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1.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623323

RESUMO

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-ß signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-ß pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-ß signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Animais , Endotélio/metabolismo , Endotélio/patologia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Masculino , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos , Camundongos Knockout , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Remodelação Vascular
3.
Cells ; 10(9)2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34572066

RESUMO

Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or ß-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure-function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Homeostase , Doenças Metabólicas/fisiopatologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Humanos , Fosforilação , Transdução de Sinais
4.
Expert Rev Clin Pharmacol ; 14(10): 1233-1252, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34591728

RESUMO

Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.


Assuntos
Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias/patologia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
Cells ; 10(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34440915

RESUMO

Fibroblast growth factors (FGFs) comprise a large family of growth factors, regulating diverse biological processes including cell proliferation, migration, and differentiation. Each FGF binds to a set of FGF receptors to initiate certain intracellular signaling molecules. Accumulated evidence suggests that in early development and adult state of vertebrates, FGFs also play exclusive and context dependent roles. Although FGFs have been the focus of research for therapeutic approaches in cancer, cardiovascular disease, and metabolic syndrome, in this review, we mainly focused on their role in germ layer specification and axis patterning during early vertebrate embryogenesis. We discussed the functional roles of FGFs and their interacting partners as part of the gene regulatory network for germ layer specification, dorsal-ventral (DV), and anterior-posterior (AP) patterning. Finally, we briefly reviewed the regulatory molecules and pharmacological agents discovered that may allow modulation of FGF signaling in research.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Camadas Germinativas/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Vertebrados/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Camadas Germinativas/embriologia , Humanos , Modelos Biológicos , Ligação Proteica , Receptores de Fatores de Crescimento de Fibroblastos/genética , Vertebrados/embriologia , Vertebrados/genética
6.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360633

RESUMO

Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.


Assuntos
Glucuronidase/metabolismo , Hiperglicemia/metabolismo , Podócitos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Glicólise , Masculino , Permeabilidade , Ratos Wistar
7.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360000

RESUMO

Growth factors belonging to the FGF family play important roles in tissue and organ repair after trauma. In this review, I discuss the regulation by FGFs of the aspects of cellular behavior important for reparative processes. In particular, I focus on the FGF-dependent regulation of cell proliferation, cell stemness, de-differentiation, inflammation, angiogenesis, cell senescence, cell death, and the production of proteases. In addition, I review the available literature on the enhancement of FGF expression and secretion in damaged tissues resulting in the increased FGF supply required for tissue repair.


Assuntos
Diferenciação Celular/genética , Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Regeneração/genética , Células-Tronco/metabolismo , Animais , Morte Celular/genética , Desdiferenciação Celular/genética , Proliferação de Células/genética , Senescência Celular/genética , Células Eucarióticas/citologia , Células Eucarióticas/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação , Família Multigênica , Neovascularização Fisiológica/genética , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Células-Tronco/citologia
8.
Methods Mol Biol ; 2312: 301-305, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34228298

RESUMO

Cell culture media are often supplemented with recombinant growth factors and cytokines to reproduce biological conditions in vitro. Basic fibroblast growth factor (bFGF) has been widely used to support the pluripotency and self-renewal activity of human induced pluripotent stem cells (hiPSCs). We had previously developed a synthetic surrogate for bFGF on the basis of a DNA aptamer that binds to one of the FGF receptors. Since DNA aptamers have advantages over recombinant proteins in terms of thermal stability and production cost, replacing recombinant growth factors in cell culture media with DNA aptamers would be of great interest. Herein, we describe our protocol for feeder-free hiPSC culture using a DNA aptamer-based mimic of bFGF.


Assuntos
Aptâmeros de Nucleotídeos/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Mimetismo Molecular , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultura , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
9.
Cells ; 10(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204560

RESUMO

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.


