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Dissecting the functional selectivity of TGFβ signaling pathway components using genome engineered human organotypic skin models

ABSTRACT: Transforming growth factor β (TGFβ) signaling is essential in cell growth and differentiation. Yet, the role of the individual TGFβ signaling components in human tissue homeostasis and transformation is still incompletely understood. Here we dissected the importance of the core components in the TGFβ signaling pathway by CRISPR/Cas9 genome editing of human keratinocytes. The edited keratinocytes were used for human organotypic skin cultures and global quantitative proteomics and phosphoproteomics by mass spectrometry. Characterization of cells and human organotypic skin tissues showed control of epithelial differentiation by Smad4-dependent TGF signaling through cell cycle regulation and ECM expression. In contrast, we found that the combined Smad4 dependent and independent pathways, governed by TGFβRII, controls epithelial homeostasis and prevents invasive growth by blocking epithelial inflammation and activation of p38 and ERK signaling. The study provides a framework for exploration of signaling pathways in human 3D tissue models and with global phosphoproteomics.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Keratinocyte, Skin

SUBMITTER: Zilu Ye

LAB HEAD: Jesper Olsen

PROVIDER: PXD024935 | Pride | 2023-02-09

REPOSITORIES: Pride

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			Action	DRS
	20200310_EXPL2_EvoPRI_ZY_SA_45min_DDA_NTERT_WT_HpH46_Human_.pdResult	Other
	20200310_EXPL2_EvoPRI_ZY_SA_45min_DDA_NTERT_WT_HpH46_Human_01.raw	Raw
	20200310_EXPL2_EvoPRI_ZY_SA_45min_DDA_NTERT_WT_HpH46_Human_02.raw	Raw
	20200310_EXPL2_EvoPRI_ZY_SA_45min_DDA_NTERT_WT_HpH46_Human_03.raw	Raw
	20200310_EXPL2_EvoPRI_ZY_SA_45min_DDA_NTERT_WT_HpH46_Human_04.raw	Raw

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Dissecting the functional selectivity of TGFβ signaling pathway components using genome engineered human organotypic skin models

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