Cells utilise signal transduction networks to respond to a mosaic of environmental cues and robustly initiate appropriate biological responses. These responses are determined by the interplay between feedforward signals and feedback regulation, whereby information from different steps of the signalling pathway is relayed either up or downstream to coordinate (i.e. enhance or suppress) signal flow as needed. Dysregulation of these complex networks often gives rise to disease, for example cancer, where hyperactive signal flow leads to uncontrolled cell proliferation.
The serine/threonine kinase Akt orchestrates a diverse array of functions including cell proliferation, differentiation and metabolism via an extensive signalling network, and it is hyperactivated and thought to play a causal role in 60% of cancers. Because of this, many pharmaceutical companies have devoted considerable effort to developing small molecule Akt inhibitors as cancer therapeutics.
Using live cell microscopy techniques to study Akt dynamics, we recently discovered a new regulatory loop in the Akt pathway that appears to play a central role in regulating signal flow. This feedback loop originates from Akt itself, and acts to limit Akt recruitment to the cell surface thereby negatively regulating Akt activity. Understanding the composition and function of regulatory loops is important because it offers potential insight into why Akt-specific inhibitors may have had mixed success in treating cancer in the clinic. For example, one might predict that drugs that do not completely inhibit Akt kinase activity might counter-intuitively hyper-activate signal flow if they preferentially block negative feedback loops. Our current work is focused on fully characterising the molecular targets of this feedback signal and establishing its importance in growth factor signalling and disease states such as in cancer.