Assuntos
Tumores do Estroma Gastrointestinal/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sarcoma/metabolismo , Transdução de Sinais/fisiologia , Animais , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Inibidores de Proteínas Quinases/farmacologia , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia
10.
Sci Rep ; 11(1): 14091, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238963

RESUMO

Development of the Drosophila embryonic mesoderm is controlled through both internal and external inputs to the mesoderm. One such factor is Heartless (Htl), a Fibroblast Growth Factor Receptor (FGFR) expressed in the mesoderm. Although Htl has been extensively studied, the dynamics of its action are poorly understood after the initial phases of mesoderm formation and spreading. To begin to address this challenge, we have developed an optogenetic version of the FGFR Heartless in Drosophila (Opto-htl). Opto-htl enables us to activate the FGFR pathway in selective spatial (~ 35 µm section from one of the lateral sides of the embryo) and temporal domains (ranging from 40 min to 14 h) during embryogenesis. Importantly, the effects can be tuned by the intensity of light-activation, making this approach significantly more flexible than other genetic approaches. We performed controlled perturbations to the FGFR pathway to define the contribution of Htl signalling to the formation of the developing embryonic heart and somatic muscles. We find a direct correlation between Htl signalling dosage and number of Tinman-positive heart cells specified. Opto-htl activation favours the specification of Tinman positive cardioblasts and eliminates Eve-positive DA1 muscles. This effect is seen to increase progressively with increasing light intensity. Therefore, fine tuning of phenotypic responses to varied Htl signalling dosage can be achieved more conveniently than with other genetic approaches. Overall, Opto-htl is a powerful new tool for dissecting the role of FGFR signalling during development.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/metabolismo , Embrião de Mamíferos/metabolismo , Mesoderma/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Animais , Desenvolvimento Embrionário , Luz , Músculos/metabolismo , Mutação/genética , Fenótipo , Fatores de Tempo
11.
Cells ; 10(6)2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207779

RESUMO

A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.


Assuntos
Transformação Celular Neoplásica/patologia , Centrossomo/metabolismo , Cílios , Neoplasias , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Cílios/metabolismo , Cílios/patologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Fusão Oncogênica
12.
Eur J Neurosci ; 54(4): 5261-5271, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34184338

RESUMO

Fibroblast growth factor 23 (FGF23) is an endocrine growth factor and known to play a pivotal role in phosphate homeostasis. Interestingly, several studies point towards a function of FGF23 in the hypothalamus. FGF23 classically activates the FGF receptor 1 in the presence of the co-receptor αKlotho, of both gene expression in the brain was previously established. However, studies on gene and protein expression of FGF23 in the brain are scarce and have been inconsistent. Therefore, our aim was to localise FGF23 gene and protein expression in the rat brain with focus on the hypothalamus. Also, we investigated the protein expression of αKlotho. Adult rat brains were used to localise and visualise FGF23 and αKlotho protein in the hypothalamus by immunofluorescence labelling. Furthermore, western blots were used for assessing hypothalamic FGF23 protein expression. FGF23 gene expression was investigated by qPCR in punches of the arcuate nucleus, lateral hypothalamus, paraventricular nucleus, choroid plexus, ventrolateral thalamic nucleus and the ventromedial hypothalamus. Immunoreactivity for FGF23 and αKlotho protein was found in the hypothalamus, third ventricle lining and the choroid plexus. Western blot analysis of the hypothalamus confirmed the presence of FGF23. Gene expression of FGF23 was not detected, suggesting that the observed FGF23 protein is not brain-derived. Several FGF receptors are known to be present in the brain. Therefore, we conclude that the machinery for FGF23 signal transduction is present in several brain areas, indeed suggesting a role for FGF23 in the brain.


Assuntos
Fatores de Crescimento de Fibroblastos , Glucuronidase , Animais , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Hipotálamo/metabolismo , Ratos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
13.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33983905

RESUMO

Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors.


