Date of Completion

5-11-2013

Embargo Period

5-11-2023

Major Advisor

Dr. Kimberly Dodge-Kafka

Associate Advisor

Dr. David Han

Associate Advisor

Dr. Lixia Yue

Associate Advisor

Dr. Asis Das

Associate Advisor

Dr. Linda Shapiro

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

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.

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