Processive phosphorylation of ERK MAP kinase in mammalian cells

Kazuhiro Aoki, Masashi Yamada, Katsuyuki Kunida, Shuhei Yasuda, Michiyuki Matsuda

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)12675-12680
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number31
Publication statusPublished - 02-08-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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