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Science 297 (5583): 1018-1023

Copyright © 2002 by the American Association for the Advancement of Science

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

Upinder S. Bhalla,1*dagger Prahlad T. Ram,2*dagger Ravi Iyengar2

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.

1 National Center for Biological Sciences, Bangalore 560065 India.
2 Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
*   These authors contributed equally to this work.

dagger    Queries regarding computational analysis should be addressed to U.S.B. (e-mail: bhalla{at}ncbs.res.in) and experimental work to P.T.R. (e-mail: prahlad.ram{at}mssm.edu

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Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors.
B. N Kholodenko (2003)
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Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer.
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J. Biol. Chem. 278, 23107-23117
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Endogenous versus exogenous glucocorticoid responses to experimental bacterial sepsis.
R. Silverstein and D. C. Johnson (2003)
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The Bio-Logic and machinery of plant morphogenesis.
K. J. Niklas (2003)
Am. J. Botany 90, 515-525
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Nicotiana benthamiana gp91phox Homologs NbrbohA and NbrbohB Participate in H2O2 Accumulation and Resistance to Phytophthora infestans.
H. Yoshioka, N. Numata, K. Nakajima, S. Katou, K. Kawakita, O. Rowland, J. D. G. Jones, and N. Doke (2003)
PLANT CELL 15, 706-718
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Identification of nucleocytoplasmic cycling as a remote sensor in cellular signaling by databased modeling.
I. Swameye, T. G. Muller, J. Timmer, O. Sandra, and U. Klingmuller (2003)
PNAS 100, 1028-1033
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SIGNAL TRANSDUCTION: History Matters.
N. T. Ingolia and A. W. Murray (2002)
Science 297, 948-949
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