Reduction of mathematical models of signal transduction networks: simulation-based approach applied to EGF receptor signalling

2004 ◽  
Vol 1 (1) ◽  
pp. 159-169 ◽  
Author(s):  
H. Conzelmann ◽  
T. Sauter ◽  
E.D. Gilles ◽  
F. Allgöwer ◽  
J. Saez-Rodriguez ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Mathematical Models ◽  
Egf Receptor ◽  
Receptor Signalling ◽  
Signal Transduction Networks ◽  
Simulation Based

scholarly journals Control Design for Signal Transduction Networks

2009 ◽  
Vol 3 ◽  
pp. BBI.S2116 ◽  
Author(s):  
Chun-Liang Lin ◽  
Yuan-Wei Liu ◽  
Chia-Hua Chuang
Keyword(s):  
Signal Transduction ◽  
Mathematical Models ◽  
Dynamic Analysis ◽  
Control Strategy ◽  
Controller Design ◽  
Control Design ◽  
Effective Control ◽  
Analysis Model ◽  
Signal Transduction Networks ◽  
Design Idea

Signal transduction networks of biological systems are highly complex. How to mathematically describe a signal transduction network by systematic approaches to further develop an appropriate and effective control strategy is attractive to control engineers. In this paper, the synergism and saturation system (S-systems) representations are used to describe signal transduction networks and a control design idea is presented. For constructing mathematical models, a cascaded analysis model is first proposed. Dynamic analysis and controller design are simulated and verified.

scholarly journals Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.

1996 ◽  
Vol 135 (6) ◽  
pp. 1633-1642 ◽  
Author(s):  
S Miyamoto ◽  
H Teramoto ◽  
J S Gutkind ◽  
K M Yamada
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Transient Activation

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.

Heartbroken is a specific downstream mediator of FGF receptor signalling in Drosophila

Development ◽  
1998 ◽  
Vol 125 (22) ◽  
pp. 4379-4389 ◽  
Author(s):  
A.M. Michelson ◽  
S. Gisselbrecht ◽  
E. Buff ◽  
J.B. Skeath
Keyword(s):  
Egf Receptor ◽  
Genetic Interaction ◽  
Egf Receptors ◽  
Tracheal System ◽  
Fgf Receptor ◽  
Receptor Signalling ◽  
Early Migration ◽  
New Gene ◽  
Developmental Responses ◽  
Downstream Mediator

Drosophila possesses two FGF receptors which are encoded by the heartless and breathless genes. HEARTLESS is essential for early migration and patterning of the embryonic mesoderm, while BREATHLESS is required for proper branching of the tracheal system. We have identified a new gene, heartbroken, that participates in the signalling pathways of both FGF receptors. Mutations in heartbroken are associated with defects in the migration and later specification of mesodermal and tracheal cells. Genetic interaction and epistasis experiments indicate that heartbroken acts downstream of the two FGF receptors but either upstream of or parallel to RAS1. Furthermore, heartbroken is involved in both the HEARTLESS- and BREATHLESS-dependent activation of MAPK. In contrast, EGF receptor-dependent embryonic functions and MAPK activation are not perturbed in heartbroken mutant embryos. A strong heartbroken allele also suppresses the effects of hyperactivated FGF but not EGF receptors. Thus, heartbroken may contribute to the specificity of developmental responses elicited by FGF receptor signalling.

Abstract 486: Artificial miRNA Based Adenoviral Adam17 Silencing Reveals Essential Role of This Metalloprotease For EGF Receptor Transactivation In Primary Cultured Vascular Smooth Muscle Cells

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Katherine Elliott ◽  
Allison Bourne ◽  
Takehiko Takayanagi ◽  
Akira Takaguri ◽  
Kunie Eguchi ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Gene Silencing ◽  
Vascular Smooth Muscle Cells ◽  
Egf Receptor ◽  
Muscle Cells ◽  
Vascular Cells ◽  
Receptor Transactivation

