The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.

• Klíčová slova
• FGFR, biased signaling, molecular biophysics, none, signal transduction, structural biology,
• MeSH
• fibroblastové růstové faktory * MeSH
• fosforylace MeSH
• lidé MeSH
• ligandy MeSH
• receptor fibroblastových růstových faktorů, typ 1 genetika   MeSH
• signální transdukce * MeSH
• těhotenství MeSH
• zkreslení výsledků (epidemiologie) MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• FGFR1 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory * MeSH
• ligandy MeSH
• receptor fibroblastových růstových faktorů, typ 1 MeSH

This study elucidated the stage-specific roles of FGF2 signaling during neural development using in-vitro human embryonic stem cell-based developmental modeling. We found that the dysregulation of FGF2 signaling prior to the onset of neural induction resulted in the malformation of neural rosettes (a neural tube-like structure), despite cells having undergone neural induction. The aberrant neural rosette formation may be attributed to the misplacement of ZO-1, which is a polarized tight junction protein and shown co-localized with FGF2/FGFR1 in the apical region of neural rosettes, subsequently led to abnormal neurogenesis. Moreover, the FGF2 signaling inhibition at the stage of neural rosettes caused a reduction in cell proliferation, an increase in numbers of cells with cell-cycle exit, and premature neurogenesis. These effects may be mediated by NUMB, to which expression was observed enriched in the apical region of neural rosettes after FGF2 signaling inhibition coinciding with the disappearance of PAX6+/Ki67+ neural stem cells and the emergence of MAP2+ neurons. Moreover, our results suggested that the hESC-based developmental system reserved a similar neural stem cell niche in vivo.

• Klíčová slova
• Embryonic stem cells, FGF2 signaling, Neural developmental modeling, Neural fate, Neural stem cell niche, Neurogenesis,
• MeSH
• buněčná diferenciace účinky léků   MeSH
• buněčné linie MeSH
• časosběrné zobrazování MeSH
• chromony farmakologie   MeSH
• fibroblastový růstový faktor 2 farmakologie   MeSH
• imunohistochemie MeSH
• lidé MeSH
• lidské embryonální kmenové buňky cytologie   metabolismus   MeSH
• malá interferující RNA metabolismus   MeSH
• membránové proteiny metabolismus   MeSH
• morfoliny farmakologie   MeSH
• nervové kmenové buňky cytologie   metabolismus   MeSH
• neurogeneze účinky léků   MeSH
• neurony cytologie   metabolismus   MeSH
• protein zonula occludens 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• proteiny nervové tkáně metabolismus   MeSH
• pyrimidiny farmakologie   MeSH
• receptor fibroblastových růstových faktorů, typ 1 metabolismus   MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one MeSH Prohlížeč
• chromony MeSH
• fibroblastový růstový faktor 2 MeSH
• malá interferující RNA MeSH
• MAP2 protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• morfoliny MeSH
• NUMB protein, human MeSH Prohlížeč
• PD 173074 MeSH Prohlížeč
• protein zonula occludens 1 MeSH
• proteiny asociované s mikrotubuly MeSH
• proteiny nervové tkáně MeSH
• pyrimidiny MeSH
• receptor fibroblastových růstových faktorů, typ 1 MeSH
• TJP1 protein, human MeSH Prohlížeč

Vertebrate primary cilium is a Hedgehog signaling center but the extent of its involvement in other signaling systems is less well understood. This report delineates a mechanism by which fibroblast growth factor (FGF) controls primary cilia. Employing proteomic approaches to characterize proteins associated with the FGF-receptor, FGFR3, we identified the serine/threonine kinase intestinal cell kinase (ICK) as an FGFR interactor. ICK is involved in ciliogenesis and participates in control of ciliary length. FGF signaling partially abolished ICK's kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. Activation of the FGF signaling pathway affected both primary cilia length and function in a manner consistent with cilia effects caused by inhibition of ICK activity. Moreover, knockdown and knockout of ICK rescued the FGF-mediated effect on cilia. We provide conclusive evidence that FGF signaling controls cilia via interaction with ICK.

