Diverse Fgfr1 signaling pathways and endocytic trafficking regulate early mesoderm development I
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ABSTRACT:
PROVIDER: PRJNA1081919 | ENA |
REPOSITORIES: ENA
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Project description:The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1 null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth, but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM-interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identify processes regulating early mesoderm development by mechanisms involving both canonical and non-canonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.
2025-02-28 | GSE260515 | GEO
Project description:The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1 null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth, but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM-interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identify processes regulating early mesoderm development by mechanisms involving both canonical and non-canonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.
2025-02-28 | GSE260514 | GEO
Project description:Diverse Fgfr1 signaling pathways and endocytic trafficking regulate early mesoderm development II
| PRJNA1081918 | ENA
Project description:Fibroblast growth factor receptor 1 (FGFR1) is a heavily N-glycosylated cell surface receptor tyrosine kinase, which in conjunction with fibroblast growth factors (FGFs) transmits signals through the plasma membrane. The balanced FGF/FGFR1 signaling is crucial for the development and homeostasis of human body and aberrant FGFR1 is often observed in various cancers. Besides predominant localization to the plasma membrane, FGFR1 was also detected inside cells, mainly in the nuclear lumen, where it modulates gene expression. However, the exact mechanism of FGFR1 nuclear transport is still unknown. In this study, we generated a glycosylation-free mutant of FGFR1, FGFR1.GF, and demonstrate that it is primarily localized to the nuclear envelope. We show that reintroduction of N-glycans in the D3 domain cannot redirect FGFR1 to the plasma membrane nor exclude the receptor from the nuclear envelope. Reestablishment of N-glycans of the D2 domain largely inhibits FGFR1 accumulation in the nuclear envelope, but receptor still accumulates inside the cell, mainly in the ER. Only the simultaneous presence of N-glycans of the D2 and D3 domains of FGFR1 supports the efficient transport of FGFR1 to the plasma membrane. Intracellular FGFR1.GF displays high level of autoactivation, suggesting the presence of nuclear FGFR1 signaling that is FGF independent. Using mass spectrometry and proximity ligation assay we identified novel binding partners of the nuclear envelope-localized FGFR1, providing insights into its cellular functions. Taken together, our data define N-glycosylation of FGFR1 as a significant regulator of FGFR1 kinase activity, and most importantly a switchable signal for FGFR1 trafficking between the nuclear envelope and the plasma membrane, which, due to the spatial restrictions, shapes the FGFR1 interactome and cellular function.
2023-10-24 | PXD042325 | Pride
Project description:The gene encoding fibroblast growth factor receptor 1 (FGFR1) amplification is associated with poor prognosis in estrogen receptor positive (ER+) breast cancer, and thus represents a potential therapeutic target. Fluorescent in situ hybridization (FISH) has been used as the gold standard methodology for detection of FGFR1 amplification, but it is a relatively long labor-intensive procedure and not efficient to process a large number of patient samples, especially formalin fixed paraffin embedded (FFPE) samples. This study sought to identify genes discriminative at the mRNA level for FGFR1 amplification and to construct a multi-gene test to facilitate efficient screening for FGFR1 amplified ER+ breast tumors.
2016-12-31 | GSE77626 | GEO
Project description:The retina is an exquisitely patterned tissue, with neuronal somata positioned at regular intervals to completely sample the visual field. Cholinergic amacrine cells are spectacular exemplars of precision, distributing in two radial layers and tangentially, forming regular mosaics. Here, we investigated how the intracellular phosphatase Pten and the cell adhesion molecule Dscam cooperate to regulate amacrine cell patterning. Using double mutants to test epistasis, we found that Pten and Dscam function in parallel pathways to regulate amacrine cell positioning. Mechanistically, Pten regulates endocytic remodeling of cell adhesion molecules (Dscam, Megf10, Fat3), which are aberrantly redistributed in Pten conditional-knock-out (cKO) cholinergic amacrine cells. Furthermore, extracellular vesicle content, including that of cell adhesion and signaling molecules, is altered in Pten cKO retinas. Consequently, Wnt signalling is attenuated, the pharmacological disruption of which phenocopies Pten cKO amacrine cell patterning defects. Pten thus controls endocytic trafficking of critical cell adhesion/signaling molecules to control amacrine cell spacing.
