AKAP-mediated desmoplakin modification: impact on cardiac desmosomes and hypertrophic signaling (19POST34370124)

Project: Research project

Project Details


Desmosomes are a major cell-cell junction that mediates adhesion by forming extracellular contacts connecting adjacent cells to intracellular intermediate filaments (IFs). In cardiac myocytes, these junctions are found at the intercalated discs (IDs) and serve to withstand the high mechanical forces experienced in the heart while maintaining tissue integrity. Defects in proteins that comprise the desmosome cause a set of cardiac pathologies including arrhythmogenic cardiomyopathy (AC), Inherited cardiomyopathy (ICM), and dilated cardiomyopathy (DCM). One of the desmosomal proteins desmoplakin (DP) directly couples the desmin containing IF-filament cytoskeleton to the rest of the desmosome. The C-terminal domain if DP is subject to a specific pattern of post-translational modifications (PTM) that affect its function and ability to interact with other binding partners. Modification of these PTM sites has been shown to alter DP dynamics, interaction with IF, and desmosomal adhesion. We identified AKAP-13 as a new DP binding partner that could facilitate recruitment of other known modification enzymes to the DP C-terminus, that regulates the DP PTM code. AKAP-13 dysfunction has been linked to cardiac hypertrophy through both the p38 activation pathway and cardiac stress signaling through NFκB. Our preliminary data suggest that AKAP-13 interacts with DP and that loss of DP PTMs affects AKAP binding to DP. We hypothesize that AKAP-13 plays a role in regulating the network of PTM enzymes acting on DP and that the absence of AKAP-13 could affect desmosome assembly and potentially impair DP-IF interactions. Additionally, both AKAP-13 and DP associate with Rho-GTPases and the absence of AKAP-13 leads to hypertrophic cardiac growth. We also hypothesize that the impairment of the DP PTMs through AKAP-13 would affect downstream desmosome mediated signaling leading to hypertrophic cardiac growth. To test our hypothesis, we aim to 1) Determine the role of AKAP-13 in regulating cardiac DP modification and desmosome assembly through a combination of proximity ligation assays, alignment assays, and contractility measurements, and 2) Determine effects of modified DP PTM patterns and AKAP-13 on cardiac myocyte stress response with implications in cardiac hypertrophy and recruitment of AKAP to desmosomal proteins under mechanical stress. We ultimately seek to understand the mechanism through which AKAP-13 regulates cardiac function in conjuncture with the desmosome.
Effective start/end date1/1/1912/31/20


  • American Heart Association (19POST34370124)


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