在正常果蝇发育过程中，Tsc2不是Akt的关键作用靶点。
Tsc2 is not a critical target of Akt during normal Drosophila development.
作者信息
Dong Jixin, Pan Duojia
机构信息
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9040, USA.
出版信息
Genes Dev. 2004 Oct 15;18(20):2479-84. doi: 10.1101/gad.1240504. Epub 2004 Oct 1.
Abstract
Signaling by insulin and target of rapamycin are both required for cell growth, but their interrelationships remain poorly defined. It was reported that Akt, an essential component of the insulin pathway, stimulates growth by phosphorylating and inhibiting tuberous sclerosis complex 2 (TSC2). Here we evaluate this model genetically in Drosophila by engineering Tsc2 mutants in which the Akt phosphorylation sites are changed to nonphosphorylatable or phospho-mimicking residues. Strikingly, such mutants completely rescue the lethality and cell growth defects of Tsc2-null mutants. Taken together, our data suggest that Tsc2 is not a critical substrate of Akt in normal Drosophila development.
摘要
胰岛素信号传导和雷帕霉素靶蛋白对于细胞生长均是必需的，但其相互关系仍不清楚。据报道，Akt作为胰岛素途径的一个重要组成部分，通过磷酸化并抑制结节性硬化复合物2（TSC2）来刺激生长。在此，我们通过构建Akt磷酸化位点被改变为不可磷酸化或磷酸化模拟残基的Tsc2突变体，在果蝇中对该模型进行遗传学评估。令人惊讶的是，这类突变体完全挽救了Tsc2基因敲除突变体的致死性和细胞生长缺陷。综上所述，我们的数据表明，在正常果蝇发育过程中，Tsc2不是Akt的关键底物。
相似文献
1
Tsc2 is not a critical target of Akt during normal Drosophila development.在正常果蝇发育过程中，Tsc2不是Akt的关键作用靶点。
Genes Dev. 2004 Oct 15;18(20):2479-84. doi: 10.1101/gad.1240504. Epub 2004 Oct 1.
2
Akt regulates growth by directly phosphorylating Tsc2.Akt通过直接磷酸化Tsc2来调节生长。
Nat Cell Biol. 2002 Sep;4(9):658-65. doi: 10.1038/ncb840.
3
TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.TSC1和TSC2肿瘤抑制因子在细胞生长过程中拮抗胰岛素信号传导。
Genes Dev. 2001 Jun 1;15(11):1383-92. doi: 10.1101/gad.901101.
4
Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity.Akt 通过调节细胞内 ATP 水平和 AMPK 活性来激活雷帕霉素的哺乳动物靶点。
J Biol Chem. 2005 Sep 16;280(37):32081-9. doi: 10.1074/jbc.M502876200. Epub 2005 Jul 15.
5
Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.促肿瘤佛波酯和活化的Ras通过p90核糖体S6激酶使结节性硬化肿瘤抑制复合物失活。
Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94. doi: 10.1073/pnas.0405659101. Epub 2004 Sep 1.
6
Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR.Tsc1/Tsc2 的缺失会激活 mTOR，并通过下调血小板衍生生长因子受体（PDGFR）来破坏 PI3K-Akt 信号传导。
J Clin Invest. 2003 Oct;112(8):1223-33. doi: 10.1172/JCI17222.
7
Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2.Akt信号通路的反馈抑制限制了缺乏Tsc2的肿瘤的生长。
Genes Dev. 2005 Aug 1;19(15):1773-8. doi: 10.1101/gad.1314605. Epub 2005 Jul 18.
8
Identification of an AMPK phosphorylation site in Drosophila TSC2 (gigas) that regulate cell growth.果蝇TSC2（gigas）中调控细胞生长的AMPK磷酸化位点的鉴定。
Int J Mol Sci. 2015 Mar 27;16(4):7015-26. doi: 10.3390/ijms16047015.
9
14-3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s).14-3-3在Akt磷酸化位点与肿瘤抑制因子结节性硬化蛋白相互作用。
Cancer Res. 2002 Nov 15;62(22):6475-80.
10
Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38.人类TSC肿瘤抑制蛋白对细胞大小的调节依赖于PI3K和FKBP38。
Oncogene. 2003 Jul 31;22(31):4786-98. doi: 10.1038/sj.onc.1206776.
引用本文的文献
1
AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.AKT介导的TSC2磷酸化调控刺激和组织特异性的mTORC1信号传导及器官生长。
Dev Cell. 2025 May 30. doi: 10.1016/j.devcel.2025.05.008.
2
AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.AKT介导的TSC2磷酸化控制刺激和组织特异性的mTORC1信号传导及器官生长。
bioRxiv. 2024 Sep 23:2024.09.23.614519. doi: 10.1101/2024.09.23.614519.
3
as a Model Organism to Study Basic Mechanisms of Longevity.作为研究长寿基本机制的模式生物。
Int J Mol Sci. 2022 Sep 24;23(19):11244. doi: 10.3390/ijms231911244.
