PREDICTION AND ANALYSIS OF THE DYNAMICAL BEHAVIORS OF ERK5, JNK AND P38 KINASE CASCADES

Abstract

All cells receive and respond to signals from their environment, whether they live freely or are part of a tissue. Network of signaling pathways detect, amplify, and integrate diverse external signals to generate responses such as changes in enzyme activity, gene expression, or ion-channel activity. MAPK (Mitogen-activated protein kinase) pathways regulate diverse cellular processes ranging from proliferation and differentiation, to apoptosis. In mammals, out of five, there are three well characterized subfamilies of MAPK pathways - ERK5 (Extracellular signal-regulated kinases), JNK(c-Jun N-terminal kinases), and P38 implicated in human diseases and are targets for drug development. Kinase cascades in MAPK pathways mediate the sensing and processing of stimuli. Cross-talks between signaling cascades is a likely phenomenon that can cause apparently different biological responses from a single pathway, on its activation. Feedback loops have the potential to greatly alter the properties of a pathway and its response to stimuli. Cell function, including growth, differentiation, division, and apoptosis, are temporal processes and can be understood only when treated as dynamic systems. To understand how signaling networks make decisions, the dynamic interactions of proteins are important rather than just creating static maps of the components and organization of signaling cascades. Differential equation models are well defined encodings of molecular interactions contributing towards the synthesis and degradation of a protein in the context of cell signaling. Thus, there is a general agreement that a systems approach is necessary to understand the causal and functional relationships that generate the dynamics of biological networks of pathways. In this thesis, based on enzyme kinetic reactions, mathematical models have been developed to predict and analyze the impact of cross—talks and feedback loops in ERK5, JNK and P38 kinase cascades. Impacts of cross-talks between ERK, JNK and P38 kinase cascades have been studied. From the numerical simulations of system of dynamical equations, it has been observed that, the cross — talks between ERK5 and JNK cascades do not have any significant influence on the manner in which ERK5 and JNKs' are activated in ERK5 and JNK cascades. Ultra sensitive and sustained manner of activation of JNK2 and JNK3, and transient manner of activation of JNK1 do not get affected due to cross — talks between JNK and P38 kinase cascades. But, it is due to these cross—talks, that P38a kinase does not get activated, transiently activated P38,8 kinase reaches its saturation earlier, and transiently activated P381 kinase is activated in an ultra sensitive and iii sustained manner. The transient activation of ERK5, JNK1 and P38,3 kinases, and the sustained activation of JNK2, JNK3 and P388 kinases do not get affected by the cross — talks between ERK5, JNK and P38 kinase cascades. But, due to cross — talks, transiently activated P38 cx kinase does not get activated, and transiently activated P387 kinase gets activated in a persistent manner. Possibilities and impact of feedback loops in JNK cascade in mammals have been studied computationally. Probability of the existence of negative feedback loops from MKKs' to ASK1 alone is low, because their existence suppresses the activation of JNK1 and it is against the observation of the functional role of JNK1. Similarly, probability of the existence of both the negative feedback loops from MKKs' to ASK1 and positive feedback loops from JNKs' to MKKs' is low, because it is against the observation of the significantly different functional roles of JNK1, JNK2 and JNK3 in mammals. The only possible feedback loops in JNK cascade in mammals are the positive feedback loops from JNKs to MKKs' which enhances the sustained action of the JNK2 and JNK3, and the transient activation of JNK1. Dynamical behaviors of ERK5, JNK and P38 kinase cascades due to cross — talks and feedback loops have been studied. From the numerical simulations of system of dynamical equations, it has been observed that, due to cross — talks and feedback loops in ERK5 and JNK cascade, ERK5 gets activated in an oscillatory manner in the absence of input signals. Feedback loops in JNK cascade do not have any significant impact on the P38 kinase cascade, which has been networked with JNK cascades due to cross talks. JNK cascade, and JNK and P38 kinase cascade are observed as robust sub — systems of ERK, JNK and P38 kinase cascade system. Cross — talks and feedback loops in ERK5, JNK and P38 kinase cascades play significant roles to form a system of ERK5, JNK and P38 cascades to process the input signals for appropriate responses.