• Klíčová slova
• FGFR, ICK, cilia length, fibroblast growth factor, intestinal cell kinase,
• MeSH
• buňky NIH 3T3 MeSH
• cilie metabolismus   MeSH
• CRISPR-Cas systémy MeSH
• fibroblastové růstové faktory metabolismus   MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• interakční proteinové domény a motivy MeSH
• lidé MeSH
• modely u zvířat MeSH
• myši knockoutované MeSH
• myši MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• proteiny hedgehog metabolismus   MeSH
• proteomika MeSH
• receptor fibroblastových růstových faktorů, typ 1 metabolismus   MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   metabolismus   MeSH
• receptor fibroblastových růstových faktorů, typ 4 metabolismus   MeSH
• receptory fibroblastových růstových faktorů genetika   metabolismus   MeSH
• signální transdukce MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• CILK1 protein, human MeSH Prohlížeč
• Cilk1 protein, mouse MeSH Prohlížeč
• FGFR1 protein, human MeSH Prohlížeč
• FGFR3 protein, human MeSH Prohlížeč
• FGFR4 protein, human MeSH Prohlížeč
• fibroblastové růstové faktory MeSH
• protein-serin-threoninkinasy MeSH
• proteiny hedgehog MeSH
• receptor fibroblastových růstových faktorů, typ 1 MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• receptor fibroblastových růstových faktorů, typ 4 MeSH
• receptory fibroblastových růstových faktorů MeSH

Although the detection of several components of the fibroblast growth factor (FGF) signaling pathway in human embryonic stem cells (hESCs) has been reported, the functionality of that pathway and effects on cell fate decisions are yet to be established. In this study we characterized expression of FGF-2, the prototypic member of the FGF family, and its receptors (FGFRs) in undifferentiated and differentiating hESCs; subsequently, we analyzed the effects of FGF-2 on hESCs, acting as both exogenous and endogenous factors. We have determined that undifferentiated hESCs are abundant in several molecular-mass isoforms of FGF-2 and that expression pattern of these isoforms remains unchanged under conditions that induce hESC differentiation. Significantly, FGF-2 is released by hESCs into the medium, suggesting an autocrine activity. Expression of FGFRs in undifferentiated hESCs follows a specific pattern, with FGFR1 being the most abundant species and other receptors showing lower expression in the following order: FGFR1 --> FGFR3 --> FGFR4 --> FGFR2. Initiation of differentiation is accompanied by profound changes in FGFR expression, particularly the upregulation of FGFR1. When hESCs are exposed to exogenous FGF-2, extracellular signal-regulated kinases are phosphorylated and thereby activated. However, the presence or absence of exogenous FGF-2 does not significantly affect the proliferation of hESCs. Instead, increased concentration of exogenous FGF-2 leads to reduced outgrowth of hESC colonies with time in culture. Finally, the inhibitor of FGFRs, SU5402, was used to ascertain whether FGF-2 that is released by hESCs exerts its activities via autocrine pathways. Strikingly, the resultant inhibition of FGFR suppresses activation of downstream protein kinases and causes rapid cell differentiation, suggesting an involvement of autocrine FGF signals in the maintenance of proliferating hESCs in the undifferentiated state. In conclusion from our data, we propose that this endogenous FGF signaling pathway can be implicated in self-renewal or differentiation of hESCs.

• MeSH
• buněčná diferenciace MeSH
• embryo savčí cytologie   MeSH
• fibroblastový růstový faktor 2 biosyntéza   fyziologie   MeSH
• fosforylace MeSH
• kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• protein - isoformy MeSH
• pyrroly farmakologie   MeSH
• receptor fibroblastových růstových faktorů, typ 2 biosyntéza   fyziologie   MeSH
• receptory fibroblastových růstových faktorů biosyntéza   fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• FGFR2 protein, human MeSH Prohlížeč
• fibroblastový růstový faktor 2 MeSH
• mitogenem aktivované proteinkinasy MeSH
• protein - isoformy MeSH
• pyrroly MeSH
• receptor fibroblastových růstových faktorů, typ 2 MeSH
• receptory fibroblastových růstových faktorů MeSH
• SU 5402 MeSH Prohlížeč

