Kimberley Dodge-Kafka, is an Associate Professor at the Department of Cell Biology at the University of Connecticut. Her research focuses on defining the intracellular communication networks that promote specificity in signal transduction. In particular, she works on A-kinase-anchoring proteins (AKAPs) that target the camp-dependent protein kinase, as well as other signaling enzymes, into discrete signaling complexes in order to regulate the phosphorylation of target proteins. In particular, concentrating on AKAP complexes in the heart, and how they regulate cardiac physiology.
Abstract
Type IIa histone deacetylases (HDACs) are transcriptional repressors whose nuclear export in the cardiac myocyte is associated with the induction of pathological gene expression and cardiac remodeling. Type IIa HDACs are regulated by multiple, functionally opposing, post-translational modifications, including phosphorylation by protein kinase D (PKD) that promotes nuclear export and phosphorylation by protein kinase A (PKA) that promotes nuclear import.
We have previously shown that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) orchestrates signaling in the cardiac myocyte required for pathological cardiac remodeling, including serving as a scaffold for both PKD and PKA. We now show that mAKAPβ is a scaffold for HDAC5 in cardiac myocytes, forming signalosomes containing both HDAC5 and PKA. Inhibition of mAKAPβ expression by RNA interference attenuated the phosphorylation of HDAC5 by PKD and PKA in response to α- and β-adrenergic receptor stimulation, respectively. Importantly, disruption of mAKAPβ-PKA anchoring using the cell-permeant AKAP-IS peptide prevented the inhibition by β-adrenergic receptor stimulation of α-adrenergic-induced HDAC5 nuclear export.
Together, these data establish that mAKAPβ signalosomes can serve to bidirectionally regulate the nuclear-cytoplasmic localization of type IIa HDACs. Thus, the mAKAPβ scaffold serves as a node in the myocyte regulatory network controlling both the repression and activation of pathological gene expression.