Activation of the Wnt Signaling Pathway: A Molecular Mechanism for Lithium Action

Abstract

Glycogen synthase kinase-3 beta (GSK-3 beta/zeste-white-3/shaggy) is a negative regulator of the wnt signaling pathway which plays a central role in the development of invertebrates and vertebrates; loss of function and dominant negative mutations in GSK-3 beta lead to activation of the wnt pathway in Drosophila and Xenopus. We now provide evidence that lithium activates downstream components of the wnt signaling pathway in vivo, leading to accumulation of beta-catenin protein. Our data indicate that this activation of the wnt pathway is a consequence of inhibition of GSK-3 beta by lithium. Using a novel assay for GSK-3 beta in oocytes, we show that lithium inhibits GSK-3 beta from species as diverse as Dictyostelium discoideum and Xenopus laevis, providing a biochemical mechanism for the action of lithium on the development of these organisms. Lithium treatment also leads to activation of an AP-1-luciferase reporter in Xenopus embryos, consistent with previous observations that GSK-3 beta inhibits c-jun activity. Activation of the wnt pathway with a dominant negative form of GSK-3 beta is inhibited by myo-inositol, similar to the previously described effect of coinjecting myo-inositol with lithium. The mechanism by which myo-inositol inhibits both dominant negative GSK-3 beta and lithium remains uncertain.

Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes

“…Hence, Wnt-1 probably influences MMP-3 production through a pathway that is independent of LEF-1 or TCF-4. Since Wnt-1 has been suggested to activate the AP-1 family of transcription factors (38) and since activated AP-1 can stimulate proMMP-3 expression (39), it is possible that Wnt-1 mediates MMP-3 synthesis in RA FLS through AP-1 activation. Thus, Wnt-1 signaling in RA FLS probably contributes to the pool of mature MMP-3 protein, which can be processed extracellularly from the precursor form by enzymes secreted by articular cartilage (45).…”

“…It has been reported that Wnt-1 can increase the activity of the activator protein 1 (AP-1) transcription factor (38). Since the proMMP-3 (precursor form of MMP-3) gene promoter has an AP-1 binding site (39), and since increased levels of MMP-3 in the joint fluid is a clear indicator of disease progression and joint destruction in RA (12,13,40), it was of interest to determine whether Wnt-1 signaling regulates proMMP-3 synthesis in RA FLS.…”

Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage

“…(5) Activation of Wnt signaling is mediated through the inhibition of glycogen synthase kinase 3 (GSK-3) and prevents the degradation of b-catenin, the main downstream effector of Wnt. (6) In vivo administration of GSK-3 inhibitors has been shown to improve the self-renewal ability of HSCs in nonobese diabetic/ severe combined immunodeficiency (NOD/SCID) mice, (5) suggesting that administration of GSK-3 inhibitors could be used to enhance expansion of stem cells with repopulation capacity. The effect of blocking GSK-3 in MSCs is less clear.…”

Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila

“…Although GSK-3b inhibition by lithium was first reported in an early developmental context in Xenopus and Drosophila (Klein and Melton, 1996;Stambolic et al, 1996;Hedgepeth et al, 1997), the body of evidence is increasing that this may be valid also in the mammalian central nervous system (CNS) (Gould et al, 2004). It is significant that Drosophila shaggy mutants lacking GSK-3b activity display lengthening of the circadian period (Martinek et al, 2001).…”