University of Connecticut

Events Calendar

CCAM Seminar Series - Kim Dodge-Kafka

Thursday, March 28, 2019
12:00pm – 1:00pm

UConn Health
CGSB, CCAM Conference Room, R1673, 400 Farmington Ave

CCAM Seminar Series Speaker: Kim Dodge-Kafka, Associate Professor, Department of Cell Biology Calhoun Cardiology Center, UConn Health Title: “mAKAP – a master regulator of cardiac hypertrophy”

Abstract: Cardiac hypertrophy is the primary response of the heart to stress and is defined as an increase in the myocyte cell size in the absence of cellular growth [1]. Key to the development of hypertrophy is an increase in gene transcription that induces pathological remodeling, allowing for changes in ion fluxes, metabolic functions, cell death and interstitial fibrosis [2]. Key studies performed in genetically modified mice have shown that activation of specific transcription factors, namely NFAT, MEF2, GATA4, NF-kB and C-MYC, drives this increase in gene transcription responsible for the pathological cardiac remodeling [2]. Therefore, defining the upstream signals that stimulate transcription factor activation has thus become an intense area of research. Significant work has defined these signaling networks to include the mitogen-activated protein kinase (MAPK), cyclic nucleotide, calcium, hypoxia and phosphoinositide-dependent pathways [3]. However, how these cytosolic signaling enzymes are directed onto the nuclear transcription factor is still unclear. One mechanism that has evolved to play a critical role in defining the specificity of signaling networks is the scaffolding protein [4]. These typically non-enzymatic proteins function to co-localize signaling enzymes into a discrete complex containing their downstream substrates, thereby increasing the speed and efficacy of signaling events while defining substrate specificity. Furthermore, as scaffolds usually bind to enzymes from multiple signaling pathways, they help to integrate multiples upstream signals, thereby providing a combinatorial regulation of signaling events.

In particular, A-Kinase anchoring proteins (AKAPs) have been shown to be important scaffolding proteins in the heart [5]. These proteins are defined by their ability to bind the regulatory subunit of Protein Kinase A (PKA), thereby sequestering the kinase into discrete cellular domains via a specific localization sequence unique for each AKAP. As they also associated with multiple other signaling enzymes such as phosphatases, phosphodiesterases, and other kinases, they incorporate multiple upstream signals to mediate phosphorylation events [5]. The first demonstration of the importance of AKAPs for cardiac physiology utilized a peptide to globally disrupt AKAP/PKA binding. Incubation of this peptide in cardiac myocytes found AKAPs play a role in the -adrenergic stimulation of calcium influx and contraction[6]. Since these original findings, AKAP have been shown to regulate many events such as potassium channel currents, sarcoplasmic calcium cycling, and G-protein coupled signaling [7-9]. Additionally, many AKAPs are involved in the induction of cardiac disease [5]. Once such AKAP is the muscle-selecti


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Center for Cell Analysis and Modeling (primary), School of Medicine

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