Date of Completion
Dr. Kimberly Dodge-Kafka
Dr. David Han
Dr. Lixia Yue
Dr. Asis Das
Dr. Linda Shapiro
Field of Study
Doctor of Philosophy
Compartmentalization of protein kinases and phosphatases through their interaction with scaffold proteins provides a regulatory mechanism to control signal transduction events at specific sites within the cell. Dynamic regulation of cellular signaling can be achieved via A-kinase anchoring proteins (AKAPs), which nucleate macromolecular complexes to bring together cAMP effectors, signal terminating enzymes and other scaffold proteins, to facilitate PKA signaling events. AKAPs orchestrate the spatial-temporal activation of anchored enzymes to ensure specificity and efficiency of substrate phosphorylation. The aim of this work is that A-kinase anchoring proteins scaffold multiple kinases, phosphatases, phosphodiesterases, adenylyl cyclases, and target substrates to coordinate diverse signaling pathways.
During my thesis, I found that AKAP5 and AKAP7 form novel associations with new proteins involved in various cellular signaling cascades. First, I identified a novel interaction between the ubiquitously expressed and promiscuous protein phosphatase 1 (PP1), and AKAP5. AKAP5 functions to regulate PP1 activity by only permitting dephosphorylation of selective targets within the cell. In subsequent studies, I found protein kinase C (PKC), adenylyl cyclase 6 (AC6), and phosphodiesterase 4D3 (PDE4D3) to be associated with the AKAP7 scaffold. PKC activity was both enhanced and focused when tethered to AKAP7. Additionally, I show evidence that AKAP7 is involved in cAMP signaling dynamics by anchoring AC6 and PDE4D3, which can effect PKA substrate phosphorylation. This work describes the multivalency of AKAPs and their ability to regulate a multitude of cellular signaling events.
Le, Andrew, "Dynamic Regulation of Cellular Signaling by A-Kinase Anchoring Proteins" (2013). Doctoral Dissertations. 71.
Available for download on Thursday, May 11, 2023