The fibroblast growth factor receptor, FGFR3, forms gradients of intact and degraded protein across the growth plate of developing bovine ribs

2002 ◽  
Vol 361 (2) ◽  
pp. 231-241 ◽  
Author(s):  
Sujata G. PANDIT ◽  
Prasanthi GOVINDRAJ ◽  
Joachim SASSE ◽  
Peter J. NEAME ◽  
John R. HASSELL
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Plate ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Hypertrophic Zone ◽  
The Matrix ◽  
Maximum Expression

Point mutations in the human fibroblast growth factor (FGF) receptor 3 gene (Fgfr3) produce a constitutively active receptor, which disrupts chondrocyte differentiation in the growth plate and results in skeletal dysplasias with severe shortening of the limbs. Alternative splicing of the Fgfr3 transcript gives rise to two isoforms, IIIc and IIIb, which vary in their specificity for FGF ligands. We examined the expression of these FGFR3 isoforms in the bovine fetal rib growth plate to determine whether levels of FGFR3 expression are zone-related. Transcripts for both Fgfr3 isoforms are expressed in rib growth plate, with maximum expression in the hypertrophic region and the least expression in the reserve zone. Fgfr3 IIIc is the predominant isoform in the growth plate. Western-blot analysis revealed the presence of full-length FGFR3 (135kDa) for both isoforms in the reserve zone, a major 98kDa fragment in all zones and smaller fragments primarily in the hypertrophic zone. Immunostaining localized FGFR3 to the pericellular region of reserve chondrocytes and to the extracellular matrix in the hypertrophic zone. These results suggest that the transmembrane form of FGFR3 increasingly undergoes proteolytic cleavage towards the hypertrophic zone to produce an extracellular-domain fragment of FGFR3, which is present in large amounts in the matrix of hypertrophic cells. These findings suggest a proteolytic regulatory mechanism for FGFR3, whereby Fgfr3 fragments could control availability of FGF for the intact receptor, and by which proteolysis could inactivate the receptor.

scholarly journals The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3029
Author(s):  
Maria Francesca Santolla ◽  
Marcello Maggiolini
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Transduction Mechanisms ◽  
Molecular Landscape ◽  
Molecular Aberrations

One of the major challenges in the treatment of breast cancer is the heterogeneous nature of the disease. With multiple subtypes of breast cancer identified, there is an unmet clinical need for the development of therapies particularly for the less tractable subtypes. Several transduction mechanisms are involved in the progression of breast cancer, therefore making the assessment of the molecular landscape that characterizes each patient intricate. Over the last decade, numerous studies have focused on the development of tyrosine kinase inhibitors (TKIs) to target the main pathways dysregulated in breast cancer, however their effectiveness is often limited either by resistance to treatments or the appearance of adverse effects. In this context, the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system represents an emerging transduction pathway and therapeutic target to be fully investigated among the diverse anti-cancer settings in breast cancer. Here, we have recapitulated previous studies dealing with FGFR molecular aberrations, such as the gene amplification, point mutations, and chromosomal translocations that occur in breast cancer. Furthermore, alterations in the FGF/FGFR signaling across the different subtypes of breast cancer have been described. Next, we discussed the functional interplay between the FGF/FGFR axis and important components of the breast tumor microenvironment. Lastly, we pointed out the therapeutic usefulness of FGF/FGFR inhibitors, as revealed by preclinical and clinical models of breast cancer.

scholarly journals Fibroblast Growth Factor Receptor-Mediated Rescue of x-Ephrin B1-Induced Cell Dissociation in XenopusEmbryos

2000 ◽  
Vol 20 (2) ◽  
pp. 724-734 ◽  
Author(s):  
Lisa D. Chong ◽  
Eui Kyun Park ◽  
Erin Latimer ◽  
Robert Friesel ◽  
Ira O. Daar
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Cell Adhesion And Migration ◽  
Membrane Bound ◽  
And Migration

ABSTRACT The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. Genetic evidence suggests that ephrins may transduce signals and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Here, we report that when we used ectopically expressed proteins, we found that an activated fibroblast growth factor (FGF) receptor associated with and induced the phosphorylation of ephrin B1 on tyrosine. Moreover, this phosphorylation reduced the ability of overexpressed ephrin B1 to reduce cell adhesion. In addition, we identified a region in the cytoplasmic tail of ephrin B1 that is critical for interaction with the FGF receptor; we also report FGF-induced phosphorylation of ephrins in a neural tissue. This is the first demonstration of communication between the FGF receptor family and the Eph ligand family and implicates cross talk between these two cell surface molecules in regulating cell adhesion.

