Glycogen synthase kinase 3 (GSK3) was initially isolated as a critical protein in energy metabolism. However, subsequent studies indicate that GSK-3 is a multi-tasking kinase that links numerous signaling pathways in a cell and plays a vital role in the regulation of many aspects of cellular physiology. As a regulator of actin and tubulin cytoskeleton, GSK3 influences processes of cell polarization, interaction with the extracellular matrix, and directional migration of cells and their organelles during the growth and development of an animal organism. In this review, the roles of GSK3–cytoskeleton interactions in brain development and pathology, migration of healthy and cancer cells, and in cellular trafficking of mitochondria will be discussed.

Recently, we have shown that the physiological roles of a multifunctional protein fructose 1,6-bisphosphatase 2 (FBP2, also called muscle FBP) depend on the oligomeric state of the protein. Here, we present several lines of evidence that in HL-1 cardiomyocytes, a forced, chemically induced reduction in the FBP2 dimer-tetramer ratio that imitates AMP and NAD⁺ action and restricts FBP2-mitochondria interaction, results in an increase in Tau phosphorylation, augmentation of FBP2-Tau and FBP2-MAP1B interactions, disturbance of tubulin network, marked reduction in the speed of mitochondrial trafficking and increase in mitophagy. These results not only highlight the significance of oligomerization for the regulation of FBP2 physiological role in the cell, but they also demonstrate a novel, important cellular function of this multitasking protein—a function that might be crucial for processes that take place during physiological and pathological cardiac remodeling, and during the onset of diseases which are rooted in the destabilization of MT and/or mitochondrial network dynamics.

Fructose 1,6-bisphosphatase 2 (FBP2) is a multifunctional protein whose cellular functions depend on its oligomeric state. Forced FBP2 tetramerization has been linked to microtubule disruption and impaired mitochondrial trafficking, accompanied by abnormal mitochondrial morphology. Here, we identify MIC60 (mitofilin), a core element of the mitochondrial contact site and cristae organizing system (MICOS), as a potential mediator of these effects. Using proximity ligation assay, protein crosslinking combined with mass spectrometry, and ultrastructural analysis, we demonstrate that FBP2 is in close proximity to MIC60 under basal conditions and this proximity is reduced upon FBP2 tetramerization or partial FBP2 depletion. Loss of this proximity coincides with marked remodeling of inner-membrane ultrastructure. These findings are consistent with a working model in which dimeric FBP2 contributes to the coordination of microtubule-dependent mitochondrial positioning with MICOS-linked intramitochondrial organization, providing a plausible mechanistic bridge between metabolic cues (AMP/NAD⁺) and mitochondrial structural integrity.