tailieunhanh - Báo cáo khoa học: Principles behind the multifarious control of signal transduction ERK phosphorylation and kinase/phosphatase control

General and simple principles are identified that govern signal transduc-tion. The effects of kinase and phosphatase inhibition on a MAP kinase pathway are first examinedin silico. Quantitative measures for the control of signal amplitude, duration and integral strength are introduced. We then identify and prove new principles, such that total control on signal ampli-tude and on final signal strength must amount to zero, and total control on signal duration and on integral signal intensity must equal)1. Collec-tively, kinases control amplitudes more than duration, whereas phospha-tases tend to control both. . | iFEBS Journal Principles behind the multifarious control of signal transduction ERK phosphorylation and kinase phosphatase control Jorrit J. Hornberg1 Frank J. Bruggeman1 Bernd Binder2 Christian R. Geest1 A. J. Marjolein Bij de Vaate1 Jan Lankelma1 3 Reinhart Heinrich2 and Hans V. Westerhoff1 4 1 Department of Molecular CellPhysiology Institute for Molecular CellBiology BioCentrum Amsterdam Vrije Universiteit Amsterdam the Netherlands 2 Department of TheoreticalBiophysics Humboldt University Berlin Germany 3 Department of MedicalOncology VU medical center Amsterdam the Netherlands 4 Swammerdam Institute for Life Sciences BioCentrum Amsterdam University of Amsterdam the Netherlands Keywords control analysis kinase MAPK pathway phosphatase systems biology Correspondence H. V. Westerhoff Department of Molecular CellPhysiology Faculty of Earth and Life Sciences Free University Amsterdam De Boelelaan 1085 1085 HV Amsterdam the Netherlands Fax 31 20 4447229 Tel 31 20 4447230 E-mail hw@ Websites http vakgroepen mcp http hwconf supplements General and simple principles are identified that govern signal transduction. The effects of kinase and phosphatase inhibition on a MAP kinase pathway are first examined in silico. Quantitative measures for the control of signal amplitude duration and integral strength are introduced. We then identify and prove new principles such that total control on signal amplitude and on final signal strength must amount to zero and total control on signal duration and on integral signal intensity must equal -1. Collectively kinases control amplitudes more than duration whereas phosphatases tend to control both. We illustrate and validate these principles experimentally a a kinase inhibitor affects the amplitude of EGF-induced ERK phosphorylation much more than its duration and b a phosphatase inhibitor influences both signal duration and signal amplitude in particular long after EGF administration. Implications

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