Assuntos
Proteínas Proto-Oncogênicas c-ets/metabolismo , Sarcoma Sinovial/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-ets/genética , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Sci Rep ; 11(1): 7832, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837264

RESUMO

Clostridium botulinum neurotoxin serotype A (BoNT/A) is a potent neurotoxin that serves as an effective therapeutic for several neuromuscular disorders via induction of temporary muscular paralysis. Specific binding and internalization of BoNT/A into neuronal cells is mediated by its binding domain (HC/A), which binds to gangliosides, including GT1b, and protein cell surface receptors, including SV2. Previously, recombinant HC/A was also shown to bind to FGFR3. As FGFR dimerization is an indirect measure of ligand-receptor binding, an FCS & TIRF receptor dimerization assay was developed to measure rHC/A-induced dimerization of fluorescently tagged FGFR subtypes (FGFR1-3) in cells. rHC/A dimerized FGFR subtypes in the rank order FGFR3c (EC50 ≈ 27 nM) > FGFR2b (EC50 ≈ 70 nM) > FGFR1c (EC50 ≈ 163 nM); rHC/A dimerized FGFR3c with similar potency as the native FGFR3c ligand, FGF9 (EC50 ≈ 18 nM). Mutating the ganglioside binding site in HC/A, or removal of GT1b from the media, resulted in decreased dimerization. Interestingly, reduced dimerization was also observed with an SV2 mutant variant of HC/A. Overall, the results suggest that the FCS & TIRF receptor dimerization assay can assess FGFR dimerization with known and novel ligands and support a model wherein HC/A, either directly or indirectly, interacts with FGFRs and induces receptor dimerization.


Assuntos
Toxinas Botulínicas Tipo A/metabolismo , Clostridium botulinum/enzimologia , Neurotoxinas/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sorogrupo , Transdução de Sinais/genética , Animais , Sítios de Ligação , Toxinas Botulínicas Tipo A/química , Membrana Celular/metabolismo , Dimerização , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gangliosídeos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurotoxinas/química , Células PC12 , Ligação Proteica , Domínios Proteicos , Ratos , Receptores de Superfície Celular/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/química , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transfecção
15.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804608

RESUMO

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that have been associated not only with various cellular processes, such as embryonic development and adult wound healing but also enhanced tumor survival, angiogenesis, and metastatic spread. Proteolytic cleavage of these single-pass transmembrane receptors has been suggested to regulate biological activities of their ligands during growth and development, yet little is known about the proteases responsible for this process. In this study, we monitored the release of membrane-anchored FGFRs 1, 2, 3, and 4 in cell-based assays. We demonstrate here that metalloprotease-dependent metalloprotease family, ADAM10 and ADAM17. Loss- and gain-of-function studies in murine embryonic fibroblasts showed that constitutive shedding as well as phorbol-ester-induced processing of FGFRs 1, 3, and 4 is mediated by ADAM17. In contrast, treatment with the calcium ionophore ionomycin stimulated ADAM10-mediated FGFR2 shedding. Cell migration assays with keratinocytes in the presence or absence of soluble FGFRs suggest that ectodomain shedding can modulate the function of ligand-induced FGFR signaling during cell movement. Our data identify ADAM10 and ADAM17 as differentially regulated FGFR membrane sheddases and may therefore provide new insight into the regulation of FGFR functions.


Assuntos
Metaloproteases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Animais , Linhagem Celular , Movimento Celular , Ativação Enzimática , Células Epiteliais/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Família Multigênica , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas , Proteína Quinase C/metabolismo , Proteólise , Receptores de Fatores de Crescimento de Fibroblastos/química , Receptores de Fatores de Crescimento de Fibroblastos/genética
16.
Cells ; 10(4)2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33918004

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
17.
Cell Prolif ; 54(4): e13009, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33655556

RESUMO

The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/tratamento farmacológico , Transdução de Sinais , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/uso terapêutico , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Int J Biol Macromol ; 180: 470-483, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33745974

