The role of scaffold proteins in information transfer in cellular signaling

VERONICA PARASCO; ALEJANDRO COLMAN-LERNER; ALEJANDRA C VENTURA

Buenos Aires

Simposio; “Frontiers in BioScience”; 2012

Max Planck Society and the Ministry of Science, Technology and Innovation

Cell signaling is carried out by a complex network of interactions between metabolites, proteins and nucleic acids. Different isolated components from the signaling network have been extensively studied and characterized in order to then predict the behavior of the integrated system from the behavior of its parts. This notion is based on the hypothesis that the properties of the individual components are not altered as these are interconnected, which is known as "modular organization". However, our work and that of others1, 2,3,4 has shown theoretically and experimentally (both in vitro and in vivo) that bio-molecular systems cannot always be connected modularly: the dynamics of the interconnection, which is inherent to the physics of the system, can dramatically change the behavior of connected modules, an effect that has been called retroactivity. Mammalian cells contains an estimated 1 trillion of protein molecules with approximately 10% of which are involved in signal transduction. Given the enormous number of molecules, it is surprising that cells can accurately process the large amount of information they receive constantly. How do signaling proteins find each other among so many proteins? In the recent decades the notion that cells organize subgroups of proteins in space and time has appeared. In this direction and about 15 years ago, the first scaffold proteins were discovered. Bringing together the two concepts previously outlined, modular organization and retroactivity on one side and scaffold proteins on the other, the following questions arise: does the behavior of a signaling module change if it is integrated into a scaffold protein?, what is the relationship between scaffold proteins and retroactivity? In this project, we characterize the interaction between scaffold proteins and retroactivity through a combination of analytical and computational tools. References: 1. Ventura AC, Sepulchre J, and Merajver SD. A hidden feedback in signaling cascades is revealed. PLoS Comput Biol, 4(3), 2008. 2. Del Vecchio D, Ninfa AJ, and Sontag ED. Modular cell biology: Retroactivity and insulation. Nature/EMBO Molecular Systems Biology, 4:161, 2008. 3. Ventura AC, Jiang P, Van Wassenhove L, Del Vecchio D, Merjaver SD, and Ninfa AJ. Signaling properties of a covalent modification cycle are altered by a downstream target, Proc Natl Acad Sci  USA.107(22):10032-7, 2010. 4. Kim Y, Paroush Z, Nairz K, Hafen E, Jiménez G, Shvartsman SY. Substrate-dependent control of MAPK phosphorylation in vivo.  Mol Syst Biol. 7:467, 2011.