siRNA mediated gene silencing has been recently utilized as a powerful molecular tool to study the functional significance of a specific protein. However, due to the transient nature of silencing and insufficient transfection efficiency, this approach can be problematic in primary cell culture. To overcome such weakness of the siRNA based silencing and in order to establish reliable gene silencing in vascular cells, we devised an adenoviral-encoded miRNA based gene silencing system. Here we report the results of silencing ADAM17 in cultured rat vascular smooth muscle cells (VSMCs) and its functional consequences in angiotensin II (AngII) signal transduction. Four distinct miRNA sequences targeting rat ADAM17 were chosen based on recommendations from Invitrogen’s Block-iT RNAi Designer algorithm. The miRNA sequences were inserted into a mammalian expression vector, pcDNA 6.2-GW/EmGFP-miR, and the effective silencing by these vectors was confirmed in HEK cells expressing HA-tagged rat ADAM17. The 4 cassettes carrying the miRNAs were inserted into pAd/CMV/V5-DEST and adenoviral solutions were obtained. Greater than 95% silencing of ADAM17 was achieved when VSMC were infected with 100-200 moi of the ADAM17 miRNA encoding adeonvirus for 72 h with enhancement of infection by fugene6. Relatively linear time and concentration dependencies were observed between 1 to 3 days and 10 to 100 moi of the infection. A miR-ADAM17 (100 moi) but not miR-control (100 moi) completely inhibited 100 nM AngII-induced HB-EGF shedding in VSMCs as assessed by a reporter assay. A miR-ADAM17 but not miR-control also inhibited AngII-induced EGF receptor transactivation and subsequent ERK1/2 activation in VSMCs as assessed by immunoblotting with phospho-selective antibodies. In conclusion, ADAM17 was found to be a major sheddase for HB-EGF contributing to the growth promoting signals induced by AngII in VSMCs. An artificial miRNA-base adenoviral approach appears to be a reliable gene-silencing strategy for signal transduction research in primary cultured vascular cells.

Evidence for epidermal growth factor (EGF)-induced intermolecular autophosphorylation of the EGF receptors in living cells

1990 ◽  
Vol 10 (8) ◽  
pp. 4035-4044
Author(s):  
A M Honegger ◽  
A Schmidt ◽  
A Ullrich ◽  
J Schlessinger
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Egf Receptor ◽  
Living Cells ◽  
Egf Receptors ◽  
Receptor Molecule ◽  
Epidermal Growth ◽  
Negative Mutant

In response to epidermal growth factor (EGF) stimulation, the intrinsic protein tyrosine kinase of EGF receptor is activated, leading to tyrosine phosphorylation of several cellular substrate proteins, including the EGF receptor molecule itself. To test the mechanism of EGF receptor autophosphorylation in living cells, we established transfected cell lines coexpressing a kinase-negative point mutant of EGF receptor (K721A) with an active EGF receptor mutant lacking 63 amino acids from its carboxy terminus. The addition of EGF to these cells caused tyrosine phosphorylation of the kinase-negative mutant by the active receptor molecule, demonstrating EGF receptor cross-phosphorylation in living cells. After internalization the kinase-negative mutant and CD63 have separate trafficking pathways. This limits their association and the extent of cross-phosphorylation of K721A by CD63. The coexpression of the kinase-negative mutant together with active EGF receptors in the same cells suppressed the mitogenic response toward EGF as compared with that in cells that express active receptors alone. The presence of the kinase-negative mutant functions as a negative dominant mutation suppressing the response of active EGF receptors, probably by interfering with EGF-induced signal transduction. It appears, therefore, that crucial events of signal transduction occur before K721A and active EGF receptors are separated by their different endocytic itineraries.

Epistemic Opacity

2019 ◽  
pp. 98-131
Author(s):  
Johannes Lenhard
Keyword(s):  
Mathematical Models ◽  
Simulation Models ◽  
Scientific Understanding ◽  
The Other ◽  
Weak Version ◽  
Simulation Based ◽  
Lower Standard ◽  
Epistemic Standards ◽  
Epistemic Opacity ◽  
Experimental Runs

This chapter shows that—and how—simulation models are epistemically opaque. Nevertheless, it is argued, simulation models can provide a means to control dynamics. Researchers can employ a series of iterated (experimental) runs of the model and can learn to orient themselves within the model—even if the dynamics of the simulation remain (at least partly) opaque. Admittedly, such an acquaintance with the model falls short of the high epistemic standards usually ascribed to mathematical models. This lower standard is still sufficient, however, when the aim is controlled intervention in technological contexts. On the other hand, opacity has to be accepted if the option for control is to remain in any way open. This chapter closes by discussing whether epistemic opacity restricts simulation-based science to a pragmatic—“weak”—version of scientific understanding.

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