Ligand and receptor numbers may not be evenly distributed on the surface of a cell, so the proposed research will develop a model which tracks their dynamics on individual segments of the cell membrane.

The identities of cells sharing any contact are also stored. Close inspection of time-lapse microscopy images of NHU cells cultured in low calcium medium (0.09 mM) revealed that although significantly fewer stable contacts are formed than in physiological calcium, cells tended to remain in contact with one another for periods of up to one hour, before migrating away to form new contacts (see additional files 1 and 2).

Thus, although it is clear that multiple, interacting signalling pathways influence cell cycle progression and proliferation ([810]), there is compelling evidence for a causal link between EGFR-Erk signalling pathway and proliferation, at least in these cells.

10.1089/ten.2006.12.2301, Walker D, Wood S, Southgate J, Holcombe M, Smallwood R: An integrated agent-mathematical model of the effect of intercellular signalling via the Epidermal Growth Factor Receptor on cell proliferation. Below is an example of the autocrine versus juxtacrine signaling modes. and height z Journal of Cell Biology. 2001, 1 (1): 159-169.



Article More recently, we have combined this model with a mathematical representation of autocrine ligand release, diffusion and binding [6]. 10.1109/TNB.2004.833680.

Figure 7b shows the mean length of the perimeter of each cell associated with this type of contact. The model described above was used to study differences in the activated EGFR-mediated conversion of Erk into its active diphosphorylated form (active Erk or Erk-PP) associated with the differing nature of contacts seen in low (0.09 mM) and near physiological (2 mM) calcium environments. Terms and Conditions,

jag1 evs

This is considered to be the primary 'output' of the model, due to its role in mediating cell behaviour [12, 13]. The first three terms on the right hand side of the equations (1) and (2) in table 1 represent changes in the numbers of species arising from receptor-ligand interactions.

In these conditions, space constraints limit cell migration and the opportunity for cells to form transient contacts, and the Erk-PP profiles are similar in both low and physiological calcium environments.

Experimentally, cell populations are usually considered to be homogeneous. Results of sensitivity analysis. 10.1073/pnas.95.26.15368. 7.) A key component of this work will be to determine the dependence of pattern wavelengths on parameters, which represents a considerable mathematical challenge. Figure 4 shows the predicted active Erk signal resulting from juxtacrine EGFR-ligand engagement and subsequent intracellular signalling when two cells (each assumed to be oblate hemispheres with horizontal radius = 20 m, and vertical height = 10 m) form contacts at different rates (as illustrated in figure 2).

If the contact is lost, as shown in case 2, the Erk-PP signal quickly decays to zero in a matter of minutes.

Each cell will have n sets of equations 15, each associated with an existing intercellular contact i.e.

[1417]).

When bound to the Notch protein, the CSL transcription factors activate their target genes. Introduction of the new bond probability rules and the concept of transient contacts described above resulted in very limited migration even in low calcium conditions; this situation did not mirror that observed in real NHU cell cultures.

AB Orientation restrictions are responsible for the release requirement. Experimental Cell Research.

10.1074/jbc.274.42.30169, Schoeberl B, Eichler-Jonsson C, Gilles ED, Mller G: Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors.

Google Scholar, Hatakeyama M, Kimura S, Naka T, Kawasak iT, Yumoto N, Ichikawa M, Kim J, Saito K, Saeki M, Shirouzu M, Yokoyama S, Konagaya A: A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. California Privacy Statement,

Waves and propagation failure in discrete space models with nonlinear coupling and feedback, A Model of Primitive Streak Initiation in the Chick Embryo, Spatiotemporal Patterning in Models of Juxtacrine Intercellular Signalling with Feedback, Gene Networks Capable of Pattern Formation: From Induction to ReactionDiffusion, Discrete model of periodic pattern formation through a combined autocrinejuxtacrine cell signaling.

PubMed Results of intracellular signalling model. We have developed a multi-scale computational model that accounts for emergent heterogeneity arising from the influences of intercellular signalling on individual cells within a population.

Cardiac valve homeostasis along with other repercussions in disorders involving the cardiovascular system, 3.) From pathway to population a multiscale model of juxtacrine EGFR-MAPK signalling. Biosystems.

