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-139254
    Indirubin-3′-oxime Inhibitor 99.10%
    Indirubin-3′-oxime (IDR3O) 是 indirubin 的合成衍生物，是细胞周期蛋白依赖性激酶 (CDKs) 和糖原合成酶激酶3β (GSK3β) 的有效抑制剂。Indirubin-3′-oxime 直接抑制JNK的所有三种亚型 (JNK1，JNK2，JNK3) 的活性，IC50s 分别为 0.8 μM、1.4 μM 和 1 μM。Indirubin-3′-oxime 可通过激活软骨细胞中的 Wnt/β-catenin 信号来促进身高增长。
    Indirubin-3′-oxime
  • HY-144290
    ARN25068 Inhibitor 99.66%
    ARN25068 是三种蛋白激酶 GSK-3β、FYN 和 DYRK1A的亚微摩尔抑制剂，可解决 tau 蛋白过度磷酸化。
    ARN25068
  • HY-117025A
    Manzamine A hydrochloride Inhibitor 99.66%
    Manzamine A hydrochloride 是一种具有口服活性的 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 hydrochloride 靶向胰腺癌细胞的 vacuolar ATPases 并抑制自噬 (autophagy)。Manzamine A hydrochloride 具有抗疟和抗癌活性。Manzamine A hydrochloride 对 HSV-1 具有较强的活性。
    Manzamine A hydrochloride
  • HY-107815
    CHIR 98024 Inhibitor 98.08%
    CHIR 98024 (Compound L) 是一种糖原合成酶激酶 3 （GSK3）抑制剂，EC50 为 0.2566 μM。
    CHIR 98024
  • HY-117822
    BRD0209 Inhibitor 99.56%
    BRD0209 是一种有效、选择性和双重的 GSK3α/β 抑制剂 (GSK3α IC50 = 19 nM; GSK3β IC50 = 5 nM)。BRD0209 还是一种可逆的 ATP 竞争性抑制剂，具有快关动力学 (Ki 分别为 4.2 nM)。BRD0209 是一种三环吡唑并四氢喹啉酮化合物。BRD0209 具有研究心境障碍疾病的潜力。
    BRD0209
  • HY-126144A
    (E/Z)-GSK-3β inhibitor 1 Inhibitor 99.03%
    (E/Z)-GSK-3β inhibitor 1 是 (E)-GSK-3β inhibitor 1 和 (Z)-GSK-3β inhibitor 1 的消旋体。GSK-3β inhibitor 1 (compound 3a) 是糖原合成酶激酶 3β (GSK-3β)的抑制剂，可用于糖尿病的研究，其对 GSK-3β 的 IC50 值为 4.9 nM。
    (E/Z)-GSK-3β inhibitor 1
  • HY-154851
    GSK-3 inhibitor 3 Inhibitor 98.72%
    GSK-3 inhibitor 3 是 GSK-3 的选择性、具有口服活性和脑渗透性的抑制剂，对 GSK-3α 和 GSK-3β 的 IC50s 分别为 0.35 nM 和 0.25 nM。在三重转基因小鼠阿尔茨海默病模型中，GSK-3 inhibitor 3 降低 Tau 蛋白 (tau protein) S396 磷酸化水平，IC50为 10 nM。GSK-3 inhibitor 3 可用于神经系统疾病研究。
    GSK-3 inhibitor 3
  • HY-112392
    GSK-3 Inhibitor XIII Inhibitor 98.61%
    GSK-3 Inhibitor XIII 是一种有效的 ATP 竞争性 GSK-3 抑制剂，Ki 为 24 nM。
    GSK-3 Inhibitor XIII
  • HY-112809
    GSK2646264 Inhibitor 98.39%
    GSK2646264 (Compound 44) 是一种有效的、选择性的脾酪氨酸激酶 (SYK) 抑制剂，pIC50 值为 7.1。GSK2646264 对其他激酶也有抑制效果，对 LCK、LRRK2、GSK3β、JAK2、VEGFR2/KDR/Flk-1、Aurora B 和 Aurora A 的 pIC50 分别为 5.4、5.4、5.3、5、4.5、<4.6 和 <4.3。GSK2646264 可渗透到皮肤的表皮和真皮层。
    GSK2646264
  • HY-13867A
    Bisindolylmaleimide I hydrochloride

    3-[1-[3-(二甲基氨基)丙基]-1H-吲哚-3-基]-4-(1H-吲哚-3-基)-1H-吡咯-2,5-二酮单盐酸盐

    		99.18%
