mAKAPβ signalosomes – A nodal regulator of gene transcription associated with pathological cardiac remodeling

• Published in: Cellular signalling Vol. 63; p. 109357
• Main Authors: Dodge-Kafka, Kimberly, Gildart, Moriah, Tokarski, Kristin, Kapiloff, Michael S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.11.2019
• Subjects: A Kinase Anchor Proteins - physiology; AKAP; Animals; cAMP; Cardiac hypertrophy; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cell Line; Gene transcription; Histone Deacetylases - metabolism; Humans; Kinase; Mice; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Transcription Factors - metabolism; Ventricular Remodeling; Cardiac hypertrophy; cAMP; Kinase; AKAP; Gene transcription
• DOI: 10.1016/j.cellsig.2019.109357
• ISSN: 0898-6568; 1873-3913

Striated myocytes compose about half of the cells of the heart, while contributing the majority of the heart's mass and volume. In response to increased demands for pumping power, including in diseases of pressure and volume overload, the contractile myocytes undergo non-mitotic growth, resulting in increased heart mass, i.e. cardiac hypertrophy. Myocyte hypertrophy is induced by a change in the gene expression program driven by the altered activity of transcription factors and co-repressor and co-activator chromatin-associated proteins. These gene regulatory proteins are subject to diverse post-translational modifications and serve as nuclear effectors for intracellular signal transduction pathways, including those controlled by cyclic nucleotides and calcium ion. Scaffold proteins contribute to the underlying architecture of intracellular signaling networks by targeting signaling enzymes to discrete intracellular compartments, providing specificity to the regulation of downstream effectors, including those regulating gene expression. Muscle A-kinase anchoring protein β (mAKAPβ) is a well-characterized scaffold protein that contributes to the regulation of pathological cardiac hypertrophy. In this review, we discuss the mechanisms how this prototypical scaffold protein organizes signalosomes responsible for the regulation of class IIa histone deacetylases and cardiac transcription factors such as NFAT, MEF2, and HIF-1α, as well as how this signalosome represents a novel therapeutic target for the prevention or treatment of heart failure. •Muscle A-kinase anchoring protein β (mAKAPβ) is a scaffolding protein localized to the nuclear envelope in striated muscle•Expression of mAKAPβ contributes to the induction of pathological hypertrophy•mAKAPβ orchestrates the regulation of gene transcription required for induction of cardiac hypertrophy•mAKAPβ regulates the activity of class IIa HDAC enzymes as well as the transcription factors NFAT, MEF2, and HIF-1α