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 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 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.

scholarly journals Structural Basis for Activation of Fibroblast Growth Factor Signaling by Sucrose Octasulfate

2002 ◽  
Vol 22 (20) ◽  
pp. 7184-7192 ◽  
Author(s):  
Brian K. Yeh ◽  
Anna V. Eliseenkova ◽  
Alexander N. Plotnikov ◽  
David Green ◽  
Jared Pinnell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Protein Interactions ◽  
Therapeutic Potential ◽  
Structural Basis ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Receptor Dimerization ◽  
Sucrose Octasulfate

ABSTRACT Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-Å resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed “two-end” model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.

scholarly journals Dynamic changes of podocytes caused by fibroblast growth factor 2 in culture

2021 ◽  
Author(s):  
Eishin Yaoita ◽  
Masaaki Nameta ◽  
Yutaka Yoshida ◽  
Hidehiko Fujinaka
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 2 ◽  
Quiescent State ◽  
Fibroblast Growth ◽  
Gene Expressions ◽  
Dynamic Changes ◽  
Ki 67

AbstractFibroblast growth factor 2 (FGF2) augments podocyte injury, which induces glomerulosclerosis, although the mechanisms remain obscure. In this study, we investigated the effects of FGF2 on cultured podocytes with interdigitating cell processes in rats. After 48 h incubation with FGF2 dynamic changes in the shape of primary processes and cell bodies of podocytes resulted in the loss of interdigitation, which was clearly shown by time-lapse photography. FGF2 reduced the gene expressions of constituents of the slit diaphragm, inflections of intercellular junctions positive for nephrin, and the width of the intercellular space. Immunostaining for the proliferation marker Ki-67 was rarely seen and weakly stained in the control without FGF2, whereas intensely stained cells were frequently found in the presence of FGF2. Binucleation and cell division were also observed, although no significant increase in cell number was shown. An in vitro scratch assay revealed that FGF2 enhanced migration of podocytes. These findings show that FGF2 makes podocytes to transition from the quiescent state into the cell cycle and change their morphology due to enhanced motility, and that the culture system in this study is useful for analyzing the pathological changes of podocytes in vivo.

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