Molecular Interaction Maps of Bioregulatory Networks

Aladjem MI, Pasa S, Parodi S, Weinstein JN, Pommier Y, and Kohn KW. Molecular interaction maps—a diagrammatic graphical language for bioregulatory networks. Sci STKE 2004: pe8, 2004.

roper cell growth depends on a complex network of interacting proteins and genes, which regulate crucial activities such as DNA synthesis, gene expression, metabolism, and information processing. Disruptions in the intricate balance between the components of this network may lead to cancer; however, interfering with signals transmitted by bioregulatory networks is an important tool for cancer therapy. In recent years, knowledge about interacting molecules that regulate cell growth has increased exponentially, but our ability to make sense of this detailed information has not. Researchers interested in using modern biology to combat cancer need tools to organize a large collection of facts, including descriptions of bioregulatory molecules, their modifications (for example, phosphorylation), and the complexes they form.

One of the main obstacles to organizing molecular knowledge is the lack of a common language that allows scientists to integrate data in a clear, standardized, and preferably computer-readable format. This article describes a graphical language that encodes molecular information in the form of diagrams, or molecular interaction maps (MIMs) (Figure 1). These MIMs are used to represent and analyze molecular interactions in the same way as circuit diagrams are used to trouble-shoot electronic devices.

Investigators usually describe biochemical pathways in cartoon-like diagrams, but these representations of molecular interactions are often incomplete and ambiguous. For example, an arrow between two components could signify an increase in quantity, an increase in activity, or a modification of one molecule by the other. In addition, enzymes in bioregulatory networks are often substrates of other enzymes, and molecules are often subject to modifications that change their binding or enzymatic capabilities. Moreover, regulatory proteins can form multi-molecular complexes, which have different activities, depending on their composition and modifications. Finally, each domain within regulatory molecules may have its own binding, modification, and/or enzymatic functions. Thus, a molecule's activity and interaction capabilities may depend on its modification state, and on the other molecules to which it may be bound. All of these interactions must be taken into account for a full understanding of the system.

In the MIM language, we use a small number of defined unambiguous graphical symbols to portray each type of molecular interaction. Each molecule is represented in a single place in a diagram, and interactions between molecules are specified by arrows or bars at the end of connecting lines. Because modified molecules and multi-molecular complexes may have different properties than the original molecules, the outcome of each interaction (such as a phosphorylated molecule, or a multi-molecular complex) is depicted as a circle, or "node," on an interaction line.

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Figure 1. A molecular interaction map portraying the signal transduction network that regulates the onset of DNA replication. Multimolecular complexes or modified forms are depicted by "nodes" placed on the lines. A line may originate either at a named molecular species or at a node, and may terminate at a molecular species, a node, or at another line. Lines that cross do not imply interaction. A detailed description of the symbols of the MIM language is available on the web site, http://discover.nci.nih.gov/mim, in the section "how to read maps." "A" followed by a number represents an annotation (accessible for each MIM at http://discover.nci.nih.gov/mim); ATM, ataxia telangiectasia mutated, a protein kinase that responds to DNA damage; ATR, a relative of ATM, responds to DNA lesions and stalled replication forks; Cdc6, a component of pre-replication complex that recruits Cdt1; Cdc25A, a dual threonine/tyrosine phosphatase; Cdc45, a component of the pre-initiation complex that recruits DNA polymerase; Cdt1, component of pre-replication complex that recruits MCM helicases; CHK1 and 2, serine/threonine kinases that relay DNA damage signals to cell cycle checkpoints; Cdk (1 and 2), a family of cyclin-dependent kinases; cyclins (CycA,E,B1), a family of cell cycle oscillating proteins that bind Cdk proteins; dpf1, the regulatory subunit of hsk1 kinase; DsB, double stranded DNA break; Gadd45, a DNA damage-inducible protein; geminin, an inhibitor of DNA replication that binds Cdt1; hsk1, a kinase that is essential for initiation of DNA replication; MCM(2–7), a helicase that forms a part of the pre-replication complex; MCM10, a protein that binds the hsk1 kinase and the pre- replication complex; MDM2, a protein that binds, regulates, and is regulated by p53; ORC (1–6), an origin recognition complex, bound to chromatin on replication initiation sites; Ori, replication origins, starting sites for DNA replication—there are many origin sites on each chromosome; P (blue), a phosphate group; P21, a regulator of Cdk activity; P53, a tumor suppressor protein often mutated in human cancers; wee1, a protein kinase involved in cell cycle regulation.

These nodes are treated in a way that allows them to form more interactions and extend the network. The symbols and conventions used in the language, as well as examples of MIMs, can be accessed at our web site: http://discover.nci.nih.gov/mim.

The graphical MIM language allows a simultaneous view of many interactions involving any given molecule. It can portray competing interactions, which are common in bioregulatory networks. An interested researcher can trace all the interactions of a given molecule from a single location. Readers can look up a molecule in a glossary or in the electronic (eMIM) diagrams; a mouse-click on the molecule name opens links to more information, including PubMed, CGAP, GeneCards, and Matchminer. Each interaction is labeled with a link to an annotated description, which includes links to cited references. The interested researcher can read the annotations to gain in-depth information on each molecular interaction, or browse the various maps to become acquainted with the general concept of how cells regulate a particular metabolic process.

The full article (referenced above) features four MIMs that describe the molecular interactions that lead to the onset of DNA replication. An electronic version of these MIMs can be found at http://discover.nci.nih.gov/mim/html/index.html. A complete map of all interactions is provided. Additional maps represent subsets of interactions that occur during specific stages of the cell cycle and in response to cellular stress. More maps describing other aspects of bioregulatory signaling will be posted at the same site.

A major task lies ahead to compile and update maps of the major biological control systems, and to integrate them in a concise manner. We may then discern common patterns of molecular interaction logic that give bioregulatory networks their remarkable flexibility and robustness.

Kurt W. Kohn, MD, PhD
Principal Investigator
Laboratory of Molecular Pharmacology

Mirit I. Aladjem, PhD
Principal Investigator
Laboratory of Molecular Pharmacology
NCI-Bethesda, Bldg. 37, Rm. 5068D
Tel: 301-435-2848
Fax: 301-402-0752
aladjemm@mail.nih.gov

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