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
  • [21] RREB1 Integrates TGF-β and RAS Signals to Drive EMT
    Fattet, Laurent
    Yang, Jing
    [J]. DEVELOPMENTAL CELL, 2020, 52 (03) : 259 - 260
  • [22] An essential role for autophosphorylation in the dissociation of activated protein kinase C from the plasma membrane
    Feng, X
    Hannun, YA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (41) : 26870 - 26874
  • [23] Evidence for Direct Activation of mTORC2 Kinase Activity by Phosphatidylinositol 3,4,5-Trisphosphate
    Gan, Xiaoqing
    Wang, Jiyong
    Su, Bing
    Wu, Dianqing
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (13) : 10998 - 11002
  • [24] The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?
    Genovese, Federica
    Manresa, Alba A.
    Leeming, Diana Julie
    Karsdal, Morten Asser
    Boor, Peter
    [J]. FIBROGENESIS & TISSUE REPAIR, 2014, 7
  • [25] Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα but not S6K1
    Guertin, David A.
    Stevens, Deanna M.
    Thoreen, Carson C.
    Burds, Aurora A.
    Kalaany, Nada Y.
    Moffat, Jason
    Brown, Michael
    Fitzgerald, Kevin J.
    Sabatini, David M.
    [J]. DEVELOPMENTAL CELL, 2006, 11 (06) : 859 - 871
  • [26] Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice
    Hathaway, Catherine K.
    Gasim, Adil M. H.
    Grant, Ruriko
    Chang, Albert S.
    Kim, Hyung-Suk
    Madden, Victoria J.
    Bagnell, C. Robert, Jr.
    Jennette, J. Charles
    Smithies, Oliver
    Kakoki, Masao
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (18) : 5815 - 5820
  • [27] Signaling Receptors for TGF-β Family Members
    Heldin, Carl-Henrik
    Moustakas, Aristidis
    [J]. COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2016, 8 (08):
  • [28] Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
    Henderson, Neil C.
    Arnold, Thomas D.
    Katamura, Yoshio
    Giacomini, Marilyn M.
    Rodriguez, Juan D.
    McCarty, Joseph H.
    Pellicoro, Antonella
    Raschperger, Elisabeth
    Betsholtz, Christer
    Ruminski, Peter G.
    Griggs, David W.
    Prinsen, Michael J.
    Maher, Jacquelyn J.
    Iredale, John P.
    Lacy-Hulbert, Adam
    Adams, Ralf H.
    Sheppard, Dean
    [J]. NATURE MEDICINE, 2013, 19 (12) : 1617 - 1624
  • [29] Early Epithelial Phenotypic Changes Predict Graft Fibrosis
    Hertig, Alexandre
    Anglicheau, Dany
    Verine, Jerome
    Pallet, Nicolas
    Touzot, Maxime
    Ancel, Pierre-Yves
    Mesnard, Laurent
    Brousse, Nicole
    Baugey, Edith
    Glotz, Denis
    Legendre, Christophe
    Rondeau, Eric
    Xu-Dubois, Yi-Chun
    [J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2008, 19 (08): : 1584 - 1591
  • [30] Mechanisms of Renal Fibrosis
    Humphreys, Benjamin D.
    [J]. ANNUAL REVIEW OF PHYSIOLOGY, VOL 80, 2018, 80 : 309 - 326
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