Spatially restricted expression of fibroblast growth factor receptor-2 during Xenopus development

Development ◽  
1992 ◽  
Vol 116 (4) ◽  
pp. 1051-1058 ◽  
Author(s):  
R. Friesel ◽  
S.A. Brown
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Sequence Similarity ◽  
Growth Factor Receptor ◽  
Otic Vesicle ◽  
Amino Acid Sequence Similarity ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Mesoderm Inducing Factors

The fibroblast growth factors (FGFs) play a role in Xenopus laevis embryonic development, particularly in the induction of ventral-type mesoderm. We have isolated a full-length cDNA from Xenopus that we have designated Xenopus fibroblast growth factor receptor-2 (XFGFR-2), with significant amino acid sequence similarity to the previously described bek gene (FGFR-2). We expressed the XFGFR-2 cDNA in COS1 cells and showed that it functions as an FGF receptor by binding radiolabeled FGF-2. RNA gel blot analysis demonstrates that unlike Xenopus fibroblast growth factor receptor-1 (XFGFR-1), XFGFR-2 mRNA expression begins during gastrulation and continues through early tadpole stages. Whole-mount in situ hybridization demonstrates that XFGFR-2 mRNA is localized to the anterior neural plate in early neurula stage embryos. Later in development, XFGFR-2 expression is found in the eye anlagen, midbrain-hindbrain boundary and the otic vesicle. In addition, XFGFR-2 transcripts are expressed in animal caps in a manner that is independent of mesoderm-inducing factors. These results indicate that XFGFR-2 may have a role in development that is distinct from that of XFGFR-1.

scholarly journals Fibroblast Growth Factor (FGF) Receptor Mutations: A Pathway to Understanding Multigenic Risk in Disease?

2013 ◽  
Vol 1 (3) ◽  
pp. 123-127
Author(s):  
Stuart J. Mires
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Disease Risk ◽  
Selection Process ◽  
Growth Factor Receptor ◽  
Paternal Age ◽  
Fibroblast Growth ◽  
Gain Of Function ◽  
Fgf Receptor ◽  
Paternal Age Effect

Fibroblast growth factor receptor (FGFR) gain-of-function mutations form the pathogenic basis of multiple congenital pathologies. A pioneering body of work over the past two decades has established that a unique mutation selection process within the testis likely underlies the paternal age effect characteristics of such diseases. This mechanism, analogous to positive selection of mutations promo­ting proliferation in tumorigenesis, sparked interest in mutation profiling of testicular and other cancers. The resulting discovery of FGFR gain-of-function mutations akin to those of congenital syndromes has enabled a novel hypothesis to be born: that mutations represent a spectrum of activation. As such, FGFR gain-of-function mutations could be pathogenic not solely in defined monogenic syndromes but within myriad disease processes with ‘low activation’ conferring increased disease risk. Do such mutations contribute to multigenic risk in multiple pathologies? This review evaluates this hypothesis, alluding to the plausible clinical implications that ensue.

Retention in the Golgi apparatus and expression on the cell surface of Cfr/Esl-1/Glg-1/MG-160 are regulated by two distinct mechanisms

2011 ◽  
Vol 440 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Yuichiro Miyaoka ◽  
Hidenori Kato ◽  
Kazuki Ebato ◽  
Shigeru Saito ◽  
Naoko Miyata ◽  
...  
Keyword(s):  
Growth Factor ◽  
Golgi Apparatus ◽  
Cell Surface ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Juxtamembrane Region ◽  
Fgf Signalling

