mAKAP-a master scaffold for cardiac remodeling

Abstract

Cardiac remodeling is regulated by an extensive intracellular signal transduction network. Each of the many signaling pathways in this network contributes uniquely to the control of cellular adaptation. In the last few years, it has become apparent that multimolecular signaling complexes or "signalosomes" are important for fidelity in intracellular signaling and for mediating crosstalk between the different signaling pathways. These complexes integrate upstream signals and control downstream effectors. In the cardiac myocyte, the protein mAKAPβ serves as a scaffold for a large signalosome that is responsive to cAMP, calcium, hypoxia, and mitogen-activated protein kinase signaling. The main function of mAKAPβ signalosomes is to modulate stress-related gene expression regulated by the transcription factors NFATc, MEF2, and HIF-1α and type II histone deacetylases that control pathological cardiac hypertrophy.

Figure 1. mAKAPβ – A Perinuclear Scaffold

Top: Mouse heart sections (left ventricle) stained for with mAKAP antibody (gray scale panels and green), Hoechst nuclear stain (blue), and wheat germ agglutinin (red, shown in enlarged control image only). Lower left panels are from control, mAKAP knock-out mice. Bar = 20 μm. Middle: Adult rat myocyte stained with antibodies to mAKAP (green) and actinin (red). Bottom: mAKAP domain structure. Direct binding partners whose sites have been finely mapped in mAKAPβ are shown. mAKAPβ starts at residue 245 of mAKAPα. Therefore, all binding sites are numbered per mAKAPα. Images are from Kritzer, et al. (8).

Figure 2. mAKAPβ Signaling Modules

mAKAPβ binds multiple signaling enzymes and gene regulatory proteins. Modules may be defined that involve cAMP, Ca²⁺, hypoxic, phosphatidylinositide and MAPK signaling. See text for details. In this figure, the mAKAPβ scaffold is presented as a yellow globe sitting on a grey base representing nesprin-1α, on which are assembled the various signaling molecules. Gold cylinders represent nuclear pore complexes inserted in the nuclear envelope.