    Bisindolylmaleimide I (GF109203X) hydrochloride 是一种具有细胞渗透性和可逆性的 PKC 抑制剂 (对 PKCα, PKCβI, PKCβII, and PKCγ 的 IC50 分别为 20 nM、17 nM、16 nM 和 20 nM)。Bisindolylmaleimide I hydrochloride 也是一种 GSK-3 抑制剂。
    Bisindolylmaleimide I hydrochloride
  • HY-100950
    ABC1183 Inhibitor 99.19%
    ABC1183 是一种具有口服活性的选择性 GSK3 和 CDK9 双重抑制剂。ABC1183 作用于 GSK3β, GSK3α 和 CDK9/cyclin T1 的 IC50 值分别是 657 nM、327 nM、321 nM。ABC1183 具有抗炎作用，抗肿瘤活性。
    ABC1183
  • HY-126144
    GSK-3β inhibitor 1 Inhibitor 98.04%
    GSK-3β inhibitor 1 (compound 3a) 抑制 GSK-3β，IC50 为 4.19 nM。 GSK-3β inhibitor 1 在肥胖链脲佐菌素治疗的大鼠中显示出很高的抗糖尿病功效。
    GSK-3β inhibitor 1
  • HY-122665
    HTH-01-091 Inhibitor 98.64%
    HTH-01-091 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 还能抑制 PIM1/2/3、RIPK2、DYRK3、smMLCK 和 CLK2。HTH-01-091 可用于乳腺癌研究。
    HTH-01-091
  • HY-134393B
    6-Me-ATP (trisodium) solution (100mM) Chemical ≥99.0%
    6-Me-ATP (N6-Methyl-ATP) trisodium solution (100mM) 是一种 N6 修饰的 ATP 衍生物。6-Me-ATP trisodium 对 GSK3 显示出很好的结合亲和力，可作为 GSK3β 催化其底物肽磷酸化的磷酸基团供体。
    6-Me-ATP (trisodium) solution (100mM)
  • HY-121035
    7BIO Inhibitor 99.20%
    7BIO (7-Bromoindirubin-3-Oxime) 是靛玉红的衍生物。7BIO (7-Bromoindirubin-3-Oxime) 对细胞周期蛋白依赖性激酶5 (CDK5) 和糖原合酶激酶-3β (GSK3β) 具有抑制作用。7BIO (7-Bromoindirubin-3-Oxime) 抑制 Aβ 寡聚体诱导的神经炎症、突触损伤、tau 过度磷酸化、星形胶质细胞和小胶质细胞的活化，并减轻 Aβ 寡聚体诱导的小鼠认知障碍[1]。
    7BIO
  • HY-112388
    GSK-3b Inhibitor XI Inhibitor 99.10%
    GSK-3b Inhibitor XI 是糖原合酶激酶 3β (GSK3β；Ki=25 nM) 的强效抑制剂。浓度为 10 μM 时，该抑制剂对 79 种激酶中的 GSK3β 具有选择性。GSK-3b Inhibitor XI 可抑制 HEK293 细胞中的 GSK3β (EC50=32 nM)。
    GSK-3b Inhibitor XI
  • HY-14679
    GSK3β inhibitor II Inhibitor 99.76%
    GSK3β inhibitor II 是 GSK3β 的抑制剂。GSK3β inhibitor II 可用于阿尔茨海默病 (AD) 的研究。
    GSK3β inhibitor II
  • HY-111055
    BIP-135 Inhibitor 99.86%
    BIP-135 是一个高效、选择性的，ATP 竞争性的 GSK-3 抑制剂，对 GSK-3α 和 GSK-3β 作用的IC50 值分别为 16 nM 和 21 nM。BIP 135 具有神经保护作用。
    BIP-135
  • HY-111930
    5-Iodo-indirubin-3'-monoxime Inhibitor 99.50%
    5-Iodo-indirubin-3'-monoxime 是一种有效的 GSK-3β，CDK5/P25 和 CDK1/cyclin B 抑制剂，与 ATP 竞争性地结合酶的催化位点，IC50 值分别为 9，20 和 25 nM。
    5-Iodo-indirubin-3'-monoxime
  • HY-147134
    GSK-3β inhibitor 10 Inhibitor 98.04%
    GSK-3β inhibitor 10 (compound 14a) 是一种糖原合酶激酶 3β (GSK-3β) 抑制剂，IC50 为 80.5 nM。GSK-3β inhibitor 10 可用于阿尔兹海默症的研究。
    GSK-3β inhibitor 10
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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