4
Differential metabolic sensitivity of insulin-like-response- and TORC1-dependent overgrowth in Drosophila fat cells.果蝇脂肪细胞中胰岛素样反应和 TORC1 依赖性过度生长的代谢敏感性差异。
Genetics. 2021 Mar 3;217(1):1-12. doi: 10.1093/genetics/iyaa010.
5
Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin.通过递送编码浓缩形式结节蛋白的腺相关病毒9型，在小鼠模型中对2型结节性硬化症进行基因治疗。
Sci Adv. 2021 Jan 8;7(2). doi: 10.1126/sciadv.abb1703. Print 2021 Jan.
6
Regulation of Body Size and Growth Control.调控体型和生长控制。
Genetics. 2020 Oct;216(2):269-313. doi: 10.1534/genetics.120.303095.
7
The Hippo pathway integrates PI3K-Akt signals with mechanical and polarity cues to control tissue growth.Hippo 通路将 PI3K-Akt 信号与机械和极性线索整合在一起，以控制组织生长。
PLoS Biol. 2019 Oct 15;17(10):e3000509. doi: 10.1371/journal.pbio.3000509. eCollection 2019 Oct.
8
Nutrient-Dependent Endocycling in Steroidogenic Tissue Dictates Timing of Metamorphosis in Drosophila melanogaster.类固醇生成组织中营养依赖的内循环决定了黑腹果蝇变态的时间。
PLoS Genet. 2017 Jan 25;13(1):e1006583. doi: 10.1371/journal.pgen.1006583. eCollection 2017 Jan.
9
14-3-3 proteins regulate Tctp-Rheb interaction for organ growth in Drosophila.14-3-3 蛋白调控 Tctp-Rheb 相互作用以控制果蝇器官生长。
Nat Commun. 2016 May 6;7:11501. doi: 10.1038/ncomms11501.
10
Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis.转化生长因子β1通过细胞外信号调节激酶-雷帕霉素复合物1-烟酰胺腺嘌呤二核苷酸磷酸氧化酶4轴诱导足细胞凋亡。
J Biol Chem. 2015 Dec 25;290(52):30830-42. doi: 10.1074/jbc.M115.703116. Epub 2015 Nov 12.
本文引用的文献
1
Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression.雷帕霉素靶蛋白（TOR）：营养和生长因子信号的整合者以及细胞生长与细胞周期进程的协调者。
Oncogene. 2004 Apr 19;23(18):3151-71. doi: 10.1038/sj.onc.1207542.
2
Interplay between growth factor and nutrient signaling: lessons from Drosophila TOR.生长因子与营养信号之间的相互作用：来自果蝇雷帕霉素靶蛋白的启示。
Curr Top Microbiol Immunol. 2004;279:153-67. doi: 10.1007/978-3-642-18930-2_10.
3
Genetic analysis of TOR signaling in Drosophila.果蝇中TOR信号传导的遗传分析。
Curr Top Microbiol Immunol. 2004;279:139-52. doi: 10.1007/978-3-642-18930-2_9.
4
Integration of growth factor and nutrient signaling: implications for cancer biology.生长因子与营养信号的整合：对癌症生物学的影响
Mol Cell. 2003 Aug;12(2):271-80. doi: 10.1016/j.molcel.2003.08.016.
5
Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.结节性硬化症复合基因产物，即结节蛋白和错构瘤蛋白，通过作为Rheb的GTP酶激活蛋白复合物来控制mTOR信号传导。
Curr Biol. 2003 Aug 5;13(15):1259-68. doi: 10.1016/s0960-9822(03)00506-2.
6
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.Rheb GTP酶是TSC2 GAP活性的直接靶点，并调节mTOR信号传导。
Genes Dev. 2003 Aug 1;17(15):1829-34. doi: 10.1101/gad.1110003. Epub 2003 Jul 17.
7
Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.雷帕霉素靶蛋白（mTOR）/核糖体蛋白S6激酶（S6K）/真核细胞起始因子4E结合蛋白（4E-BP）信号传导介质Rheb的胰岛素激活受到结节性硬化症复合物1（TSC1）和2（TSC2）的抑制。
Mol Cell. 2003 Jun;11(6):1457-66. doi: 10.1016/s1097-2765(03)00220-x.
8
Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins.Rheb是结节性硬化症肿瘤抑制蛋白的直接靶点。
Nat Cell Biol. 2003 Jun;5(6):578-81. doi: 10.1038/ncb999.
9
Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling.通过降低dS6K信号传导挽救缺乏TSC肿瘤抑制功能的果蝇的致死率。
Genes Dev. 2002 Oct 15;16(20):2627-32. doi: 10.1101/gad.239102.
10
Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing.发育中的果蝇翅膀中Ras1、dMyc和dPI3K信号之间的相互作用。
Genes Dev. 2002 Sep 1;16(17):2286-99. doi: 10.1101/gad.991102.
Zotero 插件