MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network

Science. 2002 Aug 9;297(5583):1018-23. doi: 10.1126/science.1068873.


Intracellular signaling networks receive and process information to control cellular machines. The mitogen-activated protein kinase (MAPK) 1,2/protein kinase C (PKC) system is one such network that regulates many cellular machines, including the cell cycle machinery and autocrine/paracrine factor synthesizing machinery. We used a combination of computational analysis and experiments in mouse NIH-3T3 fibroblasts to understand the design principles of this controller network. We find that the growth factor-stimulated signaling network containing MAPK 1, 2/PKC can operate with one (monostable) or two (bistable) stable states. At low concentrations of MAPK phosphatase, the system exhibits bistable behavior, such that brief stimulus results in sustained MAPK activation. The MAPK-induced increase in the amounts of MAPK phosphatase eliminates the prolonged response capability and moves the network to a monostable state, in which it behaves as a proportional response system responding acutely to stimulus. Thus, the MAPK 1, 2/PKC controller network is flexibly designed, and MAPK phosphatase may be critical for this flexible response.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Adaptation, Physiological
  • Animals
  • Cell Cycle Proteins*
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Dual Specificity Phosphatase 1
  • Feedback, Physiological*
  • Immediate-Early Proteins / metabolism*
  • MAP Kinase Signaling System*
  • Mathematics
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Phospholipases A / antagonists & inhibitors
  • Phospholipases A / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Protein Phosphatase 1
  • Protein Tyrosine Phosphatases / metabolism*


  • Cell Cycle Proteins
  • Immediate-Early Proteins
  • Protein Kinase C
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Phospholipases A
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse
  • Protein Tyrosine Phosphatases