Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes
Jan W. BuikemaSoah LeeWilliam R. GoodyerRenée G. C. MaasOrlando ChirikianGuang LiYi MiaoSharon L. PaigeDaniel LeeHaodi WuDavid T. PaikSiyeon RheeLei TianFrancisco X. GaldosNazan PulucaBenjamin BeyersdorfJames B. HuAimee BeckSneha VenkamatranSrilatha SwamiPaul J.M. WijnkerMaike SchuldtL. M. DorschAlain van MilKristy Red-HorseJoy Y. WuCaroline GeisenMichael HesseVahid SerpooshanStefan JovingeBernd K. FleischmannPieter A. DoevendansJolanda van der VeldenK. Christopher GarcíaJoseph C. WuJoost P. G. SluijterSean M. Wu
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Contact inhibition
Hippo signaling pathway
The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila . Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.
Hippo signaling pathway
Contact inhibition
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Lithium is one of the most widely used drugs for treating bipolar (manic-depressive) disorder. Despite its efficacy, the molecular mechanism underlying its action has not been elucidated. One recent study has proposed that lithium inhibits glycogen synthase kinase-3 and thereby affects multiple cellular functions. Because glycogen synthase kinase-3 regulates the phosphorylation of tau (microtubule-binding protein that forms paired helical filaments in neurons of the Alzheimer's disease brain), we hypothesized that lithium could affect tau phosphorylation by inhibiting glycogen synthase kinase-3. Using cultured human NT2N neurons, we demonstrate that lithium reduces the phosphorylation of tau, enhances the binding of tau to microtubules, and promotes microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3. These results provide new insights into how lithium mediates its effects in the central nervous system, and these findings could be exploited to develop a novel intervention for Alzheimer's disease.
GSK3B
Tau protein
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Multiple reports suggest that glycogen synthase kinase-3(GSK3)plays an important role in the pathogenesis of Alzheimer's disease(AD).The level and enzymatic activity of GSK3 is elevated in AD.Cell culture studies and animal model studies with both invertebrates and mammals find that over-activity of GSK3 causes hyper-phosphorylation of the tau protein,increased production of β-amyloid,learning and memory impairments,and associated neurodegeneration.GSK-3β inhibitors prevent tau hyper-phosphorylation in AD transgenic animals so they are of potential use in the prevention and treatment of AD.
Pathogenesis
GSK3B
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Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase, originally identified as a protein kinase by its ability to phosphorylate and inactivate glycogen synthase. It was found that the overexpression of GSK-3 is associated with some diseases, such as diabetes, Alzheimer disease and other neurodegenerative diseases. Some pharmacological inhibitors of GSK-3 have been demonstrated to mimic insulin signaling, adjust glycogen synthesis and glucose metabolism, and improve insulin resistance. So GSK-3 inhibitors are realized as a new approach of treating diabetes. This review summarizes current advances in research of GSK-3 inhibitors as a new therapeutic approach for diabetes.
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In these studies we expressed and characterized wild-type (WT) GSK-3 (glycogen synthase kinase-3) and its mutants, and examined their physiological effect on glycogen synthase activity. The GSK-3 mutants included mutation at serine-9 either to alanine (S9A) or glutamic acid (S9E) and an inactive mutant, K85,86MA. Expression of WT and the various mutants in a cell-free system indicated that S9A and S9E exhibit increased kinase activity as compared with WT. Subsequently, 293 cells were transiently transfected with WT GSK-3 and mutants. Cells expressing the S9A mutant exhibited higher kinase activity (2.6-fold of control cells) as compared with cells expressing WT and S9E (1.8- and 2.0-fold, respectively, of control cells). Combined, these results suggest serine-9 as a key regulatory site of GSK-3 inactivation, and indicate that glutamic acid cannot mimic the function of the phosphorylated residue. The GSK-3-expressing cell system enabled us to examine whether GSK-3 can induce changes in the endogenous glycogen synthase activity. A decrease in glycogen synthase activity (50%) was observed in cells expressing the S9A mutant. Similarly, glycogen synthase activity was suppressed in cells expressing WT and the S9E mutant (20-30%, respectively). These studies indicate that activation of GSK-3 is sufficient to inhibit glycogen synthase in intact cells, and provide evidence supporting a physiological role for GSK-3 in regulating glycogen synthase and glycogen metabolism.
Glycogen branching enzyme
GSK3B
Glycogen debranching enzyme
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GSK3B
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Glycogen synthase kinase-3β(GSK-3β) was initially identified as an enzyme involved in glycogen metabolism.GSK-3β phosphorylates a variety of substrates of different biological activities to regulate cellular functions,such as proliferation,differentiation and apoptosis.In the research model of the Parkinson's disease,the increase of GSK-3β activity was recently found to induce neuron apoptosis.On the other hand,when the GSK-3β activity was inhibited,both the tau protein phosphorylation and α-synuclein expression were reduced,then led to neural protection.Therefore,GSK-3β may become a new target for the treatment of Parkinson's disease.
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Abstract A series of 3‐aryl‐4‐pyrrolyl‐maleimides were designed, synthesized, and evaluated for their glycogen synthase kinase‐3β (GSK‐3β) inhibitory activity. Most compounds exhibited potent activity against GSK‐3β. Among them, compounds 11a , 11c , 11h , 11i , and 11j significantly reduced Aβ‐induced Tau hyperphosphorylation, showing the inhibition of GSK‐3β at the cellular level. Structure–activity relationships were discussed based on the experimental data obtained.
Hyperphosphorylation
GSK3B
Structure–activity relationship
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Glycogen synthase kinase-3 (GSK-3) is involved in signaling from the insulin receptor and inhibitors of it are expected to lower plasma glucose similar to insulin. It is under development for the treatment of type 2 diabetes. The target bisarylmaleimide was synthesized in seven steps in 33% overall yield from 5-fluoroindole (A).
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