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A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis

ABSTRACT: Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA – promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73147 | GEO | 2017/10/17

SECONDARY ACCESSION(S): PRJNA296097

REPOSITORIES: GEO

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A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis

Project description:Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states,termed commitment, is poorly understood. Here we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA – promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.

2017-10-18 | PXD003281 | Pride

Phospho-proteomic analysis of DUSP6 deficient Caco-2 cells

Project description:Dual-specificity phosphatase 6 (Dusp6)-deficiency enhances baseline colon barrier integrity and confers amelioration of dextran sulfate sodium (DSS)-induced colonic injury. DUSP6 is a phosphatase, and therefore it is plausible that DUSP6 knockout alters the phosphorylation status of other proteins. To access the protein phosphorylation landscape and functional network in DUSP6 deficient Caco-2 cells, we applied phosphopeptide enrichment and isobaric labeling strategies with MS-based proteomics, and identified 1323 phosphorylation sites on 580 phosphoproteins.

2021-11-02 | PXD029014 | Pride

Phosphatome profiling of estrogen receptor negative breast cancer

Project description:Purpose: To characterize the expression of phosphatases in estrogen receptor negative breast cancer Little is known about the role of phosphatases in the major estrogen receptor negative breast cancer phenotypes (i.e. those overexpressing ERBB2 and the triple negative). We carried out microarray phosphatome profiling in 41 estrogen receptor negative (ER-) breast cancer patients (as determined by immunohistochemistry (IHC)) containing both ERBB2+ and ERBB2- in order to characterize the differences between these groups by Statistical Analysis of Microarrays (SAM). Our findings point to the importance of the MAPK and PI3K pathways in ER- BCs as some of the most differentially expressed phosphatases (like DUSP4 and DUSP6) share ERK as substrate, or regulate the PI3K pathway (INPP4B, PTEN). These observations are also confirmed by pathway and GSEA analysis. It is shown that both ER- ERBB2+ and triple negative breast cancers have a distinctive pattern of phosphatase RNA expression. Surgical specimens from primary breast cancers that were estrogen receptor negative according to immunohistochemistry

2014-06-30 | E-GEOD-51999 | biostudies-arrayexpress

Phosphatome profiling of estrogen receptor negative breast cancer

2014-06-30 | GSE51999 | GEO

RNA sequencing analysis of WT and Dusp6-/- rat cardiac infiltrated macrophages transcriptomes

Project description:Dual-specificity phosphatase 6 (DUSP6), a member of MAPK phosphatase, serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in multiple species. Utilizing a rat strain harboring nonsense mutation of Dusp6, we found that Dusp6 deficiency improves cardiac function by attenuating cardiomyocyte death and fibrosis in acute inflammatory phase after MI. To investigate the effect of DUSP6 on macrophages in acute inflammatory phase of MI, we performed RNA-seq analysis using CD45+HIS36+ macrophages isolated from Dusp6-deficient and WT infarcted LV tissues 72 h after MI by fluorescent activated cell sorting (FACS).

2022-07-13 | GSE195978 | GEO

Sphingosine-1-phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis

Project description:Sphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphoryled by the actions of two S1P-specific phosphatases, sphingosine 1-phosphate phosphatase 1 and 2. To identify the physiologic functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1, deleted. Sgpp1-/- mice appeared normal at birth but during the first week of life, they exhibited stunted growth, suffered desquamation, and most died before weaning. Interestingly, the epidermal permeability barrier developed normally during embryogenesis. Sgpp1 -/- pups and surviving adults exhibited epidermal hyperplasia and abnormal expression of keratinocyte differentiation markers. Keratinocytes isolated from Sgpp1 -/- skin had increased intracellular S1P levels, and expressed a gene expression profile that indicated enhanced differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis. Comparison of KO vs. WT with five replications per treatment sample

2013-08-09 | E-GEOD-40368 | biostudies-arrayexpress

Sphingosine-1-phosphate phosphatase 1 regulates keratinocyte differentiation and epidermal homeostasis

2013-08-09 | GSE40368 | GEO

RNA-seq analysis of IL-10 treatment of wildtype and Ptpn1-/- knockout peritoneal macrophages

Project description:We report here the deep sequencing of the mRNA from peritoneal exudate cells (macrophages) purified from wildtype or Ptpn1 (PTP1B) knockout mice, either treated or untreated with IL-10. In periotenal macrophages IL-10 activates the transcription factor STAT3 to execute and anti-inflammatory gene expression programme. The tyrosine phosphatase PTPN1 targets STAT3 for dephosphorylation and leads to the deactivation of STAT3. In this study we examined the role of PTP1B in controlling the normal homeostatic level phosphorylation of STAT3 by comparing the IL-10/STAT3-mediated anti-inflammatory gene expression programme. We find that loss of PTP1B leads to an up-regulation of the activity of STAT3, both at the level of phosphorylation and also in enhanced expression of anti-inflammatory gene products. RNA-seq of wildtype and Ptpn1 (PTP1B) knockout mouse peritoneal macrophages, treated or untreated with IL-10

2014-05-12 | E-GEOD-49449 | biostudies-arrayexpress

Ablation of dual specificity phosphatase 6 protects against non-alcoholic fatty liver disease via CYP4A and MAPK

Project description:Dual specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). In this study, we used a high-fat diet (HFD)-induced murine non-alcoholic fatty liver disease (NAFLD) model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficient (HI) mice developed severe obesity and liver pathology consistent with NAFLD when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, while hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant downregulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared to WT and Dusp6-HI mice. Knockdown of DUSP6 in HepG2, a human liver-lineage cell line, also promoted a reduction of lipid accumulation, downregulation of CYP4A, and upregulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.

2023-09-04 | GSE216881 | GEO

DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells

Project description:Memory CD4+ T helper (Th) cells are crucial for acquired immunity and protection from infectious microorganisms, and also drive pathogenesis of chronic inflammatory diseases, such as asthma. ST2hi memory-type Th2 cells have been identified as a pathogenic subpopulation capable of directly inducing eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amounts of IL-5 upon stimulation via their TCR, but not in response to IL-33. In contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). We investigated the molecular mechanism that controls the innate function of IL-33-induced cytokine production, and identified a MAPK phosphatase Dusp10, as a key negative regulator of IL-33–induced cytokine production in Th2 cells. We found that Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production by preventing GATA3 activity through inhibition of p38 MAPK phosphorylation. Strikingly, deletion of Dusp10 rendered ST2hi Th2 cells able to directly respond to IL-33 exposure and produce IL-5. Thus, DUSP10 constrains IL-33–induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-mediated GATA3 function.

2018-09-23 | GSE116842 | GEO

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