Acyclic nucleoside phosphonates PMEDAP and PMEG modulate expression of selected proangiogenic genes in SD-lymphoma bearing rats. Antiangiogenic efficacy of PMEDAP is relatively weak and is manifested mainly by down-regulation of vascular endothelial growth factor (VEGF) and its receptor VEGFR detectable 24 hours after treatment. Compound PMEG (an active metabolite of the prodrug GS-9219) down-regulates selected proangiogenic genes EGF, FGF, PDGF, VEGF, EGFR, FGFR, PDGFR and VEGFR much more efficiently. Its antiangiogenic potency persists and is more intensive 48 hours after treatment. Findings show that in vivo antitumour efficacy of both antimitotic acyclic nucleoside phosphonates PMEDAP and PMEG consequently affect the angiogenesis in T-cell lymphoma.

• MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• destičkový růstový faktor genetika   metabolismus   MeSH
• epidermální růstový faktor genetika   metabolismus   MeSH
• erbB receptory genetika   metabolismus   MeSH
• fibroblastový růstový faktor 1 genetika   metabolismus   MeSH
• guanin analogy a deriváty   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lymfom T-buněčný genetika   metabolismus   patologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• organofosforové sloučeniny farmakologie   MeSH
• patologická angiogeneze metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Sprague-Dawley MeSH
• receptor 1 pro vaskulární endoteliální růstový faktor genetika   metabolismus   MeSH
• receptor fibroblastových růstových faktorů, typ 1 genetika   metabolismus   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• růstový faktor odvozený z trombocytů - receptor beta genetika   metabolismus   MeSH
• vaskulární endoteliální růstový faktor A genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 9-((2-phosphonylmethoxy)ethyl)guanine MeSH Prohlížeč
• 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine MeSH Prohlížeč
• adenin MeSH
• destičkový růstový faktor MeSH
• Egfr protein, rat MeSH Prohlížeč
• epidermální růstový faktor MeSH
• erbB receptory MeSH
• Fgfr1 protein, rat MeSH Prohlížeč
• fibroblastový růstový faktor 1 MeSH
• guanin MeSH
• messenger RNA MeSH
• organofosforové sloučeniny MeSH
• platelet-derived growth factor A MeSH Prohlížeč
• receptor 1 pro vaskulární endoteliální růstový faktor MeSH
• receptor fibroblastových růstových faktorů, typ 1 MeSH
• růstový faktor odvozený z trombocytů - receptor beta MeSH
• vascular endothelial growth factor A, rat MeSH Prohlížeč
• vaskulární endoteliální růstový faktor A MeSH

BACKGROUND/AIM: Gliomas are primary malignancies of the central nervous system (CNS). High-grade gliomas are associated with poor prognosis and modest survival rates despite intensive multimodal treatment strategies. Targeting gene fusions is an emerging therapeutic approach for gliomas that allows application of personalized medicine principles. The aim of this study was to identify detectable fusion oncogenes that could serve as predictors of currently available or newly developed targeted therapeutics in cross-sectional samples from glioma patients using next-generation sequencing (NGS). PATIENTS AND METHODS: A total of 637 patients with glial and glioneuronal tumours of the CNS who underwent tumour resection between 2017 and 2020 were enrolled. Detection of fusion transcripts in FFPE tumour tissue was performed by a TruSight Tumour 170 assay and two FusionPlex kits, Solid Tumour and Comprehensive Thyroid and Lung. RESULTS: Oncogene fusions were identified in 33 patients. The most common fusion was the KIAA1549-BRAF fusion, detected in 13 patients, followed by FGFR fusions (FGFR1-TACC1, FGFR2-CTNNA3, FGFR3-TACC3, FGFR3-CKAP5, FGFR3-AMBRA1), identified in 10 patients. Other oncogene fusions were also infrequently diagnosed, including MET fusions (SRPK2-MET and PTPRZ1-MET) in 2 patients, C11orf95-RELA fusions in 2 patients, EGFR-SEPT14 fusion in 2 patients, and individual cases of SRGAP3-BRAF, RAF1-TRIM2, EWSR1-PALGL1 and TERT-ALK fusions. CONCLUSION: The introduction of NGS techniques provides additional information about tumour molecular alterations that can aid the multimodal management of glioma patients. Patients with gliomas positive for particular targetable gene fusions may benefit from experimental therapeutics, enhancing their quality of life and prolonging survival rates.

