scholarly journals Spred2 interaction with the late endosomal protein NBR1 down-regulates fibroblast growth factor receptor signaling

2009 ◽  
Vol 187 (2) ◽  
pp. 265-277 ◽  
Author(s):  
Faraz K. Mardakheh ◽  
Mona Yekezare ◽  
Laura M. Machesky ◽  
John K. Heath
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Degradation Pathway ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Critical Function ◽  
Underlying Mechanisms

The potential for modulation of growth factor signaling by endocytic trafficking of receptors is well recognized, but the underlying mechanisms are poorly understood. We examined the regulation of fibroblast growth factor (FGF) signaling by Sprouty related with EVH1 (Ena/VASP homology 1) domain (Spred), a family of signaling inhibitors with proposed tumor-suppressive functions. The inhibitory activity of Spreds has been linked to their N-terminal EVH1 domain, but the molecular mechanism is unknown. In this study, we identify a novel late endosomal protein that directly binds to the EVH1 domain of Spred2. Neighbor of BRCA1 (NBR1) is a highly conserved multidomain protein that interacts and colocalizes with Spred2 in vivo. Attenuation of FGF signaling by Spred2 is dependent on the interaction with NBR1 and is achieved by redirecting the trafficking of activated receptors to the lysosomal degradation pathway. Our findings suggest a critical function for NBR1 in the regulation of receptor trafficking and provide a mechanism for down-regulation of signaling by Spred2 via NBR1.

scholarly journals Sulfatase modifying factor 1–mediated fibroblast growth factor signaling primes hematopoietic multilineage development

2010 ◽  
Vol 207 (8) ◽  
pp. 1647-1660 ◽  
Author(s):  
Mario Buono ◽  
Ilaria Visigalli ◽  
Roberta Bergamasco ◽  
Alessandra Biffi ◽  
Maria Pia Cosma
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
B Lymphocyte ◽  
Erythroid Differentiation ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Cell Stage ◽  
Hematopoietic Stem

Self-renewal and differentiation of hematopoietic stem cells (HSCs) are balanced by the concerted activities of the fibroblast growth factor (FGF), Wnt, and Notch pathways, which are tuned by enzyme-mediated remodeling of heparan sulfate proteoglycans (HSPGs). Sulfatase modifying factor 1 (SUMF1) activates the Sulf1 and Sulf2 sulfatases that remodel the HSPGs, and is mutated in patients with multiple sulfatase deficiency. Here, we show that the FGF signaling pathway is constitutively activated in Sumf1−/− HSCs and hematopoietic stem progenitor cells (HSPCs). These cells show increased p-extracellular signal-regulated kinase levels, which in turn promote β-catenin accumulation. Constitutive activation of FGF signaling results in a block in erythroid differentiation at the chromatophilic erythroblast stage, and of B lymphocyte differentiation at the pro–B cell stage. A reduction in mature myeloid cells and an aberrant development of T lymphocytes are also seen. These defects are rescued in vivo by blocking the FGF pathway in Sumf1−/− mice. Transplantation of Sumf1−/− HSPCs into wild-type mice reconstituted the phenotype of the donors, suggesting a cell autonomous defect. These data indicate that Sumf1 controls HSPC differentiation and hematopoietic lineage development through FGF and Wnt signaling.

scholarly journals Fibroblast growth factor receptor influences primary cilium length through an interaction with intestinal cell kinase

2019 ◽  
Vol 116 (10) ◽  
pp. 4316-4325 ◽  
Author(s):  
Michaela Kunova Bosakova ◽  
Alexandru Nita ◽  
Tomas Gregor ◽  
Miroslav Varecha ◽  
Iva Gudernova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Growth Factor Receptor ◽  
Conclusive Evidence ◽  
Intestinal Cell ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Intestinal Cell Kinase

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.

Epithelial Fibroblast Growth Factor Receptor 1 Regulates Enamel Formation

2008 ◽  
Vol 87 (3) ◽  
pp. 238-243 ◽  
Author(s):  
K. Takamori ◽  
R. Hosokawa ◽  
X. Xu ◽  
X. Deng ◽  
P. Bringas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tooth Development ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Enamel Formation ◽  
Enamel Structure ◽  
A Cell

The interaction between epithelial and mesenchymal tissues plays a critical role in the development of organs such as teeth, lungs, and hair. During tooth development, fibroblast growth factor (FGF) signaling is critical for regulating reciprocal epithelial and mesenchymal interactions. FGF signaling requires FGF ligands and their receptors (FGFRs). In this study, we investigated the role of epithelial FGF signaling in tooth development, using the Cre-loxp system to create tissue-specific inactivation of Fgfr1 in mice. In K14-Cre;Fgfr1 fl/fl mice, the apical sides of enamel-secreting ameloblasts failed to adhere properly to each other, although ameloblast differentiation was unaffected at early stages. Prior to eruption, enamel structure was compromised in the K14-Cre;Fgfr1 fl/fl mice and displayed severe enamel defects that mimic amelogenesis imperfecta (AI), with a rough, irregular enamel surface. These results suggest that there is a cell-autonomous requirement for FGF signaling in the dental epithelium during enamel formation. Loss of Fgfr1 affects ameloblast organization at the enamel-secretory stage and, hence, the formation of enamel.