RESUMO

Fibroblast growth factor receptors (FGFRs) are integral membrane proteins involved in various biological processes including proliferation, migration and apoptosis. There are a number of regulatory mechanisms of FGFR signaling, which tightly control the specificity and duration of transmitted signals. The effect of the FGFRs spatial distribution in the plasma membrane on receptor-dependent functions is still largely unknown. We have demonstrated that oligomerization of FGF1 with coiled-coil motifs largely improves FGF1 affinity for FGFRs and heparin. Set of developed FGF1 oligomers evoked prolonged activation of FGFR1 and receptor-downstream signaling pathways, as compared to the wild type FGF1. The majority of obtained oligomeric FGF1 variants showed increased stability, enhanced mitogenic activity and largely improved internalization via FGFR1-dependent endocytosis. Importantly, FGF1 oligomers with the highest oligomeric state exhibited reduced ability to stimulate FGFR-dependent glucose uptake, while at the same time remained hyperactive in the induction of cell proliferation. Our data implicate that oligomerization of FGF1 alters the biological activity of the FGF/GFR1 signaling system. Furthermore, developed FGF1 oligomers, due to improved stability and proliferative potential, can be applied in the regenerative medicine or as drug delivery vehicles in the ADC approach against FGFR1-overproducing cancers.


Assuntos
Proliferação de Células , Fator 1 de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Células 3T3-L1 , Animais , Ligação Competitiva , Linhagem Celular Tumoral , Fator 1 de Crescimento de Fibroblastos/química , Heparina/metabolismo , Humanos , Camundongos , Microscopia de Fluorescência , Células NIH 3T3 , Ligação Proteica , Multimerização Proteica
19.
G3 (Bethesda) ; 11(3)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33729500

RESUMO

Folded gastrulation (Fog) is a secreted ligand that signals through the G-protein-coupled receptors Mist and Smog and the G-protein Concertina to activate downstream effectors to elicit cell-shape change during gastrulation. In the embryonic central nervous system (CNS), Fog has roles in axon guidance and glial morphogenesis. However, the elements of the pathway as well as mechanisms required for transducing the signal in this context have not been determined. We find that while Concertina is essential for Fog signaling, Mist is dispensable and Smog, surprisingly, functions as a negative regulator of the pathway in the CNS. Interestingly Heartless, a fibroblast growth factor receptor, also functions as a negative regulator. Furthermore, both Heartless and Smog interact in a synergistic manner to regulate Fog signaling. Our results thus identify Heartless and Smog as part of a common regulatory pathway that functions to restrict Fog signaling in the embryonic CNS and highlights the context-specific role for Fog receptors during development.


Assuntos
Proteínas de Drosophila , Drosophila , Receptores de Fatores de Crescimento de Fibroblastos , Receptores Acoplados a Proteínas G , Animais , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Gastrulação , Neuroglia/metabolismo , Proteínas Tirosina Quinases , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
20.
Eur J Med Chem ; 214: 113205, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33556787

RESUMO

Fibroblast growth factor receptor (FGFR) includes four highly conserved transmembrane receptor tyrosine kinases (FGFR1-4). FGF and FGFR regulate many biological processes, such as angiogenesis, wound healing and tissue regeneration. The abnormal expression of FGFR is related to the tumorigenesis, tumor progression and drug resistance of anti-tumor treatments in many types of tumors. Nowadays there are many anti-cancer drugs targeting FGFR. However, traditional single-target anti-tumor drugs are easy to acquire drug resistance. The therapeutic effect can be enhanced by simultaneously inhibiting FGFR and another target (such as VEGFR, EGFR, PI3K, CSF-1R, etc.). We know drug combination can bring problems such as drug interactions. Therefore, the development of FGFR dual target inhibitors is an important direction. In this paper, we reviewed the research on dual FGFR inhibitors in recent years and made brief comments on them.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Antineoplásicos/química , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/química , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
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