• Klíčová slova
• Glioma, gene fusion, molecular genetics, next-generation sequencing, targeted therapy,
• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• gliom * genetika   patologie   MeSH
• kvalita života MeSH
• lidé MeSH
• onkogenní fúze * MeSH
• onkogeny genetika   MeSH
• protein-serin-threoninkinasy MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• průřezové studie MeSH
• tyrosinfosfatasy receptorového typu, třída 5 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• AMBRA1 protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• proteiny asociované s mikrotubuly MeSH
• PTPRZ1 protein, human MeSH Prohlížeč
• SRPK2 protein, human MeSH Prohlížeč
• TACC3 protein, human MeSH Prohlížeč
• tyrosinfosfatasy receptorového typu, třída 5 MeSH

Mild hypoxia (5% O2) as well as FGFR1-induced activation of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and MAPK signaling pathways markedly support pluripotency in human pluripotent stem cells (hPSCs). This study demonstrates that the pluripotency-promoting PI3K/AKT signaling pathway is surprisingly attenuated in mild hypoxia compared to the 21% O2 environment. Hypoxia is known to be associated with lower levels of reactive oxygen species (ROS), which are recognized as intracellular second messengers capable of upregulating the PI3K/AKT signaling pathway. Our data denote that ROS downregulation results in pluripotency upregulation and PI3K/AKT attenuation in a hypoxia-inducible factor 1 (HIF-1)-dependent manner in hPSCs. Using specific MAPK inhibitors, we show that the MAPK pathway also downregulates ROS and therefore attenuates the PI3K/AKT signaling-this represents a novel interaction between these signaling pathways. This inhibition of ROS initiated by MEK1/2-ERK1/2 may serve as a negative feedback loop from the MAPK pathway toward FGFR1 and PI3K/AKT activation. We further describe the molecular mechanism resulting in PI3K/AKT upregulation in hPSCs-ROS inhibit the PI3K's primary antagonist PTEN and upregulate FGFR1 phosphorylation. These novel regulatory circuits utilizing ROS as second messengers may contribute to the development of enhanced cultivation and differentiation protocols for hPSCs. Since the PI3K/AKT pathway often undergoes an oncogenic transformation, our data could also provide new insights into the regulation of cancer stem cell signaling.

• Klíčová slova
• HIF-1, MAPK, PI3K/AKT, hPSCs, hypoxia, reactive oxygen species,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. METHODS: Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed. RESULTS: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. CONCLUSIONS: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

• Klíčová slova
• RNA sequencing, actionable drivers, molecular profiling, pLGG, rare gene fusions,
• MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   MeSH
• gliom * patologie   MeSH
• individualizovaná medicína MeSH
• lidé MeSH
• molekulární patologie MeSH
• protoonkogenní proteiny B-Raf * genetika   MeSH
• protoonkogenní proteiny genetika   MeSH
• sekvenování transkriptomu MeSH
• transkripční faktory genetika   MeSH
• tyrosinkinasy MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• protoonkogenní proteiny B-Raf * MeSH
• protoonkogenní proteiny MeSH
• transkripční faktory MeSH
• tyrosinkinasy MeSH
• VGLL1 protein, human MeSH Prohlížeč

