Characterization of TGF-β signaling in a human organotypic skin model reveals that loss of TGF-βRII induces invasive tissue growth
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Characterization of TGF-β signaling in a human organotypic skin model reveals that loss of TGF-βRII induces invasive tissue growth. / Ye, Zilu; Kilic, Gülcan; Dabelsteen, Sally; Marinova, Irina N; Thøfner, Jens F B; Song, Ming; Rudjord-Levann, Asha M; Bagdonaite, Ieva; Vakhrushev, Sergey Y; Brakebusch, Cord H; Olsen, Jesper V; Wandall, Hans H.
In: Science Signaling, Vol. 15, No. 761, eabo2206, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Characterization of TGF-β signaling in a human organotypic skin model reveals that loss of TGF-βRII induces invasive tissue growth
AU - Ye, Zilu
AU - Kilic, Gülcan
AU - Dabelsteen, Sally
AU - Marinova, Irina N
AU - Thøfner, Jens F B
AU - Song, Ming
AU - Rudjord-Levann, Asha M
AU - Bagdonaite, Ieva
AU - Vakhrushev, Sergey Y
AU - Brakebusch, Cord H
AU - Olsen, Jesper V
AU - Wandall, Hans H
PY - 2022
Y1 - 2022
N2 - Transforming growth factor-β (TGF-β) signaling regulates various aspects of cell growth and differentiation and is often dysregulated in human cancers. We combined genetic engineering of a human organotypic three-dimensional (3D) skin model with global quantitative proteomics and phosphoproteomics to dissect the importance of essential components of the TGF-β signaling pathway, including the ligands TGF-β1, TGF-β2, and TGF-β3, the receptor TGF-βRII, and the intracellular effector SMAD4. Consistent with the antiproliferative effects of TGF-β signaling, the loss of TGF-β1 or SMAD4 promoted cell cycling and delayed epidermal differentiation. The loss of TGF-βRII, which abrogates both SMAD4-dependent and SMAD4-independent downstream signaling, more strongly affected cell proliferation and differentiation than did loss of SMAD4, and it induced invasive growth. TGF-βRII knockout reduced cell-matrix interactions, and the production of matrix proteins increased the production of cancer-associated cell-cell adhesion proteins and proinflammatory mediators and increased mitogen-activated protein kinase (MAPK) signaling. Inhibiting the activation of the ERK and p38 MAPK pathways blocked the development of the invasive phenotype upon the loss of TGF-βRII. This study provides a framework for exploring TGF-β signaling pathways in human epithelial tissue homeostasis and transformation using genetic engineering, 3D tissue models, and high-throughput quantitative proteomics and phosphoproteomics.
AB - Transforming growth factor-β (TGF-β) signaling regulates various aspects of cell growth and differentiation and is often dysregulated in human cancers. We combined genetic engineering of a human organotypic three-dimensional (3D) skin model with global quantitative proteomics and phosphoproteomics to dissect the importance of essential components of the TGF-β signaling pathway, including the ligands TGF-β1, TGF-β2, and TGF-β3, the receptor TGF-βRII, and the intracellular effector SMAD4. Consistent with the antiproliferative effects of TGF-β signaling, the loss of TGF-β1 or SMAD4 promoted cell cycling and delayed epidermal differentiation. The loss of TGF-βRII, which abrogates both SMAD4-dependent and SMAD4-independent downstream signaling, more strongly affected cell proliferation and differentiation than did loss of SMAD4, and it induced invasive growth. TGF-βRII knockout reduced cell-matrix interactions, and the production of matrix proteins increased the production of cancer-associated cell-cell adhesion proteins and proinflammatory mediators and increased mitogen-activated protein kinase (MAPK) signaling. Inhibiting the activation of the ERK and p38 MAPK pathways blocked the development of the invasive phenotype upon the loss of TGF-βRII. This study provides a framework for exploring TGF-β signaling pathways in human epithelial tissue homeostasis and transformation using genetic engineering, 3D tissue models, and high-throughput quantitative proteomics and phosphoproteomics.
KW - Humans
KW - Transforming Growth Factor beta1
KW - Signal Transduction
KW - Skin
KW - Cell Differentiation
KW - Cell Proliferation
U2 - 10.1126/scisignal.abo2206
DO - 10.1126/scisignal.abo2206
M3 - Journal article
C2 - 36413597
VL - 15
JO - Science Signaling
JF - Science Signaling
SN - 1945-0877
IS - 761
M1 - eabo2206
ER -
ID: 327054759