scholarly journals FGFRL1 Promotes Ovarian Cancer Progression by Crosstalk with Hedgehog Signaling

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Haiyan Tai ◽  
Zhiyong Wu ◽  
Su’an Sun ◽  
Zhigang Zhang ◽  
Congjian Xu
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Hh Signaling ◽  
And Migration

Fibroblast growth factor receptor-like-1 (FGFRL1) has been identified as the fifth fibroblast growth factor receptor. So far, little is known about its biological functions, particularly in cancer development. Here, for the first time, we demonstrated the roles of FGFRL1 in ovarian carcinoma (OC). An array and existing databases were used to investigate the expression profile of FGFRL1 and the relationship between FGFRL1 expression and clinicopathological parameters. FGFRL1 was significantly upregulated in OC patients, and high FGFRL1 expression was correlated with poor prognosis. In vitro cell proliferation, apoptosis and migration assays, and in vivo subcutaneous xenograft tumor models were used to determine the role of FGFRL1. Loss of function of FGFRL1 significantly influenced cell proliferation, apoptosis, and migration of OC cells in vitro and tumor growth in vivo. Chromatin immunoprecipitation PCR analysis and microarray hybridization were performed to uncover the mechanism. FGFRL1 expression could be induced by hypoxia through hypoxia-inducible factor 1α, which directly binds to the promoter elements of FGFRL1. FGFRL1 promoted tumor progression by crosstalk with Hedgehog (Hh) signaling. Taken together, FGFRL1 is a potential predictor and plays an important role in tumor growth and Hh signaling which could serve as potential therapeutic targets for the treatment of OC.

Divergent fibroblast growth factor signaling pathways in lung fibroblast subsets: where do we go from here?

2015 ◽  
Vol 309 (8) ◽  
pp. L751-L755 ◽  
Author(s):  
Jordi Ruiz-Camp ◽  
Rory E. Morty
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Fibroblast Growth Factor ◽  
Lung Development ◽  
Fluorescent Protein ◽  
Growth Factor Receptor ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Growth Factor Signaling ◽  
Fibroblast Growth

Lung fibroblasts play a key role in postnatal lung development, namely, the formation of the alveolar gas exchange units, through the process of secondary septation. Although evidence initially highlighted roles for fibroblasts in the production and remodeling of the lung extracellular matrix, more recent studies have described the presence of different fibroblast subsets in the developing lung. These subsets include myofibroblasts and lipofibroblasts and their precursors. These cells are believed to play different roles in alveologenesis and are localized to different regions of the developing septa. The precise roles played by these different fibroblast subsets remain unclear. Understanding the signaling pathways that control the discrete functions of these fibroblast subsets would help to clarify the roles and the regulation of lung fibroblasts during lung development. Here, we critically evaluate a recent report that described divergent fibroblast growth factor (FGF) signaling pathways in two different subsets of lung fibroblasts that express different levels of green fluorescent protein (GFP) driven by the platelet-derived growth factor receptor-α promoter. The GFP expression was used as a surrogate for lipofibroblasts (GFPlow) and myofibroblasts (GFPhigh). It was suggested that Fgf10/Fgf1 and Fgf18/Fgfr3 autocrine pathways may be operative in GFPlow and GFPhigh cells, respectively, and that these pathways might regulate the proliferation and migration of different fibroblast subsets during alveologenesis. These observations lay important groundwork for the further exploration of FGF function during normal lung development, as well as in aberrant lung development associated with bronchopulmonary dysplasia.

scholarly journals FGF2 Enhances Odontoblast Differentiation by αSMA+ Progenitors In Vivo

2018 ◽  
Vol 97 (10) ◽  
pp. 1170-1177 ◽  
Author(s):  
I. Vidovic-Zdrilic ◽  
K.H. Vining ◽  
A. Vijaykumar ◽  
I. Kalajzic ◽  
D.J. Mooney ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Dental Pulp ◽  
Lineage Tracing ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Odontoblast Differentiation ◽  
Reparative Dentin

The goal of this study was to examine the effects of early and limited exposure of perivascular cells expressing α (αSMA) to fibroblast growth factor 2 (FGF2) in vivo. We performed in vivo fate mapping by inducible Cre-loxP and experimental pulp injury in molars to induce reparative dentinogenesis. Our results demonstrate that early delivery of exogenous FGF2 to exposed pulp led to proliferative expansion of αSMA-tdTomato+ cells and their accelerated differentiation into odontoblasts. In vivo lineage-tracing experiments showed that the calcified bridge/reparative dentin in FGF2-treated pulps were lined with an increased number of Dspp+ odontoblasts and devoid of BSP+ osteoblasts. The increased number of odontoblasts derived from αSMA-tdTomato+ cells and the formation of reparative dentin devoid of osteoblasts provide in vivo evidence for the stimulatory effects of FGF signaling on odontoblast differentiation from early progenitors in dental pulp.

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