Myoepithelial carcinoma of salivary glands is an underrecognized and challenging entity with a broad morphologic spectrum, including an EWSR1-rearranged clear cell variant. Myoepithelial carcinoma is generally aggressive with largely unknown genetic features. A retrospective review of Salivary Gland Tumor Registry in Pilsen searching for the key words "clear cell myoepithelial carcinoma," "hyalinizing clear cell," and "clear cell malignant myoepithelioma" yielded 94 clear cell myoepithelial carcinomas (CCMCs) for molecular analysis of EWSR1 rearrangement using fluorescence in situ hybridization (FISH). Tumors positive for EWSR1 gene rearrangement were tested by next-generation sequencing (NGS) using fusion-detecting panels. NGS results were confirmed by reverse-transcription polymerase chain reaction or by FISH. Twenty-six tumors originally diagnosed as CCMC (26/94, 27.6%) revealed split signals for EWSR1 by FISH. Six of these tumors (6/26, 23%) displayed amplification of the EWSR1 locus. Fifteen cases were analyzable by NGS, whereas 9 were not, and tissue was not available in 2 cases. None of the CCMCs with EWSR1 rearrangements detected by FISH had an EWSR1 fusion transcript. Fusion transcripts were detected in 6 cases (6/15, 40%), including LIFR-PLAG1 and CTNNB1-PLAG1, in 2 cases each, and CHCHD7-PLAG1 and EWSR1-ATF1 fusions were identified in 1 case each. Seven cases, including those with PLAG1 fusion, were positive for PLAG1 rearrangement by FISH, with notable exception of CHCHD7-PLAG1, which is an inversion not detectable by FISH. One single case with EWSR1-ATF1 fusion in NGS showed ATF1 gene rearrangement by FISH and was reclassified as clear cell carcinoma (CCC). In addition, another 4 cases revealed ATF1 rearrangement by FISH and were reclassified as CCC as well. Moreover, 12/68 (17%) CCMCs with intact EWSR1 gene were selected randomly and analyzed by NGS. PLAG1 fusions were found in 5 cases (5/12, 41.6%) with LIFR (2 cases), FGFR1 (2 cases), and CTNNB1 (1 case) as partner genes. Overall, PLAG1 gene rearrangements were detected in 10/38 (26%) tested cases. None of the tumors had SMARCB1 loss by immunohistochemistry as a possible explanation for the EWSR1 abnormalities in FISH. Novel findings in our NGS study suggest that EWSR1-FISH positive CCMC is a gene fusion-driven disease with frequent oncogenic PLAG1 fusions, including LIFR-PLAG1 and CTNNB1-PLAG1 in most cases. Productive EWSR1 fusions are found only in a minority of EWSR1-ATF1-rearranged cases, which were in part reclassifiable as CCCs. Detectable EWSR1-FISH abnormality in CCMCs without gene fusion perhaps represents a passenger mutation with minor or no oncologic effect.

• MeSH
• DNA vazebné proteiny genetika   MeSH
• dospělí MeSH
• genová přestavba MeSH
• lidé středního věku MeSH
• lidé MeSH
• myoepiteliální nádor genetika   MeSH
• nádory slinných žláz genetika   MeSH
• onkogenní fúze MeSH
• protein EWS vázající RNA genetika   MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• EWSR1 protein, human MeSH Prohlížeč
• PLAG1 protein, human MeSH Prohlížeč
• protein EWS vázající RNA MeSH

Sustained activation of extracellular signal-regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs). We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4. We report that loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling. Mutant forms of SHIP2 lacking phosphoinositide phosphatase activity still associated with FGFRs and did not prevent FGF-induced sustained ERK activation, demonstrating that the adaptor rather than the catalytic activity of SHIP2 was required. SHIP2 recruited Src family kinases to the FGFRs, which promoted FGFR-mediated phosphorylation and assembly of protein complexes that relayed signaling to ERK. SHIP2 interacted with FGFRs, was phosphorylated by active FGFRs, and promoted FGFR-ERK signaling at the level of phosphorylation of the adaptor FRS2 and recruitment of the tyrosine phosphatase PTPN11. Thus, SHIP2 is an essential component of canonical FGF-FGFR signal transduction and a potential therapeutic target in FGFR-related disorders.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• aktivace enzymů MeSH
• extracelulárním signálem regulované MAP kinasy genetika   metabolismus   MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy genetika   metabolismus   MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• lidé MeSH
• MAP kinasový signální systém * MeSH
• membránové proteiny genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• receptory fibroblastových růstových faktorů genetika   metabolismus   MeSH
• skupina kinas odvozených od src-genu genetika   metabolismus   MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• extracelulárním signálem regulované MAP kinasy MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• FRS2 protein, human MeSH Prohlížeč
• INPPL1 protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• PTPN11 protein, human MeSH Prohlížeč
• receptory fibroblastových růstových faktorů MeSH
• skupina kinas odvozených od src-genu MeSH
• tyrosinfosfatasa nereceptorového typu 11 MeSH