2. Signaling Pathways
  3. PI3K/Akt/mTOR
    Stem Cell/Wnt
  4. GSK-3

GSK-3 (糖原合成酶激酶3)

Glycogen synthase kinase-3; Glycogen synthase kinase 3

糖原合酶激酶 3 (GSK-3) 是一种多功能丝氨酸/苏氨酸激酶，由两种亚型组成，即 α 和 β。它是受体酪氨酸激酶、细胞因子和 Wnt 信号通路的高度保守负调节剂。这些通路的刺激会抑制 GSK-3 调节各种下游效应因子，包括转录因子、营养传感器、糖原合成、线粒体功能、昼夜节律和细胞命运。GSK-3 还调节响应 T 细胞受体激活的选择性剪接，最近的磷酸化蛋白质组学研究表明，多种剪接因子和 RNA 生物合成调节因子以 GSK-3 依赖的方式进行磷酸化。

GSK-3 的功能障碍或异常活动会导致多种疾病，如阿尔茨海默病 (AD) 和其他神经退行性疾病，以及其他类型的疾病，如糖尿病、心血管疾病和癌症。GSK-3 还与针对病原体的先天免疫反应有关，这使得 GSK-3 成为治疗干预的绝佳靶点。

Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase consisting of two isoforms, alpha and beta. It is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK-3 to modulate diverse downstream effectors that include transcription factors, nutrient sensors, glycogen synthesis, mitochondrial function, circadian rhythm, and cell fate. GSK-3 also regulates alternative splicing in response to T-cell receptor activation, and recent phosphoproteomic studies have revealed that multiple splicing factors and regulators of RNA biosynthesis are phosphorylated in a GSK-3-dependent manner.

The malfunction or aberrant activity of GSK-3 leads to several of disorders, such as Alzheimer's disease (AD) and other neurodegenerative pathologies, and other type of diseases as diabetes, cardiovascular disorders and cancer. GSK-3 is also related to innate immune response against pathogens, which makes GSK-3 an excellent target for therapeutic intervention.

GSK-3 亚型特异性产品:

GSK-3 Isoform Comparison
Cat. No. Product Name Effect Purity Chemical Structure
  • HY-N12625
    (R)-(+)-O-Demethylbuchenavianine Inhibitor 98.67%
    (R)-(+)-O-Demethylbuchenavianine 一种细胞周期蛋白依赖性激酶 (CDK) 抑制剂。(R)-(+)-O-Demethylbuchenavianine 可抑制 CDK1、CDK5、糖原合酶激酶 3 (GSK3)、cdc2 样激酶 (CLK1) 和双特异性酪氨酸磷酸化调节激酶 1A (DYRK1A)，IC50 分别为 1.1、0.95、>10、>10 和 >10 μM。
    (R)-(+)-O-Demethylbuchenavianine
  • HY-141480
    GSK-3β inhibitor 3 Inhibitor 99.22%
    GSK-3β inhibitor 3 是一种有效，选择性，不可逆和共价的糖原合酶激酶 3β (GSK-3β) 抑制剂，IC50 值为 6.6 μM。GSK-3β inhibitor 3 可用于急性早幼粒细胞白血病的研究。
    GSK-3β inhibitor 3
  • HY-120902
    GSK-3β inhibitor 8 Inhibitor ≥99.0%
    GSK-3β inhibitor 8 是一种噻吩嘧啶衍生物，是有效和选择性的 GSK-3β 抑制剂 (IC50=64 nM)。GSK-3β inhibitor 8 负调控 Wnt 信号通路，刺激 β 细胞增殖。
    GSK-3β inhibitor 8
  • HY-134622
    GSK-3/CDK5/CDK2-IN-1 Inhibitor 98.10%
    GSK-3/CDK5/CDK2-IN-1，一种咪唑衍生物，是 cdk5，cdk2 和 GSK-3 的抑制剂。GSK-3/CDK5/CDK2-IN-1 可用于癌症和神经退行性疾病的研究。详细信息请参考专利文献 WO2002010141A1 中的化合物 9a。
    GSK-3/CDK5/CDK2-IN-1
  • HY-Q48328
    GSK3-IN-1 Inhibitor 99.86%
    GSK3-IN-1 (compound 11) 是一种 GSK-3 抑制剂， IC50 值为 12 μM。GSK3-IN-1可用于糖尿病的研究。
    GSK3-IN-1
  • HY-103381
    NSC693868 Inhibitor ≥99.0%
    NSC693868 是一种选择性的 CDK1 和 CDK5 抑制剂，IC50s 分别为 600 nM 和 400 nM。NSC693868 对 GSK3β 也有较弱的抑制作用，IC50 为 1 µM，且不影响细胞分裂周期因子25 (CDC25) 活性。NSC693868 用于研究 CDK1 和 CDK5 在各种信号通路中的作用。
    NSC693868
  • HY-P2558
    GSK3 Substrate, α, β subunit 99.87%
    GSK3 Substrate, α, β subunit 是糖原合酶激酶-3 (GSK-3) 的肽底物，可用于测量 GSK-3 活性。
    GSK3 Substrate, α, β subunit
  • HY-B0712A
    Ceftriaxone sodium hydrate