2024-08-09 | PXD036221 | Pride
Project description:The 8p11 myeloproliferative syndrome (EMS), also referred to as the stem cell leukemia/lymphoma syndrome, is a chronic myeloproliferative disorder that rapidly progresses into an acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the FGFR1 gene, resulting in constitutive activation of the tyrosine kinase activity within FGFR1. The two most common fusion genes in human EMS are ZMYM2/FGFR1 (previously known as ZNF198/FGFR1) and BCR/FGFR1. To study the transcriptional programs becoming deregulated by the FGFR1 fusion genes, global gene expression analysis on human CD34+ cord blood cells expressing either of the fusion oncogenes ZMYM2/FGFR1 and BCR/FGFR1 was performed. As a reference gene we also included the more studied BCR/ABL1 fusion oncogene associated with chronic myeloid leukemia. We found that the 3 different fusion oncogenes had in common the upregulation of several genes involved in the JAK/STAT signalling pathway and also other sets of genes. However, the gene expression profiles were not identical, suggesting that both the tyrosine kinase containing gene and the partner gene would affect the transcription of downstream target genes. Bicistronic retroviral murine stem cell virus (MSCV) vectors expressing ZMYM2/FGFR1, BCR/FGFR1or P210 BCR/ABL1 and GFP were used. The MIG control vector expressed GFP only. Two days post transfection of human CD34+ umbilical cord blood cells, GFP-sorted cells were collected in three biological replicates and RNA was isolated immediately. In total, 12 samples were hybridized and scanned.
2010-05-27 | E-GEOD-15811 | biostudies-arrayexpress
Project description:We aimed to identify genes that are regulated by FGFR1 in brown adipose tissues of adult male ob/ob mice by injecting 1 mg/kg anti-FGFR1 agonistic antibody. Brown adipose tissues were isolated from adult male ob/ob mice at day 4 after a single intraperitoneal injection of 1 mg/kg anti-FGFR1 agonistic antibody or pair-fed mice injected with control IgG. N=6 mice per each group.
2012-01-06 | E-GEOD-32316 | biostudies-arrayexpress
Project description:We report the genome-wide binding patterns of nuclear FGFR1, RXR? and Nur77 in pluripotenet mESC and as mESC differentiate towared a neuronal lineage in response to high levels of Retinoic Acid treatment in vitro. We also report the genome-wide incorporation of histone varant H3.3 into chromatin specifically during Retinoic Acid-induced differentiation. This study presents nuclear FGFR1 as a global factor that controls genomic function by binding within the promoters of thousands of genes, both alone and in cooperation with RXR, Nur77 and histone H3.3, by targeting consensus DNA sequences of diverse transcription factor families. As such, it identifies a previously unknown, multifaceted form of control of major ontogenic pathways and gene networks targeted by the nuclear form of FGFR1. Examination of nuclear FGFR1, RXR?, and Nur77 binding sites in 2 celluar states. Examination of H3.3 incorporation in 1 cellular state.
2015-05-01 | E-GEOD-65695 | biostudies-arrayexpress
Project description:Using ChIP-Seq analysis of ER+/FGFR1-amplified breast cancer cells and PDXs, we found FGFR1 occupancy at transcription start sites with high overlap with histone modifications associated with active gene transcription. Mass spectrometry analysis of the nuclear and chromatin-bound FGFR1 interactome identified RNA-Polymerase II (Pol II) and FOXA1, with FOXA1 silencing impairing FGFR1 recruitment to chromatin. Transduction of FGFR1(SP-)(NLS) into MCF7 cells resulted in overexpression of nuclear FGFR1 and resistance to antiestrogens. Finally, an expression signature associated with nuclear FGFR1 correlated with endocrine resistance in patients treated with antiestrogens
2021-07-27 | GSE153285 | GEO