Profibrotic regulation of FGFR3 signaling in fibroblasts
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA625273 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We employed dermal fibroblasts isolated from Fgfr3G374Rneo+ mice, which do not express functional Fgfr3 (Fgfr3KO), from Fgfr3G374Rneo- mice with ligand-independent constitutive activation of Fgfr3 (Fgfr3Act) and from wildtype (WT) mice with normal expression of Fgfr3. Total RNA from these murine dermal fibroblasts (passage 4) were extracted and after quality control, were hybridized to the murine genome U74 gene chip. We have identified that Fgfr3 regulates important profibrotic pathways in fibroblasts. Selective upregulation of fibroblast growth factor receptor 3 (FGFR3) and its ligand FGF9 promote fibroblast activation and tissue fibrosis Transcriptome profiling, in silico analysis and functional experiments revealed that FGFR3 synergistically induces multiple profibrotic pathways including Endothelin-, Interleukin-4- and CTGF-signaling in a CREB-dependent manner. Inhibition of FGFR3 signaling by fibroblast-specific knockout of FGFR3 or FGF9 or pharmacological inhibition of FGFR3 inhibited fibroblast activation and attenuated experimental skin fibrosis. We have characterized FGFR3 as an upstream regulator of a network of profibrotic mediators and as a potential target for the treatment of fibrosis.
2020-10-01 | GSE148643 | GEO
Project description:Reciprocal Zeb1-Fgfr3 Regulation Controls Skeletal Development
| PRJNA1450670 | ENA
Project description:We provide an original multi-stage approach identifying a gene signature to assess the fibroblast polarization. Prototypic polarizations (inflammatory/fibrotic) were induced by seeded mouse embryonic fibroblasts (MEFs) with TNFα or TGFß1, respectively. The transcriptomic and proteomic profiles were obtained by RNA microarray and LC/MS-MS. Gene Ontology and pathways analysis were performed among the differentially expressed genes (DEGs) and proteins (DEPs). Balb/c mice underwent daily intradermal injections of HOCl (or PBS) as an experimental murine model of inflammation-mediated fibrosis in a time-dependent manner. As results, 1,456 and 2,215 DEGs, and 289 and 233 DEPs were respectively found in MEFs in response to TNFα or TGFß1, respectively. Among the most significant pathways, we combined 26 representative genes to encompass the proinflammatory and profibrotic polarizations of fibroblasts. Based on principal component analysis, this signature deciphered baseline state, proinflammatory polarization, and profibrotic polarization as accurately as did RNA microarray and LC/MS-MS. Then, we assessed the gene signature on dermal fibroblasts isolated from the experimental murine model. We observed a proinflammatory polarization at day 7, and a mixture of a proinflammatory and profibrotic polarizations at day 42 in line with histological findings. Our approach provides a small-size and convenient gene signature to assess murine fibroblast polarization.
2022-07-12 | PXD034078 | Pride
Project description:Receptor tyrosine kinases (RTKs) that undergo N-linked glycosylation undergo protein quality control in the endoplasmic reticulum (ER) and subsequently transfer to the Golgi apparatus, where they acquire a diverse array of glycan structures. The family of receptor tyrosine kinases (RTKs) known as FGFR (Fibroblast Growth Factor Receptor) possesses N-glycosylation potential sites within their extracellular domains. Mutations in the modification site of FGFR3 have been documented in conditions such as Achondroplasia (ACH) and hypochondroplasia (HCH). While it is believed that ACH and HCH are associated with the overactivity of FGFR3 and accumulation in the ER, there has yet to be a case where the root cause has been explained from the perspective of glycosylation. This study furnishes a site-specific profile of N-glycans on FGFR3 through structural analysis of the extracellular domain of FGFR3 containing N-glycosylation potential sites, conducted via nLC-MS/MS. Moreover, we generated mutants of FGFR3 with a single glycan deficiency at each site and examined the impact of N-glycans at these sites on the receptor. The findings demonstrated reduced phosphorylation in the N98 glycosylation deficient mutant and accumulation in the ER in the N262 glycosylation deficient mutant, indicating ligand-independent autophosphorylation of the receptor. Hence, it is proposed that N-glycans in FGFR3 may play a role in functional regulation, offering fresh perspectives on disease etiology from a glycosylation standpoint.
2026-08-05 | PXD047309 | Pride
Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of UMUC-14 cell lines, which endogenously expressed a mutated activated form of FGFR3 (FGFR3-S249C), the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.
2020-12-31 | GSE125547 | GEO
Project description:FGFR3 gain-of-function mutations cause achondroplasia, the most common form of dwarfism, yet trigger paradoxical cerebral overgrowth and skeletal stunting. Here， we demonstrate that mutant FGFR3 drives enhanced ERK activation, which then represses Fgfr3 expression and downregulates ERK signaling. In the developing cortex, this mechanism transiently expands cortical stem cells by activating ERK, then shifts signaling to downregulate Fgfr3/ERK/PKA and enhance YAP/TAZ, promoting premature ependymal maturation and cerebral overgrowth. In growing bones, mutant Fgfr3 first elevates ERK to inhibit chondrocyte hypertrophy, then downregulates Fgfr3/ERK/PKA and upregulates YAP/TAZ to accelerate hypertrophy and ossification. Our findings establish that FGFR3 mutations limit bone yet expand brain size via an ERK negative feedback loop, revealing a unified disease mechanism and novel therapeutic targets.
2026-01-16 | GSE316124 | GEO
Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of MGH-U3 cell lines, which were derived from a human bladder tumor and endogenously expressed a mutated activated form of FGFR3 (FGFR3-Y375C), the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.
2018-02-16 | GSE84731 | GEO
Project description:To better understand the molecular mechanisms underlying altered-FGFR3 oncogenic activity in bladder carcinomas, we made use of RT112 cell lines, which were derived from a human bladder tumor and endogenously expressed the FGFR3-TACC3 fusion protein, the growth and transformation of these cell lines being dependent on activated-FGFR3 activity. We conducted a gene expression analysis using Affymetrix DNA arrays in this cell line treated or not with FGFR3 siRNAs.
2018-02-16 | GSE84732 | GEO
Project description:GPCR-induced YAP activation sensitizes fibroblasts to profibrotic effects of TGFβ1
| PRJNA516663 | ENA