scholarly journals Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

2017 ◽  
Author(s):  
Leia C. Shuhaibar ◽  
Jerid W. Robinson ◽  
Ninna P. Shuhaibar ◽  
Jeremy R. Egbert ◽  
Giulia Vigone ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Plate ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Bone Growth ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Activating Mutations ◽  
Bone Elongation

AbstractActivating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase cause similar forms of dwarfism, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, by use of a mouse model in which NPR2 cannot be dephosphorylated, we show that bone elongation is opposed when NPR2 is dephosphorylated and thus produces less cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP levels in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. Thus FGF signaling lowers cyclic GMP in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.

scholarly journals Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Leia C Shuhaibar ◽  
Jerid W Robinson ◽  
Giulia Vigone ◽  
Ninna P Shuhaibar ◽  
Jeremy R Egbert ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Bone Growth ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Activating Mutations ◽  
Bone Elongation ◽  
Gmp Production

Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. The dephosphorylation requires a PPP-family phosphatase. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.

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 Author response: Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor

2017 ◽  
Author(s):  
Leia C Shuhaibar ◽  
Jerid W Robinson ◽  
Giulia Vigone ◽  
Ninna P Shuhaibar ◽  
Jeremy R Egbert ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Guanylyl Cyclase ◽  
Bone Growth ◽  
Author Response ◽  
Fibroblast Growth

Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 4977-4988 ◽  
Author(s):  
M.C. Naski ◽  
J.S. Colvin ◽  
J.D. Coffin ◽  
D.M. Ornitz
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Signaling Pathway ◽  
Growth Plate ◽  
Bone Growth ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Growth Plate Cartilage ◽  
Bmp4 Expression

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal growth and activating mutations in Fgfr3 cause achondroplasia, the most common genetic form of dwarfism in humans. Little is known about the mechanism by which FGFR3 inhibits bone growth and how FGFR3 signaling interacts with other signaling pathways that regulate endochondral ossification. To understand these mechanisms, we targeted the expression of an activated FGFR3 to growth plate cartilage in mice using regulatory elements from the collagen II gene. As with humans carrying the achondroplasia mutation, the resulting transgenic mice are dwarfed, with axial, appendicular and craniofacial skeletal hypoplasia. We found that FGFR3 inhibited endochondral bone growth by markedly inhibiting chondrocyte proliferation and by slowing chondrocyte differentiation. Significantly, FGFR3 downregulated the Indian hedgehog (Ihh) signaling pathway and Bmp4 expression in both growth plate chondrocytes and in the perichondrium. Conversely, Bmp4 expression is upregulated in the perichondrium of Fgfr3−/− mice. These data support a model in which Fgfr3 is an upstream negative regulator of the hedgehog (Hh) signaling pathway. Additionally, Fgfr3 may coordinate the growth and differentiation of chondrocytes with the growth and differentiation of osteoprogenitor cells by simultaneously modulating Bmp4 and patched expression in both growth plate cartilage and in the perichondrium.

Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3521-3528 ◽  
Author(s):  
Suzanne Trudel ◽  
Scott Ely ◽  
Yildiz Farooqi ◽  
Maurizio Affer ◽  
Davide F. Robbiani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Myeloma Cell ◽  
Fibroblast Growth ◽  
Genetic Changes ◽  
Functional Changes ◽  
Activating Mutations ◽  
Molecule Inhibitor

Abstract We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant FGFR3 autophosphorylation by the small molecule inhibitor, PD173074. Inhibition of FGFR3 in human myeloma cell lines was associated with decreased viability and tumor cell growth arrest. Further, morphologic, phenotypic, and functional changes typical of plasma cell (PC) differentiation, including increase in light-chain secretion and expression of CD31, were observed and this was followed by apoptosis. Finally, using a mouse model of FGFR3 myeloma, we demonstrate a delay in tumor progression and prolonged survival of mice treated with PD173074. These results indicate that inhibition of FGFR3, even in advanced disease associated with multiple genetic changes, may allow the cell to complete its developmental program and render it sensitive to apoptotic signals. In addition, this represents the validation of a therapeutic target in MM that may benefit patients who have a very poor prognosis with currently available treatments. (Blood. 2004;103:3521-3528)

scholarly journals Differential Regulation of Fibroblast Growth Factor (FGF) Receptor-1 mRNA and Protein by Two Molecular Forms of Basic FGF

1996 ◽  
Vol 271 (10) ◽  
pp. 5663-5670 ◽  
Author(s):  
Agnes Estival ◽  
Veronique Monzat ◽  
Karine Miquel ◽  
François Gaubert ◽  
Etienne Hollande ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Differential Regulation ◽  
Molecular Forms ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Basic Fgf
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