GSK-3 (EC, originally identified in 1980, is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands[1]. It has been implemented in the mechanisms that regulate cellular proliferation, migration, inflammation and immune responses, glucose regulation, and apoptosis. For example: active GSK-3 suppresses pro-proliferation substrates, such as β-catenin, Myc, Jun and Snail, and enhances pro-differentiation substrates, such as p53, Rb, PTEN and TSC1/2Although the original name suggests the enzyme is involved only in the process of glycogen metabolism, recent findings have revealed over 50 substrates that are phosphorylated by GSK-3, among them the microtubule-associated protein, tau, that is the predominant component of neurofibrillary tangles in Alzheimer’s disease. Despite the impressive number of processes the enzyme is involved in, only four key mechanisms have been identified that contribute to regulating the actions of GSK3 in a substrate-specific manner. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway activated in response to insulin and many other growth factors often is a major regulator of GSK3 because Akt phosphorylates GSK3 on these inhibitory serine residues, but several other kinases also can phosphorylate these regulatory serines, such as protein kinase C and protein kinase A[2].
Recently, researchers found that inhibition of GSK-3 activity desensitizes cells to mTOR inhibitors but sensitizes cells to PLK1 inhibitors. In line with this observation, it has been hypothesized that GSK-3 inhibitors could be used to enhance the efficacy of PLK1 inhibitors, for example. Additionally, if GSK-3 activity were increased or reactivated by a targeted small molecule, cells would become resensitized to drugs from diverse drug classes, from nucleotide analogs to tyrosine kinase inhibitors[3].

[1] D.Wu, W.Pan. GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci. 2010 Mar;35(3):161-8.
[2] Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. RS Jope, CJ Yuskaitis,E Beurel. Neurochem. Res. 2007, 32, 577-595.
From: C.A. Thorne et al. GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. Nat Chem Biol. 2015 Jan;11(1):58-63.

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2128 Stem Cell 2i inhibitor Set Set of MEK inhibitor PD0325901 (Axon 1408) and GSK-3 inhibitor CHIR99021 (Axon 1386) €90.00

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