A systems approach to understanding lipid, Ca2+ and MAPK signalling networks.
Sensing and interpretation of external stimulus by the cell often involves the recruitment of several cross-regulating signalling pathways. For many years we have studied the biochemical determinant of neuroadaptation by the medium-sized spiny neuron of the striatum. In this model, synaptic plasticity and dendritic remodeling, involve several intracellular kinase-dependent signalling pathways acting with different timescales. For instance, CaMKII, PI3K and PKC trigger short-term plasticity in seconds through protein modifications and translocation. PKA, ERK (MAPK) and CaMKIV persistently modulate gene regulatory networks and change gene expression. TrkB, a tyrosine kinase receptor for neurotrophins and PI3K/PKB are also involved in long-term effects on for instance dendritic remodelling and neuronal survival. All these kinase pathways are linked through the activation/inhibition of phosphatases, ultimately forming a network of kinases, phosphatases and substrate phosphoproteins with variable dynamics. However, at present the knowledge of these phosphorylation-dependent signalling pathways remains fragmented and largely descriptive.
Our activity within the signalling Institute Strategic Programme follows two lines:
- we will continue to study the role of Ca2+ signals in synaptic plasticity, developing highly realistic models. Those models will help in understanding the respective roles of the proteins constituting the Ca2+-sensitive, long-term potentiation cycle - glutamate ionotropic receptors, calmodulin, neurogranin, calcineurin and CaMKII – in decoding amplitude, frequency and duration of Ca2+ signals. A better grasp Ca2+ homeostasis and dynamics is now acknowledged to be a key to understanding synaptic ageing.
- We will use synaptic signalling as a model system to understand the mechanisms and consequences of integrating multiple signalling pathways. The initial focus will be, in addition to Ca2+, on MAPK cascades and phosphoinositide signalling.
How do cells shape and interpret PIP3 signals?
Class I PI3K signaling is one of the most important signalling networks in mammalian cells and is under intense investigation by the pharmaceutical sector. However, many of the underlying principles by which it operates are still unknown, thereby limiting our understanding of many aspects of biology, such as cell migration and growth, and hindering drug development. In collaboration with the group of Len Stephens and Phil Hawkins, we tackle this problem by applying a combination of novel lipidomics, modern cell biology and modelling methods to understand the key factors that shape PIP3 signalling in response to hormones and oncogenic mutation in a non-transformed, human, breast epithelial cell line. More information can be found on the BBSRC website.