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MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network (2002)

U. S. Bhalla ; P. T. Ram ; R. Iyengar

American Association for the Advancement of Science (AAAS)

In: Science. 297(5583): 1018-23. doi: 10.1126/science.1068873.

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Publication Date: 2002-08-10

Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhalla, Upinder S -- Ram, Prahlad T -- Iyengar, Ravi -- CA-79134/CA/NCI NIH HHS/ -- CA-81050/CA/NCI NIH HHS/ -- GM-54508/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2002 Aug 9;297(5583):1018-23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Center for Biological Sciences, Bangalore 560065 India. bhalla@ncbs.res.in〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12169734" target="_blank"〉PubMed〈/a〉

Keywords: 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/metabolism ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Kinase C/metabolism ; Protein Phosphatase 1 ; Protein Tyrosine Phosphatases/*metabolism

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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Stat3-mediated transformation of NIH-3T3 cells by the constitutively active Q205L Galphao protein (1999)

P. T. Ram ; C. M. Horvath ; R. Iyengar

American Association for the Advancement of Science (AAAS)

In: Science. 287(5450): 142-4.

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Publication Date: 1999-12-30

Description: Expression of Q205L Galphao (Galphao*), an alpha subunit of heterotrimeric guanine nucleotide-binding proteins (G proteins) that lacks guanosine triphosphatase (GTPase) activity in NIH-3T3 cells, results in transformation. Expression of Galphao* in NIH-3T3 cells activated signal transducer and activator of transcription 3 (Stat3) but not mitogen-activated protein (MAP) kinases 1 or 2. Coexpression of dominant negative Stat3 inhibited Galphao*-induced transformation of NIH-3T3 cells and activation of endogenous Stat3. Furthermore, Galphao* expression increased activity of the tyrosine kinase c-Src, and the Galphao*-induced activation of Stat3 was blocked by expression of Csk (carboxyl-terminal Src kinase), which inactivates c-Src. The results indicate that Stat3 can function as a downstream effector for Galphao* and mediate its biological effects.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ram, P T -- Horvath, C M -- Iyengar, R -- 1F32 CA79134-01/CA/NCI NIH HHS/ -- DK-38671/DK/NIDDK NIH HHS/ -- GM-54508/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2000 Jan 7;287(5450):142-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Immunobiology Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. ramp01@doc.mssm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10615050" target="_blank"〉PubMed〈/a〉

Keywords: 3T3 Cells ; Animals ; Cell Line, Transformed ; *Cell Transformation, Neoplastic ; DNA-Binding Proteins/*metabolism ; Enzyme Activation ; GTP-Binding Protein alpha Subunits ; Genes, Reporter ; Heterotrimeric GTP-Binding Proteins/genetics/*metabolism ; MAP Kinase Signaling System ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Neurites/physiology ; Neuronal Plasticity ; Neurons/metabolism/physiology ; Phosphorylation ; Phosphotyrosine/metabolism ; Protein-Tyrosine Kinases/metabolism ; STAT3 Transcription Factor ; Signal Transduction ; Trans-Activators/*metabolism ; Transfection ; src-Family Kinases

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Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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Formation of regulatory patterns during signal propagation in a Mammalian cellular network (2005)

A. Ma'ayan ; S. L. Jenkins ; S. Neves ; [et al.]

American Association for the Advancement of Science (AAAS)

In: Science. 309(5737): 1078-83. doi: 10.1126/science.1108876.

