A-Kinase Anchoring Proteins: from kinase anchors to spatial cell biology

Host: Dario Alessi

Venue: MSI Small Lecture Theatre, SLS

Abstract:

John Scott’s principal contribution was the discovery of AKAP signalling complexes that cluster the broad specificity signaling enzyme protein kinase A (PKA) with additional enzymes at defined subcellular locations. Using a combination of structural and biochemical approaches he defined the structural basis for PKA anchoring by showing that a conserved amphipathic helix on the AKAP slots into a grove in the docking and dimerization domain of the protein kinase A regulatory subunit. Then Scott identified multivalent AKAPs that target PKA and protein phosphatases to catalyze the phosphorylation and dephosphorylation of synaptic glutamate receptors. This permits bi-directional control of ion channel activity during excitatory synaptic transmission. He also defined AKAP complexes that incorporate phosphodiesterases to locally degrade cAMP and thus rapidly terminate the second messenger signal in the vicinity of anchored PKA. Using a combination of biochemical, cellular, and genetic approaches he has demonstrated that anchored complexes of signalling enzymes locally regulate second messenger mediated signal transduction events. The biological relevance of these discoveries is underscored by functional studies that have established the contribution of AKAP signalling complexes in the organization of physiological and pathophysiological processes. Recent studies have shown that defects in AKAP signalling underlie synaptic transmission, endocrine disorders including type 2 Diabetes and Cushing’s syndrome and the adolescent cancer Fibrolamellar carcinoma.

Bio:

John Scott is a world leader in studies of cell-signalling and an academic leader in pharmacology. He discovered the family of A-Kinase Anchoring Proteins and showed how they organize cell-signalling pathways in time and space at the molecular and structural levels. His scientific work has markedly altered our perceptions about the dynamic organization of intracellular signalling pathways. He is Professor and Chair of Pharmacology and Edwin Krebs-Hilma Speights Professor of Cell Signalling and Cancer Biology at University of Washington.