The richness and complexity of the molecular regulatory network governing cell proliferation requires a concise and unambiguous method of representation. It is becoming difficult or impossible to keep in mind all of the molecular interactions that may be pertinent to the planning and interpretation of experiments in a given area or to generating functional hypotheses. Difficulties arise especially because of the rich cross-connectivity among different signaling pathways that control cell proliferation and DNA repair. In order to utilize extant information optimally, a road map of the known or suspected molecular interactions would be useful, if not essential. Not only must the information itself be handy, but literature citations for the pertinent evidence must be readily accessible. Moreover, the molecular interaction maps must be in a form that allows frequent updating to accommodate corrections and new data. Molecular interaction maps must be able to cope with the complexities that extensive experimental work has revealed. A diagram convention was therefore devised that allows protein-protein interactions and protein modification states to be clearly represented and that can cope with highly complex systems. During the previous year, comprehensive molecular interaction maps were completed of the G1/S cell cycle control network and its connections to DNA repair, replication, and transcription. These maps were published in the August, 1999 issue of Mol. Biol. Cell 10: 2703-2734, together with a presentation of the diagram conventions. Also included were an annotation list for the interactions depicted and reference citations. The map was also placed on our Laboratory's web site where it can be conveniently updated and is publicly accessible (http://discover.nci.nih.gov/kohnk/interaction_maps.html). The monomolecular species are listed in an alphabetical index which gives the map coordinates where each species can be found. Multimolecular species are depicted by means of a convention of arrowed lines that connect the monomolecular components. Another convention is used to depict the complexities of protein modifications, especially phosphorylations. Symbol conventions also are defined for enzymatic action, stimulation, and inhibition. Each interaction is marked with a symbol that refers to an annotation list where salient facts and literature references can be found. During the current year, the mapping conventions were extended so as to accommodate (1) intramolecular controls (e.g. Src), (2) events at the plasma membrane (e.g. interactions involving the EGF receptor family), (3) gene regulation events (e.g. the complex controls on E2F-dependent gene expression), and (4) controls involving phosphoinositides (e.g. involving PI-3-kinase, PTEN, and Akt/PKB). Preliminary molecular interaction maps of these networks have been prepared and relevant recent literature has been collected and organized. A formal version of the extended mapping conventions has been submitted for publication, together with illustrative versions of the essentials of the above interaction maps. Interaction maps and associated annotations have also been prepared for controls of apoptosis, including the subsystems centered (1) at mitochondris, (2) at TNF/Fas receptors at the plasma membrane, and (3) at effector caspases. A map also underway centers on the control of beta-catenin, involving E-cadherin, APC, GSK-beta, Axin, as well as inputs from Wnt. The mapping efforts were focused on systems that are often defective in common types of human cancer. Understanding of the functional consequences of these defects is a basis upon which new targeted therapies can be directed. Molecular interaction maps will help to guide these endeavors.
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