Signal transduction is a complex protein signaling process with a rich network of multifunctional interactions that occur in a non‐linear fashion. Mitogen‐activated protein kinase (MAPK) signal transduction pathways regulate diverse cellular processes ranging from proliferation and differentiation to apoptosis. In mammals, out of five, there are three well characterized subfamilies of MAPKs ‐ ERKs (Extracellular signal‐regulated kinases), JNKs (c‐Jun N‐terminal kinases), and P38 kinases, and their activators, are implicated in human diseases and are targets for drug development. Kinase cascades in MAPK pathways mediate the sensing and processing of stimuli. To understand how cells makes decisions, the dynamic interactions of components of signaling cascades are important rather than just creating static maps. Based on enzyme kinetic reactions, we have developed a mathematical model to analyze the impact of the cross‐talks between JNK and P38 kinase cascades. Cross‐talks between JNK and P38 kinase cascades influence the activities of P38 kinases. Responses of the signals should be studied for network of kinase cascades by considering cross‐talks.

BackgroundFolding of a protein into its three dimensional structure is influenced by both local and global interactions within a protein. Higher order residue interactions, like pairwise, triplet and quadruplet ones, play a vital role in attaining the stable conformation of the protein structure. It is generally agreed that higher order interactions make significant contribution to the potential energy landscape of folded proteins and therefore it is important to identify them to estimate their contributions to overall stability of a protein structure.ResultsWe developed HORI [Higher order residue interactions in proteins], a web server for the calculation of global and local higher order interactions in protein structures. The basic algorithm of HORI is designed based on the classical concept of four-body nearest-neighbour propensities of amino-acid residues. It has been proved that higher order residue interactions up to the level of quadruple interactions plays a major role in the three-dimensional structure of proteins and is an important feature that can be used in protein structure analysis.ConclusionHORI server will be a useful resource for the structural bioinformatics community to perform analysis on protein structures based on higher order residue interactions. HORI server is a highly interactive web server designed in three modules that enables the user to analyse higher order residue interactions in protein structures. HORI server is available from the URL: http://caps.ncbs.res.in/hori

Abstract:The classical concept of linear pathways is being increasingly challenged by network representations, which emphasize the importance of interactions between components of a biological system, and motivates for adopting a system-level approach in biology. We have developed a dynamical system that integrates quantitative, dynamic and topological representation of network of ERK5 (Extracellular signal-regulated kinases 5), JNK(c-Jun N-terminal kinases) and P38 kinase cascades. We have observered that, the transient activation of ERK5, JNK1 and P38β kinase, and the persistent activation of JNK2, JNK3 and P38 δ kinase does not get affected due to the cross-talks between ERK5, JNK and P38 kinase cascades. But it is due to the cross -talks, the transiently activated P38α kinase become inactivated, and the transiently activated P38γ kinase become persistently activated. The impacts of one-way cross-talks between the cascades are insignificant and differ from the impact of two-way cross-talks. We generate a hypothesis that, signaling pathways should be studied as a system by considering the cross-talks between the two adjacent cascades.