MAP Kinase Phosphatase as a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network

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 sy...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2002-08, Vol.297 (5583), p.1018-1023
Main Authors: Bhalla, Upinder S., Ram, Prahlad T., Iyengar, Ravi
Format: Article
Language:English
Subjects:
3T3 Cells
Adaptation, Physiological
Animals
Antibodies
Biological and medical sciences
Cell cycle
Cell Cycle Proteins
Cell cycle, cell proliferation
Cell physiology
Cellular biology
Cellular signal transduction
Computer analysis
Computer Simulation
Design analysis
Dose-Response Relationship, Drug
Dual Specificity Phosphatase 1
Experiment design
Feedback (Response)
Feedback, Physiological
Fibroblasts
Fundamental and applied biological sciences. Psychology
Immediate-Early Proteins - metabolism
MAP Kinase Signaling System
Mathematics
Mental stimulation
Mice
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
Models, Biological
Molecular and cellular biology
Networks
NIH 3T3 cells
Phosphatases
Phospholipases
Phospholipases A - antagonists & inhibitors
Phospholipases A - metabolism
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Physiological regulation
Protein Kinase C - metabolism
Protein Phosphatase 1
Protein tyrosine kinase
Protein Tyrosine Phosphatases - metabolism
Proteins
Signal transduction
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1068873