Abstract
In the post-genomic era, the first step in any study of protein function is a homology search against the complete genome sequence of the organism of interest. By analogy, if we also wish to elucidate the cadre of signaling and regulatory pathways in the cell, an extremely powerful first step is to construct a complete network of protein-protein and transcriptional interactions and then search through this network to identify critical pathways in a top-down fashion. Like genomic sequence, the molecular interaction network provides a broad foundation for more directed studies to follow. We illustrate this strategy using a large network of 12,232 interactions in yeast. A variety of applications are discussed, including screening the network to identify pathways responsible for gene expression changes observed in galactose-induced cells, and identifying groups of interacting proteins that are essential (by phenotypic assay) for the cellular response to DNA damage.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bader, G. D., Donaldson, I., Wolting, C, Ouellette, B. F. F., Pawson, T., and Hogue, C. W. V., 2001, BIND-The biomolecular interaction network database, Nucleic Acids Res. 29:242–245.
Begley, T. J., Rosenbach, A. S., Ideker, T., and Samson, L. D., 2002, Damage Recovery Pathways In Saccharomyces cerevisiae Revealed by Genomic Phenotyping and Interactome Mapping, Mol. Cancer Res. 1:103–112.
Ideker, T., Thorsson, V., Ranish, J. A., Christmas, R., Buhler, J., Eng, J. K., Bumgarner, R., Goodlett, D. R., Aebersold, R., and Hood, L., 2001, Integrated genomic and proteomic analysis of a systematically perturbed metabolic network, Science 292:929–934.
Ideker, T., Ozier, O., Schwikowski, B., and Siegel, A. F., 2002, Discovering regulatory and signaling circuits in molecular interaction networks, Bioinformatics 18 Suppl 1:S233–240.
Ideker, T., Thorsson, V., Siegel, A. F., and Hood, L., 2000, Testing for differentially-expressed genes by maximum likelihood analysis of microarray data, J. Comput. Biol. 7:805–817.
Ito, T., Chiba, T., and Yoshida, M., 2001, Exploring the protein interactome using comprehensive two-hybrid projects, Trends Biotechnol. 19:S23–S27.
Lee, T. I., Rinaldi, N. J., Robert, F., Odom, D. T., Bar-Joseph, Z., Gerber, G. K., Hannett, N. M, Harbison, C. T., Thompson, C M., Simon, I., Zeitlinger, J., Jennings, E. G., Murray, H. L., Gordon, D. B., Ren, B., Wyrick, J. J., Tagne, J. B., Volkert, T. L., Fraenkel, E., Gifford, D. K., and Young, R. A., 2002, Transcriptional regulatory networks in Saccharomyces cerevisiae, Science 298:799–804.
Lohr, D., Venkov, P., and Zlatanova, J., 1995, Transcriptional regulation in the yeast GAL gene family: a complex genetic network, FASEB J 9:777–787.
Mann, M., Hendrickson, R., and Pandey, A., 2001, Analysis of proteins and proteomes by mass spectrometry, Annu. Rev. Biochem. 70:437–473.
Wingender, E., Chen, X., Fricke, E., Geffers, R., Hehl, R., Liebich, I., Krull, M, Matys, V., Michael, H., Ohnhauser, R., Pruss, M, Schacherer, F., Thiele, S., and Urbach, S., 2001, The TRANSFAC system on gene expression regulation, Nucleic Acids Res. 29:281–283.
Xenarios, I., and Eisenberg, D., 2001, Protein interaction databases, Curr. Opin. Biotechnol. 12:334–339.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2004 Springer Science+Business Media New York
About this paper
Cite this paper
Ideker, T. (2004). A Systems Approach to Discovering Signaling and Regulatory Pathways —or, how to digest large interaction networks into relevant pieces. In: Opresko, L.K., Gephart, J.M., Mann, M.B. (eds) Advances in Systems Biology. Advances in Experimental Medicine and Biology, vol 547. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8861-4_3
Download citation
DOI: https://doi.org/10.1007/978-1-4419-8861-4_3
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4695-1
Online ISBN: 978-1-4419-8861-4
eBook Packages: Springer Book Archive