Journal of Theoretical Biology. [25]) and parameters for membrane-bound receptor-ligand interactions might be expected to vary quite significantly.

Unlike conventional modelling of intracellular signalling pathways, agent modelling allows the response of signalling to be interpreted at the cellular level. Proc Nat Acad Sci USA. In our agent-based model, this is currently represented by an arbitrary rule that a cell exits the mitotic cycle when it has n bonds with neighbouring cells. This multi-scale, multi-paradigm approach has enabled us to simulate Extracellular signal-regulated kinase (Erk) activation in a population of cells and to examine the consequences of interpretation at a single cell or population-based level using virtual assays.

where clen is the length of cell boundary involved in non specific contacts, b1 and b2 are the number of E-cadherin mediated bonds that have existed for less and more than one hour respectively, and P1 and P2 are the levels of functional E-cadherin expression (between 0 and 1). Case 3 shows the signal arising from an 'instantaneously' formed 12 m contact.

By necessity, the model presented here is a simplification of the real intracellular pathway, which may include up to 19,000 distinct molecular species ([29]).

Fibronectin receptor complexes bind fibronectin on the outside of the cell and bind the cytoskeleton proteins on the inside of the cell.

A common of example of the latter in a cell biology context is the interpretation of Western blotting data obtained from cultured cell populations. Part of This could have important potential implications for understanding how proliferation controls are lost in the event of malignant transformation and how such malignant cells behave in comparison to their normal counterparts during carcinogenesis. Diffusion of EGFR and ligands in and out of the contact area is ignored. evs jag1 inhibit huvecs These results provide an important insight into the potential pitfalls of interpreting experimental data that is averaged over relatively large cell numbers. These receptor proteins are known as integrins because they integrate extracellular and intracellular scaffolds, allowing them to work together. This leads to the following formulation for total adhesion force acting on a cell: AF = (0.32 * clen) + (P1 * P2(100 * b 1 + 200 * b 2)). Cell behaviour can be modelled by representing individual cells as computational entities or software agents.

We have extended our previous, simple sigmoidal relationship between extracellular calcium and E-cadherin-mediated cell contact to a more sophisticated rule set which more quantitatively reflects the observations in [21, 22].

2) A receptor on one cell binds to its ligand on the extracellular matrix given off by another cell.

These results suggest that in populations where the cell density is relatively high, but growth is not contact-inhibited (ie pre-confluent cultures with several hundred cells per mm2), the activated Erk signal averaged over the population would be higher in low calcium (e.g.

2000, 97 (8): 4005-4010. A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal.

As described in [3], transition through this checkpoint is dependent on cell:cell bonding and cell spreading, with the underpinning rule set mimicking the phenomenon of contact inhibition of growth. Below are the links to the authors original submitted files for images. 2000, 22: 818-826. We have also demonstrated how an agent-based computational approach has a role as an iterative, predictive tool by generating 'virtual assays' to bring new insight into the interpretation of cell biological experiments. 10.1016/j.jtbi.2006.04.020, Varley C, Hill G, Pellegrin S, Shaw N, Selby P, Trejdosiewicz L, Southgate J: Autocrine Regulation of Human Urothelial Cell Proliferation and Migration during Regenerative Responses In Vitro.

10.1074/jbc.274.27.19347.

10.1016/S0006-3495(93)81253-0.

By contrast, in physiological calcium, stable contacts are formed quickly. The cleaved portion enters the nucleus and binds to an inactive transcription factor of the CSL family.

We have previously developed Epitheliome, an agent-based model of epithelial cell populations.

The architecture of intercellular contacts within beta cell islets has been shown to result in heterogenous production of insulin [2].

The ability of a cell to bind to Laminin and Fibronectin depends on its expression of a cell membrane receptor for the cell-binding site of these large molecules.

This page was last edited on 28 July 2019, at 20:45. autocrine signaling cell quorum sensing paracrine figure spectrum ends extreme common

The maximum migration velocity was estimated from time-lapse images of NHU cells to be in the region of 80 m/hour.

The constant k1 is the receptor-ligand association constant; k-1 the dissociation constant; k

During this period of transient contact, it is feasible that juxtacrine signals may be exchanged between cells and therefore, we have chosen to include the concept of transient cell contact in our agent model.

