Systems studies on spatiotemporal dynamics of kinase signaling

Life is all about making the right decisions at the right time. Consequently, cells have evolved to “read” external signals, process this information and make decisions through a vast array of signaling molecules. Kinases are a key class of these signaling molecules that interact with other signaling molecules precisely in space and time to form exceedingly complex and dynamic signaling networks. As a result, these networks abound in non-linear connections leading to the emergence of interesting spatial and temporal changes in signaling activities such as oscillations. However, these are not just academically interesting emergent phenomena; cells have evolved to exploit such dynamics of signaling in space and time to process information efficiently and regulate crucial cellular processes ranging from insulin secretion to cellular adhesion. How kinase signaling networks help cells process information through such spatiotemporal dynamics is the central question of this dissertation. We used a combination of modeling and experimentation to understand how kinases process information. In pancreatic beta-cells, information is conveniently encoded in the form of calcium oscillations. We found that the same input calcium signal may be decoded in different ways by distinct downstream pathways. This differential decoding may be optimized for regulating various cellular functions. Protein Kinase A (PKA) and calcium form a tightly integrated oscillatory circuit with the ability to tune temporal features of the oscillations. Such temporal modulation enables PKA to change its mode of action. The Extracellular-signal regulated kinase (ERK) cascade on the other hand employs sequential processing that integrates the calcium signals so as to produce sustained pathway outputs. In neuroendocrine PC12 cells, ERK not only displays interesting temporal dynamics, but striking spatial differences as well. Such spatiotemporal differences manifest as a result of complex kinase-interaction networks, and these differences help to optimally regulate multiple cellular processes simultaneously