AKAP95: a multifunctional scaffold kinase anchoring protein, role in pathophysiology and perspectives for its therapeutic use

Regulatory enzymes fulfill critical roles within specific subcellular compartments. Scaffolding proteins orchestrate enzyme activity and signal transduction by confining these processes to distinct spatial locations, thereby forming functional microdomains or signaling islands. The A kinase anchoring protein (AKAP) family represents a unique class of scaffolding proteins. AKAPs bind to protein kinase A (PKA) and its substrates to spatiotemporally regulate phosphorylation processes within these microdomains. Dysregulation of AKAPs in humans has been implicated in diverse pathologies. Moreover, AKAPs are emerging as platforms for precision drug therapy because of their compartmentalized signaling capabilities. AKAP95 (also termed AKAP8), a nuclear protein belonging to the AKAP family, has functions that extend beyond PKA signaling, including participation in liquid-liquid phase separation (LLPS) and transcriptional regulation. Additionally, it plays critical roles in cellular development and disease pathogenesis. Despite its importance, no comprehensive review has yet emphasized its molecular mechanisms, biological functions, and disease associations. This article delineates the regulatory roles of AKAP95 both within and beyond the PKA pathway through the conformation of nonmembrane compartments and microdomains, highlights its contributions to viral life cycles and oncogenesis, and reviews its potential as a therapeutic target in precision medicine.