TGFβ instructs mTORC2 to activate PKCβII for increased TWIST1 expression in proximal tubular epithelial cell injury

被引：2
作者：
Das, Falguni [1 ,2 ]
Ghosh-Choudhury, Nandini [3 ]
Maity, Soumya [2 ]
Kasinath, Balakuntalam S. [2 ]
Choudhury, Goutam Ghosh [1 ,2 ,4 ,5 ]
机构：
[1] South Texas Vet Hlth Care Syst, Educ & Clin Ctr, 1VA Res & 4Geriatr Res, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA
[2] UT Hlth San Antonio, Dept Med, San Antonio, TX USA
[3] UT Hlth San Antonio, Dept Pathol, San Antonio, TX USA
[4] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA
[5] UT Hlth San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA
来源：
FEBS LETTERS | 2023年 / 597卷 / 09期
关键词：
kidney fibrosis; matrix protein expansion; protein kinase C; transforming growth factor-beta; TWIST1; PROTEIN-KINASE-C; TO-MESENCHYMAL TRANSITION; HIGH GLUCOSE; AKT KINASE; RAPAMYCIN COMPLEXES; MAMMALIAN TARGET; OXIDATIVE STRESS; IN-VIVO; SMAD; PATHWAY;
D O I：
10.1002/1873-3468.14599
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The plasticity of proximal tubular epithelial cells in response to TGF beta contributes to the expression of TWIST1 to drive renal fibrosis. The mechanism of TWIST1 expression is not known. We show that both PI3 kinase and its target mTORC2 increase TGF beta-induced TWIST1 expression. TGF beta enhances phosphorylation on Ser-660 in the protein kinase C beta II (PKC beta II) hydrophobic motif site. Remarkably, phosphorylation-deficient PKC beta IIS660A, kinase-dead PKC beta II, and PKC beta II knockdown blocked TWIST1 expression by TGF beta. Inhibition of TWIST1 arrested TGF beta-induced tubular cell hypertrophy and the expression of fibronectin, collagen I (alpha 2), and alpha-smooth muscle actin. By contrast, TWIST1 overexpression induced these pathologies. Interestingly, the inhibition of PKC beta II reduced these phenomena, which were countered by the expression of TWIST1. These results provide the first evidence for the involvement of the mTORC2-PKC beta II axis in TWIST1 expression to promote tubular cell pathology.
引用
收藏
页码：1300 / 1316
页数：17
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共 73 条
  • [11] Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy
    Das, Falguni
    Ghosh-Choudhury, Nandini
    Kasinath, Balakuntalam S.
    Choudhury, Goutam Ghosh
    [J]. CELLULAR SIGNALLING, 2018, 42 : 44 - 53
  • [12] PDGF receptor-β uses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I (α2) expression
    Das, Falguni
    Ghosh-Choudhury, Nandini
    Venkatesan, Balachandar
    Kasinath, Balakuntalam S.
    Choudhury, Goutam Ghosh
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2017, 313 (02) : F291 - F307
  • [13] High Glucose Forces a Positive Feedback Loop Connecting Akt Kinase and FoxO1 Transcription Factor to Activate mTORC1 Kinase for Mesangial Cell Hypertrophy and Matrix Protein Expression
    Das, Falguni
    Ghosh-Choudhury, Nandini
    Dey, Nirmalya
    Bera, Amit
    Mariappan, Meenalakshmi M.
    Kasinath, Balakuntalam S.
    Choudhury, Goutam Ghosh
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (47) : 32703 - 32716
  • [14] TGF-induced PI 3 kinase-dependent Mnk-1 activation is necessary for Ser-209 phosphorylation of eIF4E and mesangial cell hypertrophy
    Das, Falguni
    Ghosh-Choudhury, Nandini
    Bera, Amit
    Kasinath, Balakuntalam S.
    Choudhury, Goutam Ghosh
    [J]. JOURNAL OF CELLULAR PHYSIOLOGY, 2013, 228 (07) : 1617 - 1626
  • [15] Transforming Growth Factor β Integrates Smad 3 to Mechanistic Target of Rapamycin Complexes to Arrest Deptor Abundance for Glomerular Mesangial Cell Hypertrophy
    Das, Falguni
    Ghosh-Choudhury, Nandini
    Bera, Amit
    Dey, Nirmalya
    Abboud, Hanna E.
    Kasinath, Balakuntalam S.
    Choudhury, Goutam Ghosh
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (11) : 7756 - 7768
  • [16] Unrestrained Mammalian Target of Rapamycin Complexes 1 and 2 Increase Expression of Phosphatase and Tensin Homolog Deleted on Chromosome 10 to Regulate Phosphorylation of Akt Kinase
    Das, Falguni
    Ghosh-Choudhury, Nandini
    Dey, Nirmalya
    Mandal, Chandi Charan
    Mahimainathan, Lenin
    Kasinath, Balakuntalam S.
    Abboud, Hanna E.
    Choudhury, Goutam Ghosh
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (06) : 3808 - 3822
  • [17] A single combination gene therapy treats multiple age-related diseases
    Davidsohn, Noah
    Pezzone, Matthew
    Vernet, Andyna
    Graveline, Amanda
    Oliver, Daniel
    Slomovic, Shimyn
    Punthambaker, Sukanya
    Sun, Xiaoming
    Liao, Ronglih
    Bonventre, Joseph V.
    Church, George M.
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (47) : 23505 - 23511
  • [18] TGFβ-Stimulated MicroRNA-21 Utilizes PTEN to Orchestrate AKT/mTORC1 Signaling for Mesangial Cell Hypertrophy and Matrix Expansion
    Dey, Nirmalya
    Ghosh-Choudhury, Nandini
    Kasinath, Balakuntalam S.
    Choudhury, Goutam Ghosh
    [J]. PLOS ONE, 2012, 7 (08):
  • [19] Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal
    Du, Rui
    Xia, Lin
    Ning, Xiaoxuan
    Liu, Limin
    Sun, Wenjuan
    Huang, Chen
    Wang, Hanmin
    Sun, Shiren
    [J]. MOLECULAR BIOLOGY OF THE CELL, 2014, 25 (17) : 2650 - 2659
  • [20] Hedgehog-Gli Pathway Activation during Kidney Fibrosis
    Fabian, Steven L.
    Penchev, Radostin R.
    St-Jacques, Benoit
    Rao, Anjali N.
    Sipila, Petra
    West, Kip A.
    McMahon, Andrew P.
    Humphreys, Benjamin D.
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2012, 180 (04) : 1441 - 1453
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