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Publication Date: 2005-08-16

Description: We developed a model of 545 components (nodes) and 1259 interactions representing signaling pathways and cellular machines in the hippocampal CA1 neuron. Using graph theory methods, we analyzed ligand-induced signal flow through the system. Specification of input and output nodes allowed us to identify functional modules. Networking resulted in the emergence of regulatory motifs, such as positive and negative feedback and feedforward loops, that process information. Key regulators of plasticity were highly connected nodes required for the formation of regulatory motifs, indicating the potential importance of such motifs in determining cellular choices between homeostasis and plasticity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032439/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032439/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma'ayan, Avi -- Jenkins, Sherry L -- Neves, Susana -- Hasseldine, Anthony -- Grace, Elizabeth -- Dubin-Thaler, Benjamin -- Eungdamrong, Narat J -- Weng, Gehzi -- Ram, Prahlad T -- Rice, J Jeremy -- Kershenbaum, Aaron -- Stolovitzky, Gustavo A -- Blitzer, Robert D -- Iyengar, Ravi -- DA15863/DA/NIDA NIH HHS/ -- GM-072853/GM/NIGMS NIH HHS/ -- GM-54508/GM/NIGMS NIH HHS/ -- GM-62754/GM/NIGMS NIH HHS/ -- GM-65065/GM/NIGMS NIH HHS/ -- P50 GM071558/GM/NIGMS NIH HHS/ -- P50 GM071558-01A20007/GM/NIGMS NIH HHS/ -- P50 GM071558-020007/GM/NIGMS NIH HHS/ -- P50 GM071558-030007/GM/NIGMS NIH HHS/ -- R01 GM054508/GM/NIGMS NIH HHS/ -- R01 GM054508-12/GM/NIGMS NIH HHS/ -- R01 GM072853/GM/NIGMS NIH HHS/ -- R01 GM072853-01/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2005 Aug 12;309(5737):1078-83.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Biological Chemistry Mount Sinai School of Medicine, New York, NY 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16099987" target="_blank"〉PubMed〈/a〉

Keywords: Algorithms ; Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Feedback, Physiological ; Glutamic Acid/metabolism ; Hippocampus/*cytology/physiology ; Homeostasis ; Ligands ; Long-Term Potentiation ; Mammals ; Mathematics ; Mitogen-Activated Protein Kinases/metabolism ; Models, Neurological ; Neuronal Plasticity ; Neurons/*physiology ; Norepinephrine/metabolism ; Protein Kinase C/metabolism ; Receptors, AMPA/metabolism ; *Signal Transduction ; Software ; Systems Biology

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Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

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G protein pathways (2002)

S. R. Neves ; P. T. Ram ; R. Iyengar

American Association for the Advancement of Science (AAAS)

In: Science. 296(5573): 1636-9. doi: 10.1126/science.1071550.

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Publication Date: 2002-06-01

Description: The heterotrimeric guanine nucleotide-binding proteins (G proteins) are signal transducers that communicate signals from many hormones, neurotransmitters, chemokines, and autocrine and paracrine factors. The extracellular signals are received by members of a large superfamily of receptors with seven membrane-spanning regions that activate the G proteins, which route the signals to several distinct intracellular signaling pathways. These pathways interact with one another to form a network that regulates metabolic enzymes, ion channels, transporters, and other components of the cellular machinery controlling a broad range of cellular processes, including transcription, motility, contractility, and secretion. These cellular processes in turn regulate systemic functions such as embryonic development, gonadal development, learning and memory, and organismal homeostasis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neves, Susana R -- Ram, Prahlad T -- Iyengar, Ravi -- CA-81050/CA/NCI NIH HHS/ -- DK-38761/DK/NIDDK NIH HHS/ -- F31GM65065/GM/NIGMS NIH HHS/ -- GM-54508/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2002 May 31;296(5573):1636-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12040175" target="_blank"〉PubMed〈/a〉

Keywords: Animals ; DNA-Binding Proteins/chemistry/metabolism ; GTP-Binding Protein alpha Subunits, G12-G13 ; GTP-Binding Protein alpha Subunits, Gi-Go/chemistry/metabolism ; GTP-Binding Protein alpha Subunits, Gq-G11 ; GTP-Binding Protein alpha Subunits, Gs/chemistry/metabolism ; Heterotrimeric GTP-Binding Proteins/chemistry/*metabolism ; Humans ; Models, Biological ; Receptors, Cell Surface/*metabolism ; *Signal Transduction

Print ISSN: 0036-8075

Electronic ISSN: 1095-9203

Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics

Published by American Association for the Advancement of Science (AAAS)

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