecular mechanism remains unclear. To dissect these input-output behaviors, we quantitatively measured the kinetic parameters involved in the MEK (MAPK/ERK kinase)-ERK MAP kinase signaling module in HeLa cells. Using a numerical analysis based on experimentally determined parameters, we predicted in silico and validated in vivo that ERK is processively phosphorylated in HeLa cells. Finally, we identified molecular crowding as a critical factor that converts distributive phosphorylation into processive phosphorylation. We proposed the term quasi-processive phosphorylation to describe this mode of ERK phosphorylation that is operated under the physiological condition of molecular crowding. 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The distributive kinetic mechanism of two-site MAP kinase phosphorylation inherently generates a nonlinear switch-like response. However, a linear graded response of MAP kinase has also been observed in mammalian cells, and its molecular mechanism remains unclear. To dissect these input-output behaviors, we quantitatively measured the kinetic parameters involved in the MEK (MAPK/ERK kinase)-ERK MAP kinase signaling module in HeLa cells. Using a numerical analysis based on experimentally determined parameters, we predicted in silico and validated in vivo that ERK is processively phosphorylated in HeLa cells. Finally, we identified molecular crowding as a critical factor that converts distributive phosphorylation into processive phosphorylation. We proposed the term quasi-processive phosphorylation to describe this mode of ERK phosphorylation that is operated under the physiological condition of molecular crowding. 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| subjects | Algorithms Amino Acid Sequence Antibodies Biological Sciences Blotting, Western Cell Nucleus - metabolism Cells Coefficients Computer Simulation Cytoplasm - metabolism Extracellular Signal-Regulated MAP Kinases - genetics Extracellular Signal-Regulated MAP Kinases - metabolism Fluorescence Resonance Energy Transfer HEK293 Cells HeLa Cells Humans Input output Kinetics Luminescent Proteins - genetics Luminescent Proteins - metabolism Mammals MAP Kinase Kinase 1 - genetics MAP Kinase Kinase 1 - metabolism MAP Kinase Signaling System mitogen-activated protein kinase Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase 1 - metabolism Modeling Models, Biological Phosphorylation post-translational modification Protein Kinases - genetics Protein Kinases - metabolism Proteins RNA Interference Scaffolds Simulations Western blotting |
| title | Processive phosphorylation of ERK MAP kinase in mammalian cells |
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