    头孢曲松钠水合物

    		Inhibitor 99.25%
    Ceftriaxone sodium hydrate (Ro 13-9904 sodium hydrate) 是一种广谱 β-内酰胺类三代头孢菌素类抗生素，对多种革兰氏阴性菌和阳性菌有良好的抗菌活性。Ceftriaxone sodium hydrate 是 GSK3β 的共价抑制剂，IC50 值为 0.78 μM。 Ceftriaxone sodium hydrate 是 Aurora B 的抑制剂。Ceftriaxone sodium hydrate 具有抗炎、抗肿瘤和抗氧化活性。Ceftriaxone sodium hydrate 可用于治疗细菌性感染和脑膜炎的研究。
    Ceftriaxone sodium hydrate
  • HY-131177
    yGsy2p-IN-H23 Inhibitor 99.91%
    yGsy2p-IN-H23 是一种有效的酵母糖原合酶 2 (yGsy2p) 抑制剂，对人糖原合酶 1 (hGYS1) 的 IC50 为 875 μM。yGsy2p-IN-H23 结合在 yGsy2p 的尿苷二磷酸葡萄糖结合口袋内。yGsy2p-IN-H23 用于糖原储存疾病 (GSDs) 的相关研究。
    yGsy2p-IN-H23
  • HY-124607
    (R)-BRD3731 Inhibitor 98.22%
    (R)-BRD3731 是一种 GSK3 的抑制剂，对 GSK3β 和 GSK3α 的 IC50 值分别为 1.05 和 6.7 μM。详细信息请参考专利文献 US20160375006A1 中的化合物 273。
    (R)-BRD3731
  • HY-P1113A
    Phospho-Glycogen Synthase Peptide-2(substrate) TFA 98.02%
    Phospho-Glycogen Synthase Peptide-2 (substrate) 是糖原合酶激酶-3 (GSK-3) 的肽底物，可用于蛋白丝氨酸激酶的亲和纯化。
    Phospho-Glycogen Synthase Peptide-2(substrate) TFA
  • HY-122665A
    HTH-01-091 TFA Inhibitor 99.48%
    HTH-01-091 TFA 是一种强效且选择性的 maternal embryonic leucine zipper kinase (MELK) 抑制剂，其 IC50 为 10.5 nM。HTH-01-091 TFA 还能抑制 PIM1/2/3、RIPK2、DYRK3、smMLCK 和 CLK2。HTH-01-091 TFA 可用于乳腺癌研究。
    HTH-01-091 TFA
  • HY-117025
    Manzamine A Inhibitor
    Manzamine A 是一种口服活性 β-carboline 生物碱，抑制 GSK-3β 和 CDK-5 的 IC50 值为 10.2 μM 和 1.5 μM。Manzamine A 靶向胰腺癌细胞的 vacuolar ATPases 并抑制自噬 (autophagy)。Manzamine A 具有抗疟和抗癌活性。Manzamine A 对 HSV-1 具有较强的活性。
    Manzamine A
  • HY-10096
    TCS2002 Inhibitor 99.8%
    TCS2002 (Compound 9b) 是一种高选择性、口服有效的 GSK-3β 抑制剂，IC50 为 35 nM。TCS2002 具有良好的药代动力学特征，且可透过血脑屏障。TCS2002 可用于阿尔茨海默病的研究。
    TCS2002
  • HY-162675
    COB-187 Inhibitor
    COB-187 是一种有效的、ATP 竞争性的、选择性的 GSK-3β 抑制剂。COB-187 通过可逆的、半胱氨酸 (Cys)-199 依赖性机制抑制 GSK-3。COB-187 可抑制 LPS 诱导的细胞因子产生和 SARS-CoV-2 刺突蛋白诱导的 CXCL10 产生。
    COB-187
  • HY-114903
    (E/Z)-BIO-acetoxime Inhibitor
    (E/Z)-BIO-acetoxime (GSK-3 Inhibitor X) 是一种有效的选择性 GSK-3α/β 抑制剂，IC50 为 10 nM。(E/Z)-BIO-acetoxime 对 GSK-3α/β 具有超过 CDK5/p25，CDK2/cyclin A 和 CDK1/cyclin B (IC50=2.4, 4.3, 63 μM) 200 倍的选择性。
    (E/Z)-BIO-acetoxime
  • HY-126771
    Chrysomycin A Inhibitor ≥98.0%
    Chrysomycin A (Chr-A) 是一种抗生素，能够来源于链霉菌。Chrysomycin A 表现出抗肿瘤和抗结核和 MRSA 活性。特别是在胶质母细胞瘤中，Chrysomycin A 通过 Akt/GSK-3β/β-catenin 信号通路抑制癌细胞的增殖、迁移和侵袭。
    Chrysomycin A
  • HY-N1121
    Triptonodiol Inhibitor ≥98.0%
    Triptonodiol 可从 Trypterygium wilfordii 中分离得到。Triptonodiol 具有抗炎和抗癌活性。Triptonodiol 抑制 GSK 的生物学活性。
    Triptonodiol
  • HY-148132
    GSK-3β inhibitor 11 Inhibitor 98.02%
    GSK-3β inhibitor 11 (compound 21) 是一种糖原合成酶-3β (GSK-3β) 抑制剂 (IC50=10.02 μM)。GSK-3β inhibitor 11 可用于神经退行性疾病的研究。
    GSK-3β inhibitor 11
  • HY-B0320AR
    Cromolyn (sodium) (Standard)