Cfr (cysteine-rich fibroblast growth factor receptor) is an Fgf (fibroblast growth factor)-binding protein without a tyrosine kinase. We have shown previously that Cfr is involved in Fgf18 signalling via Fgf receptor 3c. However, as Cfr is also known as Glg (Golgi apparatus protein)-1 or MG-160 and occurs in the Golgi apparatus, it remains unknown how the distribution of Cfr is regulated. In the present study, we performed a mutagenic analysis of Cfr to show that two distinct regions contribute to its distribution and stability. First, the C-terminal region retains Cfr in the Golgi apparatus. Secondly, the Cfr repeats in the extracellular juxtamembrane region destabilizes Cfr passed through the Golgi apparatus. This destabilization does not depend on the cleavage and secretion of the extracellular domain of Cfr. Furthermore, we found that Cfr with a GPI (glycosylphosphatidylinositol) anchor was predominantly expressed on the cell surface in Ba/F3 cells and affected Fgf18 signalling in a similar manner to the full-length Cfr, indicating that the interaction of Cfr with Fgfs on the cell surface is important for its function in Fgf signalling. These results suggest that the expression of Cfr in the Golgi apparatus and on the plasma membrane is finely tuned through two distinct mechanisms for exhibiting different functions.

scholarly journals Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3

2011 ◽  
Vol 22 (20) ◽  
pp. 3861-3873 ◽  
Author(s):  
Catherine R. Degnin ◽  
Melanie B. Laederich ◽  
William A. Horton
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Plate ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Intramembrane Proteolysis ◽  
Ligand Activation ◽  
Regulated Intramembrane Proteolysis

Fibroblast growth factor receptor 3 (FGFR3) is a major negative regulator of bone growth that inhibits the proliferation and differentiation of growth plate chondrocytes. Activating mutations of its c isoform cause dwarfism in humans; somatic mutations can drive oncogenic transformation in multiple myeloma and bladder cancer. How these distinct activities arise is not clear. FGFR3 was previously shown to undergo proteolytic cleavage in the bovine rib growth plate, but this was not explored further. Here, we show that FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3. The ectodomain is proteolytically cleaved (S1) in response to ligand-induced receptor activation, but unlike most RIP target proteins, it requires endocytosis and does not involve a metalloproteinase. S1 cleavage generates a C-terminal domain fragment that initially remains anchored in the membrane, is phosphorylated, and is spatially distinct from the intact receptor. Ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus. We identify the S1 cleavage site and show that γ-secretase mediates the S2 cleavage event. In this way we demonstrate a mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease.

Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak

Development ◽  
1997 ◽  
Vol 124 (14) ◽  
pp. 2829-2841 ◽  
Author(s):  
B.G. Ciruna ◽  
L. Schwartz ◽  
K. Harpal ◽  
T.P. Yamaguchi ◽  
J. Rossant
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Primitive Streak ◽  
Paraxial Mesoderm ◽  
Fibroblast Growth ◽  
Primary Defect ◽  
Fgf Receptor ◽  
Neural Tubes ◽  
Morphogenetic Movement

Fibroblast growth factor (FGF) signaling has been implicated in the patterning of mesoderm and neural lineages during early vertebrate development. In the mouse, FGF receptor-1 (FGFR1) is expressed in an appropriate spatial and temporal manner to be orchestrating these functions. Mouse embryos homozygous for a mutated Fgfr1 allele (fgfr1(delta tmk)) die early in development, show abnormal growth and aberrant mesodermal patterning. We have performed a chimeric analysis to further study FGFR1 function in the morphogenesis and patterning of the mesodermal germ layer at gastrulation. At E9.5, fgfr1(delta tmk)/fgfr1(delta tmk) cells showed a marked deficiency in their ability to contribute to the extra-embryonic, cephalic, heart, axial and paraxial mesoderm, and to the endoderm of chimeric embryos. Analysis at earlier stages of development revealed that fgfr1(delta tmk)/fgfr1(delta tmk) cells accumulated within the primitive streak of chimeric embryos, and consequently failed to populate the anterior mesoderm and endodermal lineages at their inception. We suggest that the primary defect associated with the fgfr1(delta tmk) mutation is a deficiency in the ability of epiblast cells to traverse the primitive streak. fgfr1(delta tmk)/fgfr1(delta tmk) cells that accumulated within the primitive streak of chimeric embryos tended to form secondary neural tubes. These secondary neural tubes were entirely fgfr1(delta tmk)/fgfr1(delta tmk) cell derived. The adoption of ectopic neural fate suggests that normal morphogenetic movement through the streak is essential not only for proper mesodermal patterning but also for correct determination of mesodermal/neurectodermal cell fates.

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