We have so far neglected possible membrane diffusion of receptors and ligands, potential targeting of newly synthesised EGFR and ligand to, or clustering at, stable E-cadherin-mediated contacts.

Although there is variation in the amplitude and duration of the ERK-PP signals when kinetic parameters are altered, none of the parameter variations affected the fundamental result that transient contacts result in a relatively large, transient response, compared to the smaller but sustained response associated with slowly-growing stable contacts. where clen is the length of the non-specific contact length and max_r is 1.5 times the larger of the two cell radii The form of this relationship is somewhat arbitrary, but the range of contact lengths produced gives a reasonable agreement with that observed in microscopy images of growing NHU cell cultures ([20], additional file 1). Biophysical Journal.

The agent (rule-based) and signalling (ODE-based) models are run alternately. Virtual Western Blots. When an integrin on a cell membrane of one cell binds to the fibronection or collagen secreted by a neighboring cell, integrins can activate tyrosine kinase cascades through an adaptor protein-like complex that connects the integrins to a Ras G protein.

The authors would like to thank RCUK, who provide the Academic Fellowship held by DW. This can be particularly problematic when the parameters are difficult to measure experimentally and are thus estimated or assumed. The signalling pathway model was solved for both a transient, 15 m contact and a growing then stable 3 m contact.

Figure 7a shows the relative frequency of E-cadherin mediated contacts in the case of a seeding density of 200 cells/mm2 (2 104 cells/cm2). Epithelial tissues express the cadherin subgroup, E-cadherin, which is critical for forming initial adherens contacts between cells in developing tissues or cell cultures, allowing more established structures such as tight junctions and desmosomes to develop. 2005, 306 (1): 216-229. An example of this could be the situation where an E-cadherinnull cell arises by mutation and the fate of the population subset is determined relative to its interactions with the rest of the population.

Our approach of using an individual-based paradigm naturally lends itself to examining heterogeneity, either by varying the internal parameters (memory state) of each agent, or by observing the emergent behaviour of agents in differing micro-environments.

Google Scholar, Walker D, Southgate J, Hill G, Holcombe M, Hose D, Wood S, Macneil S, Smallwood R: The Epitheliome: modelling the social behaviour of cells. The length of E-cadherin mediated contacts grow linearly with time until a maximum length of 1.5 times the cell radius is reached (as specified by equation 6 in table 2).

For instance, V16, V18 and V24, (which describe the maximal rate of Raf, Mek and Erk dephosphorylation respectively see table 3), all had a significant influence on signal amplitude; by contrast, parameters describing the rate of receptor ligand binding, receptor dimerisation, activation and internalisation had a much less significant effect.

Direct Transmission of Signals through Gap Junctions.

Regulation of cell-fate in mammary glands at several development stages. 1994, 71 (4): 583-594. The end point of this model pathway is the activation (diphosphorylation) of the cytoplasmic protein, Erk. G ProteinCoupled Estrogen Receptor and Its Pharmacologic Modulators, Cell Membrane Biology and Juxtacrine Signal Conversion, Techniques for analysing pattern formation in populations of stem cells and their progeny, Cellular automata and integrodifferential equation models for cell renewal in mosaic tissues, Collective migration of an epithelial monolayer in response to a model wound, A Framework for Discrete Modeling of Juxtacrine Signaling Systems, Biological Physics of the Developing Embryo, Effect of time delay on pattern formation: Competition between homogenisation and patterning, Identification of strong interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines, Spatial Patterning in Explicitly Cellular Environments: Activity-Regulated Juxtacrine Signalling, Reactiondiffusion models of development with state-dependent chemical diffusion coefficients, Discrete Models of Autocrine Cell Communication in Epithelial Layers. Biochemistry.

, fixed at 5 m (a reasonable value considering the flattened morphology of adherent epithelial cells).

When two identical connexons come together to form a gap junction, it is called a homotypic gap junction.

(AVI 11 MB).

[3, 6]), only cells with zero intercellular contacts were able to migrate. 10.1016/j.jtbi.2007.01.019.

Conzelmann H, Saez-Rodriguez J, Sauter T, Bullinger E, Allgower F, Gilles E: Reduction of mathematical models of signal transduction networks: simulation-based approach applied to EGF receptor signalling.
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