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Reconstruction of cellular signalling networks and analysis of their properties

Nature Reviews Molecular Cell Biology volume 6, pages 99–111 (2005)Cite this article

Key Points

  • Cellular signalling networks are beginning to be reconstructed at a genome-scale.

  • An order-of-magnitude analysis of the human signalling network provides an estimate of the number of network components, their degree of interconnectivity, and informative functional constraints on network function.

  • Signalling network reconstructions are expanding in scope and detail through the development of new experimental approaches.

  • With integrative and iterative approaches, network reconstructions can be refined to provide increasingly more accurate representations of signalling systems.

  • Structural analyses of signalling networks have successfully identified crucial network components, and allowed for mathematical definitions of network properties.

  • When parameters are well characterized, dynamic analyses of signalling networks have successfully modelled time profiles of component concentrations, which provides insight into network function.

Abstract

The study of cellular signalling over the past 20 years and the advent of high-throughput technologies are enabling the reconstruction of large-scale signalling networks. After careful reconstruction of signalling networks, their properties must be described within an integrative framework that accounts for the complexity of the cellular signalling network and that is amenable to quantitative modelling.

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Figure 1: Integrative and iterative process of cellular signalling network reconstruction.
Figure 2: Structural analyses of signalling networks.
Figure 3: Dynamic analyses of cellular signalling networks.

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Acknowledgements

We would like to thank the Whitaker Foundation for a Graduate Fellowship to J.P., and acknowledge grants from the National Institutes of Health to S.S. T.H. is a Frank and Else Schilling American Cancer Society Research Professor. B.O.P. is a member of the Scientific Advisory Board of Genomatica Inc. We would also like to acknowledge valuable input from A. Hoffmann, and thank T. Allen, S. Becker, N. Price and J. Reed for detailed feedback on the manuscript.

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Authors and Affiliations

  1. Department of Bioengineering, 9500 Gilman Drive, Mail Code 0412, University of California, San Diego, La Jolla, 92093-0412, California, USA

    Jason A. Papin, Bernhard O. Palsson & Shankar Subramaniam

  2. Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia, 22908, USA

    Jason A. Papin

  3. The Salk Institute for Biological Studies, Molecular and Cellular Biology Laboratory, 10010 North Torrey Pines Road, La Jolla, 92037-1099, California, USA

    Tony Hunter

  4. Department of Chemistry & Biochemistry, San Diego Supercomputing Center, University of California, 9500 Gilman Drive, San Diego, 92093-0505, California, USA

    Shankar Subramaniam

Authors
  1. Jason A. Papin
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  2. Tony Hunter
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  3. Bernhard O. Palsson
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  4. Shankar Subramaniam
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Corresponding authors

Correspondence to Bernhard O. Palsson or Shankar Subramaniam.

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DATABASES

Entrez

CD44

NFKBIB

TTID

Saccharomyces genome database

Fus3

Swiss-Prot

GFP

IκBβ

JNK

RAS

SOS

TNFα

FURTHER INFORMATION

Alliance for Cellular Signaling

Bioinformatics and Computational Biology

Cell Migration Consortium

Genomatica

Human Proteomics Initiative

LIPID MAPS consortium

Molecular and Cellular Biology laboratory

Systems Biology Research Group

Glossary

NETWORK RECONSTRUCTION

The process of integrating different data sources to create a representation of the chemical events that underlie a biochemical reaction network.

ORDER OF MAGNITUDE

A simple, quantitative estimate of a parameter.

AUTOCRINE

Describing, or relating to, a cell that produces the ligands by which it is activated.

PARACRINE

Describing, or relating to, a regulatory cell that secretes an agonist into intercellular spaces from which it diffuses to a target cell other than the one that produces it.

ENDOCRINE

Describing, or relating to, a gland or group of cells that makes hormones and secretes them into the blood, lymph or intercellular fluid.

HELPER T CELL

A T cell that functions as an inducer of the effector cells for humoral and cell-mediated immunity. These cells recognize and bind to antigen.

PHAGOCYTOSIS

An actin-dependent process by which cells engulf external particulate material by extension and fusion of pseudopods.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G proteins to stimulate or inhibit the activity of a downstream enzyme.

MAST CELL

A type of leukocyte with large secretory granules that contain histamine and various protein mediators.

MEGAKARYOCYTES

Bone-marrow precursor cells that give rise to blood platelets. During differentiation, megakaryocytes become polyploid by endoreplication.

EXTRACELLULAR MATRIX

(ECM). The complex, multi-molecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, it provides cellular microenvironments and it regulates various cellular functions.

SIGNALLING NODE

A highly connected compound in an intracellular signalling network.

SIGNALLING PATHWAY

A linear set of reactions that connects an input to an output in an intracellular signalling network.

SIGNALLING MODULE

An intuitive grouping of reactions from an intracellular signalling network that have a related function.

CONTEXTUAL SPECIFICITY

This takes into account the context in which a given signalling network property is observed — for example, splice variants of a particular protein might only exist in a cell when it is in a particular differentiated state.

L-TYPE CA2+ CHANNELS

A form of voltage-operated Ca2+ channel in cardiac muscle that has a high electrical threshold.

YEAST TWO-HYBRID ASSAY

A technique that is used to test whether two proteins physically interact with each other. One protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. The expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

(GEF). A protein that facilitates the exchange of GDP (guanine diphosphate) for GTP (guanine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

ICAT

(isotope coded affinity tag). ICAT probes have different masses, but are chemically identical. They incorporate a reactive cysteine, a biotin moiety, and eight deuteriums in place of eight hydrogens, and they are used to specifically label, by mass-difference, identical proteins in two separate samples for the identification and semiquantitative comparison of abundance.

SILAC

(stable isotope labelling by amino acids in culture). An experimental technique used to study hormone-activated protein complexes.

SH2 PROFILING

A technique based on the Far-Western assay that is used to identify SH2-binding domains in protein extracts.

TAIS

(target-assisted iterative screening). A method for screening protein products of a cDNA library that bind to a target protein.

RNAi

(RNA interference). A form of post-transcriptional gene silencing in which expression or transfection of dsRNA induces degradation — by nucleases — of the homologous endogenous transcripts. This mimics the effect of the reduction, or loss, of gene activity.

GREEN FLUORESCENT PROTEIN

(GFP). An autofluorescent protein that was originally identified in the jellyfish Aequorea victoria.

FRET

(fluorescence resonance energy transfer). The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore that is typically <80 Å away. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation of the acceptor.

CLUSTERING ANALYSIS

An approach for identifying and grouping similar data points.

SPECTRAL ANALYSIS

A method derived from graph theory that describes high-level structures in complicated networks of relationships.

MONTE CARLO SAMPLING

An approach for choosing pseudo-random data points that represent the characteristics of a larger population or function.

BISTABLE BEHAVIOUR

A property in which there are two stable points of a dynamic system, which provides a sense of 'memory'.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis.

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Papin, J., Hunter, T., Palsson, B. et al. Reconstruction of cellular signalling networks and analysis of their properties. Nat Rev Mol Cell Biol 6, 99–111 (2005). https://doi.org/10.1038/nrm1570

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