Fibroblast Growth Factor Receptor 3 Induces Gene Expression Primarily through Ras-independent Signal Transduction Pathways

Choi, Deog Young; Toledo‐Aral, Juan José; Lin, Hsiang Yin; Ischenko, Irene; Medina, Lillian; Safo, Patrick; Mandel, Gail; Levinson, S. Rock; Halegoua, Simon; Hayman, Michael J.

doi:10.1074/jbc.m002959200

Cited by 39 publications

(19 citation statements)

References 29 publications

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“…Consistent with this, here we show that, in OL progenitors, FGF-2/ FGFR1 signaling leads to proliferation and robust MAP kinase activation, whereas FGF-8/FGFR3 does not. Nevertheless, FGFR3 does induce strong signals for gene expression, primarily through Ras-independent signaling pathways in PC12 cells (Choi et al, 2001). The specific signaling pathways emerging from the activation of each FGF ligand/receptor pair in the OL lineage cells remain to be determined.…”

Section: Fgf/fgfr Specificitymentioning

confidence: 99%

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Fortin¹,

Rom²,

Sun³

et al. 2005

J. Neurosci.

144

166

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Fibroblast growth factors (FGFs) have been implicated in numerous cellular processes, including proliferation, migration, differentiation, and survival. Whereas FGF-2, the prototypic ligand in a family of 22 members, activates all four tyrosine kinase FGF receptors (FGFR1-FGFR4), other members demonstrate a higher degree of selectivity. Oligodendrocytes (OLs), the myelin-producing cells of the CNS, are highly influenced by FGF-2 at all stages of their development. However, how other FGFs and their cognate receptors orchestrate the development of OLs is essentially undefined. Using a combination of specific FGF ligands and receptor blocking antibodies, we now show that FGF-8 and FGF-17 target OL progenitors, inhibiting their terminal differentiation via the activation of FGFR3, whereas FGF-9 specifically targets differentiated OLs, triggering increases in process growth via FGFR2 signaling; FGF-18 targets both OL progenitors and OLs via activation of both FGFR2 and FGFR3. These events are highly correlated with changes in FGF receptor expression from FGFR3 to FGFR2 as OL progenitors differentiate into mature OLs. In addition, we demonstrate that, although activation of FGFR1 by FGF-2 leads to proliferation of OL progenitors, it produces deleterious effects on differentiated OLs (i.e., aberrant reentry into cell cycle and downregulation of myelin proteins with a loss of myelin membrane). These data suggest that ligand availability, coupled with changes in FGF receptor expression, yield a changing repertoire of ligand-receptor signaling complexes that contribute critically to the regulation of both normal OL development and potential OL/myelin pathogenesis.

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Section: Fgf/fgfr Specificitymentioning

confidence: 99%

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Fortin¹,

Rom²,

Sun³

et al. 2005

J. Neurosci.

144

166

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“…All FGFs act via a dual receptor system comprising four high-affinity tyrosine kinase receptors (FGFR-1 to -4) and a class of low-affinity receptors (the heparan sulfate proteoglycans) (23,24). Multiple layers of regulation control the activity of FGFs, including tissue-specific expression of ligands and receptors, modulation of binding specificity by alternative splicing of FGFRs and by sequence differences between FGFs and FGFRs, and modulation of binding affinity and specificity by heparan sulfate molecules with specific patterns of sulfation (23,(25)(26)(27). In addition to localization in the plasma membrane, FGFRs are also expressed within the nuclear envelope and matrix (28).…”

Section: Fgf-1: Key Regulator Of Human Adipogenesismentioning

confidence: 99%

Fibroblast Growth Factor 1

et al. 2004

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Obesity, with its related problems, is recognized as the fastest growing disease epidemic facing the world, yet we still have limited insight into the regulation of adipose tissue mass in humans. We have previously shown that adipose-derived microvascular endothelial cells (MVECs) secrete a factor(s) that increases proliferation of human preadipocytes. We now demonstrate that coculture of human preadipocytes with MVECs significantly increases preadipocyte differentiation, evidenced by dramatically increased triacylglycerol accumulation and glycerol-3-phosphate dehydrogenase activity compared with controls. Subsequent analysis identified fibroblast growth factor (FGF)-1 as an adipogenic factor produced by MVECs. Expression of FGF-1 was demonstrated in MVECs but not in preadipocytes, while preadipocytes were shown to express FGF receptors 1-4. The proliferative effect of MVECs on human preadipocytes was blocked using a neutralizing antibody specific for FGF-1. Pharmacological inhibition of FGF-1 signaling at multiple steps inhibits preadipocyte replication and differentiation, supporting the key adipogenic role of FGF-1. We also show that 3T3-L1 cells, a highly efficient murine model of adipogenesis, express FGF-1 and, unlike human preadipocytes, display no increased differentiation potential in response to exogenous FGF-1. Conversely, FGF-1-treated human preadipocytes proliferate rapidly and differentiate with high efficiency in a manner characteristic of 3T3-L1 cells. We therefore suggest that FGF-1 is a key human adipogenic factor, and these data expand our understanding of human fat tissue growth and have significant potential for development of novel therapeutic strategies in the prevention and management of human obesity. Diabetes 53: [3097][3098][3099][3100][3101][3102][3103][3104][3105][3106] 2004

