Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics

Abstract

Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer's disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.

Fig. 1

Mechanisms that regulate the actions of GSK3. Four mechanisms act in concert to regulate the phosphorylation of substrates by GSK3. (1) Primed substrate—substrate phosphorylation by GSK3 is limited by the activity of a priming kinase which prepares the substrate for GSK3. This is because GSK3 most often phosphorylates primed substrates that are prephosphorylated four residues C-terminal to the GSK3 phosphorylation site. The example shows the substrate, glycogen synthase (GS), primed by casein kinase II (CKII) followed by sequential phosphorylation by GSK3 at multiple sites spaced four residues apart toward the N-terminal end of GS. (2) Phosphorylation of regulatory serine—a major mechanism for inhibiting the activity of GSK3 is by serine-phosphorylation, so activity is inhibited when serine-9 of GSK3β or serine-21 of GSK3α is phosphorylated. Conversely, the activity of GSK3 is optimal when phosphorylated on tyrosine-216 of GSK3β or tyrosine-279 of GSK3α (not shown). Many kinases are capable of phosphorylating the regulatory serines of GSK3α/β. The example shows this being carried out by Akt (also known as protein kinase B) which itself is activated by phosphorylation on two sites, one mediated by phosphoinositide-dependent kinase-1 (PDK1) and the other by an unidentified kinase. Akt activation follows stimulation-induced activation of PI3K, and its catalysis of the formation of 3′-phosphoinositides, by receptors for insulin, insulin-like growth factors (IGFs), and other receptor sub-types. When the substrate is prephosphorylated and GSK3 is active, with the regulatory serine dephosphorylated, two spatial restrictions also contribute to regulating the actions of GSK3, its subcellular localization and its association with other proteins in regulatory complexes. (3) Subcellular localization—GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones, so dynamic regulation of the subcellular localization of GSK3 can regulate its access to substrates within subcellular compartments. The example depicted shows GSK3 transport into the nucleus where it can phosphorylate a variety of substrates, including several transcription factors (TF). (4) Complex formation—in addition to this gross cellular distribution of GSK3, its distribution in the cell is constrained by its propensity to be associated in protein complexes which provides an important mechanism for regulating its phosphorylation of specific substrates that are colocalized in such complexes. The example shows that a complex of cdc42, Par6, and protein kinase C-ζ (PKCζ) binds GSK3β and catalyzes the phosphorylation of serine-9 to inhibit GSK3β to regulate the phosphorylation of APC and thereby control the association of APC with the plus-end of microtubules. Thus, substrate-specific regulation of phosphorylation by GSK3 is achieved by regulation of the priming kinase activity, phosphorylation of GSK3, the subcellular localization of GSK3, and assembly of GSK3 in protein complexes

Fig. 2

GSK3 may be an important component of multiple inflammatory diseases. GSK3 can influence inflammation throughout the body which may influence many inflammation-associated conditions. Neuroinflammation within the CNS is mediated by microglia and astrocytes, as well as infiltrating cells, which likely contributes to a wide variety of diseases, such as multiple sclerosis, mood disorders, and neurodegenerative disorders, including Alzheimer’s disease (AD). Peripheral inflammation is mediated in part by monocytes and macrophages, and GSK3 promotes inflammatory conditions such as colitis and arthritis. Localized inflammation, such as cytokine production by adipocytes, apparently contributes to the development of diabetic conditions which may be exacerbated by active GSK3. Inflammation also contributes to numerous types of cancer and inhibition of GSK3 exacerbates tumorigenesis