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Processive phosphorylation of ERK MAP kinase in mammalian cells

Kazuhiro Aoki, Masashi Yamada, Katsuyuki Kunida, Shuhei Yasuda and Michiyuki Matsuda
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 31 (August 2, 2011), pp. 12675-12680
Stable URL: http://www.jstor.org/stable/27979070
Page Count: 6
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Abstract

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.

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