Many faces and functions of GSKIP: a temporospatial regulation view

Glycogen synthase kinase 3 (GSK3)-β (GSK3β) interaction protein (GSKIP) is one of the smallest A-kinase anchoring proteins that possesses a binding site for GSK3β. Recently, our group identified the protein kinase A (PKA)-GSKIP-GSK3β-X axis; knowledge of this axis may help us decipher the many roles of GSKIP and perhaps help explain the evolutionary reason behind the interaction between GSK3β and PKA. In this review, we highlight the critical and multifaceted role of GSKIP in facilitating PKA kinase activity and its function as a scaffolding protein in signaling pathways. We also highlight how these pivotal PKA and GSK3 kinases can control context-specific functions and interact with multiple target proteins, such as β-catenin, Drp1, Tau, and other proteins. GSKIP is a key regulator of multiple mechanisms because of not only its location at certain subcellular compartments but also its serial changes during the developmental process. Moreover, the involvement of critical upstream regulatory signaling pathways in GSKIP signaling in various cancers, such as miRNA (microRNA) and lncRNA (long noncoding RNA), may help in the identification of therapeutic targets in the era of precision medicine and personalized therapy. Finally, we emphasize on the model of the early stage of pathogenesis of Alzheimer Disease (AD). Although the model requires validation, it can serve as a basis for diagnostic biomarkers development and drug discovery for early-stage AD.