    色甘酸钠 (标准品)

    		Inhibitor
    Cromolyn (sodium) (Standard) 是 Cromolyn (sodium) 的分析标准品。本产品用于研究及分析应用。 Cromolyn sodium (Disodium Cromoglycate; FPL-670) 是抗过敏化合物。Cromolyn sodium 是一种 GSK-3β 抑制剂，IC50 为 2.0 μM。
    Cromolyn (sodium) (Standard)
目录号 产品名 / 同用名 种属 表达系统
目录号 产品名 / 同用名 应用 反应物种
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Download GSK-3 Signaling Pathway Map.

Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. GSK-3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnt, PI3K, growth factors, cytokines, and ligands for G protein-coupled receptors. The PI3K pathway is known for regulating metabolism, cell growth, and cell survival. The PI3K activity is stimulated by diverse oncogenes and growth factor receptors. PI3K-mediated production of PIP3 leads to the activation of Akt. The activation of Akt leads to the phosphorylation of GSK-3, which is active in resting cells, but is inactivated by the phosphorylation. The GSK-3 has been linked to the regulation of an assembly of transcription factors, including β-catenin, NF-κB, c-Jun, CREB, and STAT. Thus, the altered activity of GSK-3 causes various effects on cytokine expression. 

 

In the absence of Wnt signaling, β-catenin is phosphorylated by CK1 and GSK-3. This phosphorylation leads to recognition by β-TrCP, leading to the ubiquitylation of β-catenin and degradation by the proteasome. Upon binding of a lipid-modified Wnt protein to the receptor complex, a signaling cascade is initiated. LRP is phosphorylated by CK1/CK2 and GSK-3, and Axin is recruited to the plasma membrane. The kinases in the β-catenin destruction complex are inactivated and β-catenin translocates to the nucleus to form an active transcription factor complex with TCF, leading to transcription of a large set of target genes.

 

Some endogenous growth factors could bind to and activate the tyrosine kinase receptor. This facilitates the recruitment of other proteins (SHC, SOS), which results in the activation of the ERK-MAPK cascade and the inhibition of GSK-3. GSK-3 exerts many cellular effects: it regulates cytoskeletal proteins, and is important in determining cell survival/cell death. GSK-3 has also been identified as a target for the actions of lithium. GSK-3 can inhibit glycogen synthase, the enzyme that catalyzes the transfer of glucose from UDPG to glycogen[1][2].

 

Reference:

[1]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die.Nat Rev Immunol. 2015 Jun;15(6):362-74. 
[2]. Conrad M, et al. Regulated necrosis: disease relevance and therapeutic opportunities.Nat Rev Drug Discov. 2016 May;15(5):348-66. 

GSK-3 Isoform Comparison

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