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“…These observations indicate that FGF and FGFR3 signaling play major roles in the regulation of bone growth. To date, four signaling pathways have been shown to propagate FGF3 signals: the STAT, MAPKextracellular signal-regulated kinase (ERK), phospholipase C-␥, and phosphatidylinositol 3-kinase-AKT pathways (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Recently, it has been shown that constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism in mice and rescues the FGFR3-deficient mouse phenotype (32).…”

mentioning

confidence: 99%

Gene Disruption of Spred-2 Causes Dwarfism

Bundschu

Knobeloch

Ullrich³

et al. 2005

Journal of Biological Chemistry

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The impact of the fibroblast growth factor receptor 3 (FGFR3)-mediated signaling pathway on bone growth has been demonstrated by various genetic approaches. Overexpression of fibroblast growth factors (FGFs), several gain-of-function mutations in the FGFR3, and constitutive activation of mitogen-activated protein kinase (MAPK) kinase (MEK1) in chondrocytes have been shown to cause dwarfism in mice by activation of the MAPK signaling pathway. To investigate the previously reported inhibitory role of Spred in the FGFR3/MAPK pathway, we generated mice with a trapped Spred-2 gene. Here we show that lack of functional Spred-2 protein in mice caused a dwarf phenotype, similar to achondroplasia, the most common form of human dwarfism. Spred-2 ؊/؊ mice showed reduced growth and body weight, they had a shorter tibia length, and showed narrower growth plates as compared with wild-type mice. We detected promoter activity and protein expression of Spred-2 in chondrocytes, suggesting an important function of Spred-2 in chondrocytes and bone development. Stimulation of chondrocytes with different FGF concentrations showed earlier and augmented ERK phosphorylation in Spred-2 ؊/؊ chondrocytes in comparison to Spred-2 ؉/؉ chondrocytes. Our observations suggest a model in which loss of Spred-2 inhibits bone growth by inhibiting chondrocyte differentiation through up-regulation of the MAPK signaling pathway.Long bone growth is determined mainly by the process of endochondral ossification, a strictly regulated process that requires proliferation and differentiation of chondrocytes. During this process, chondrocytes in the reserve zone that arise from mesenchymal cells first undergo proliferation, they then exit the cell cycle, undergo terminal hypertrophic differentiation, and finally the synthesized cartilage matrix calcifies and is replaced by bone (1). Various signaling molecules have been shown to regulate and coordinate this complex process of endochondral ossification. Fibroblast growth factor (FGF) 1 signaling plays a major role in a variety of developmental processes and recent results have highlighted its function in the regulation of bone morphogenesis (for review, see Ref.2). FGFs are a large family of at least 23 polypeptides that signal through their binding to specific tyrosine kinase receptors (FGFRs), which constitute a four-member gene family (3). FGF receptor 3 (FGFR3) is expressed in proliferating and prehypertrophic chondrocytes in the epiphyseal growth plates (4 -6). Activating mutations in FGFR3 cause different forms of human dwarfism like achondroplasia, hypochondroplasia, and thanatophoric dysplasia (7-10). The most common form of human dwarfism is achondroplasia with a prevalence at birth of about 1/26,000 (11). Expression of activating FGFR3 mutants in mice reproduces the dwarf phenotype of these skeletal diseases (5, 12-17).In contrast, lack of FGFR3 in mice causes skeletal overgrowth, indicating that FGFR3 signaling inhibits endochondral bone growth (18,19). Similarly, transgenic mice overexpressing FGFs...

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Fibroblast Growth Factor Receptor 3 Induces Gene Expression Primarily through Ras-independent Signal Transduction Pathways

Cited by 39 publications

References 29 publications

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage

Fibroblast Growth Factor 1

Gene Disruption of Spred-2 Causes Dwarfism

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