Tyrosine Kinase Expressed in Hepatocellular Carcinoma, TEC, Controls Pluripotency and Early Cell Fate Decisions of Human Pluripotent Stem Cells via Regulation of Fibroblast Growth Factor-2 Secretion

Váňová, Tereza; Konečná, Žaneta; Zbonakova, Zuzana; Venuta, Giuseppe La; Zoufalova, Karolina; Jelínková, Šárka; Vařecha, Miroslav; Rotrekl, Vladimír; Krejčı́, Pavel; Nickel, Walter; Dvořák, Petr; Bosakova, Michaela Kunova

doi:10.1002/stem.2660

Cited by 6 publications

(5 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human embryonic stem cells (hESC) or induced pluripotent stem cells (hiPSC) express FGFR1-4 (Supplementary Material, Table S1) (16), exhibit a particularly strong response to FGF stimulus and require continuous stimulation with high FGF2 doses for self-renewal and maintenance of stemness (17). Treatment with FGF2 significantly (P < 0.001) shortened primary cilia in hESC and hiPSC when compared with untreated cells, while chemical inhibition of high endogenous levels of FGF signaling in hESC and hiPSC (18) extended primary cilia length over the controls (Fig. 2B).…”

Section: Sustained Activation Of Fgf Signaling Results In Shortening Of Primary Ciliamentioning

confidence: 99%

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies

Bosakova

Vařecha

Hampl

et al. 2018

Human Molecular Genetics

Self Cite

View full text Add to dashboard Cite

Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.

show abstract

Section: Sustained Activation Of Fgf Signaling Results In Shortening Of Primary Ciliamentioning

confidence: 99%

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies

Bosakova

Vařecha

Hampl

et al. 2018

Human Molecular Genetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…This was supported by an investigation carried out by Chen et al [ 127 ] exploring TEC protein expression in hepatocellular carcinoma and TEC phosphorylation in 200 specimens of cancerous and non-cancerous liver tissue. A more recent study by Vanova et al [ 128 ] with interest in the expression of TEC in hepatocellcular carcinoma, identified TEC as a regulator in controlling pluripotent cell fate in human pluripotent stem cells, acting through the regulation of fibroblast growth factor-2 secretion. Such studies provide further support and evidence of the broad activities and roles of tyrosine kinase preferentially expressed in hepatocellular carcinoma.…”

Section: Non Receptor Tyrosine Kinase Familiesmentioning

confidence: 99%

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

et al. 2018

View full text Add to dashboard Cite

Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

show abstract

“…For example, mutations in TEC (Tec protein tyrosine kinase, c.A122G, p.Y41C) and ABR (Active breakpoint cluster region-related protein, c.C1079G, p.P360R) were embedded in PH (Pleckstrin homology) domain, a critical domain to bind phosphoinositides for regulation of intracellular signaling [ 44 ]. Tec kinase is an integral component of T cell signaling and controls early cell fate decisions of human pluripotent stem cells via regulation of fibroblast growth factor-2 secretion [ 45 ]. ABR is an important regulator of neuronal development [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of novel CTNNB1 mutation in Craniopharyngioma by whole-genome sequencing

Zeng

Wang

et al. 2021

Mol Cancer

View full text Add to dashboard Cite

Background Craniopharyngioma (CP) is rare histologically benign but clinically challenging tumor because of its intimate relationship with the critical structure in the central brain. CP can be divided into two major histologic subtypes: adamantinomatous-type CP (ACP) and papillary-type CP (PCP). Although some genetic aberrations for both categories have been revealed in previous studies, the complete spectrum of genetic changes of this tumor remains unknown. Methods In this study, we conducted whole genome sequencing (WGS) on twenty-six CPs including 16 ACPs and 10 PCPs together with their matched blood samples. Somatic variants (SNVs, InDels, SVs and CNVs) were identified and mutational signatures were characterized for each patient. We investigated the impact of a novel CTNNB1 mutant on its protein stability, ubiquitination and Wnt pathway activity. Cell proliferation ability of the CTNNB1 mutant in ACP primary cells was additionally analyzed by CCK8 and colony formation assays. Results We found that CPs had showed less complexity with fewer somatic mutations compared with malignant tumors. Moreover, mutations in CTNNB1 (68.75% of ACP) and BRAF V600E (70.00% of PCP) are mutually exclusive in ACP and PCP, consolidating that the driving roles of these two genes in ACP and PCP, respectively. A novel mutation in the exon 3 of CTNNB1 which compromised both a transversion and in-frame deletion was identified in ACP. This mutation was experimentally validated to confer β-catenin increased stability by inhibiting its ubiquitination, thus activating Wnt-signaling pathway and promoting cell proliferation. Conclusions Whole genome landscape for CP was revealed by WGS analysis, and a novel mutation in the exon 3 of CTNNB1 was identified. This novel mutation activates Wnt-signaling pathway through increasing the stability of β-catenin. Our findings provided us with more comprehensive insight into the spectrum of genetic alterations in CP.

show abstract

Tyrosine Kinase Expressed in Hepatocellular Carcinoma, TEC, Controls Pluripotency and Early Cell Fate Decisions of Human Pluripotent Stem Cells via Regulation of Fibroblast Growth Factor-2 Secretion

Cited by 6 publications

References 52 publications

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies

Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

Characterization of novel CTNNB1 mutation in Craniopharyngioma by whole-genome sequencing

Contact Info

Product

Resources

About