Substrate-dependent control of MAPK phosphorylation in vivo

Yoosik Kim, Ze'Ev Paroush, Knud Nairz, Ernst Hafen, Gerardo Jiménez, Stanislav Y. Shvartsman

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71 Scopus citations


Phosphorylation of the mitogen-activated protein kinase (MAPK) is essential for its enzymatic activity and ability to control multiple substrates inside a cell. According to the current models, control of MAPK phosphorylation is independent of its substrates, which are viewed as mere sensors of MAPK activity. Contrary to this modular view of MAPK signaling, our studies in the Drosophila embryo demonstrate that substrates can regulate the level of MAPK phosphorylation in vivo. We demonstrate that a twofold change in the gene dosage of a single substrate can induce a significant change in the phosphorylation level of MAPK and in the conversion of other substrates. Our results support a model where substrates of MAPK counteract its dephosphorylation by phosphatases. Substrate-dependent control of MAPK phosphorylation is a manifestation of a more general retroactive effect that should be intrinsic to all networks with covalent modification cycles.

Original languageEnglish (US)
Article number467
JournalMolecular Systems Biology
StatePublished - 2011

All Science Journal Classification (ASJC) codes

  • General Immunology and Microbiology
  • Applied Mathematics
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


  • MAPK cascades
  • cell signaling
  • network biology


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