Epithelial Fibroblast Growth Factor Receptor 1 Regulates Enamel Formation

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1800338116 ◽

2019 ◽

Vol 116 (10) ◽

pp. 4316-4325 ◽

Cited By ~ 10

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.

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Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner

Oncogene ◽

10.1038/onc.2009.280 ◽

2009 ◽

Vol 28 (48) ◽

pp. 4306-4316 ◽

Cited By ~ 64

Author(s):

E di Martino ◽

C G L'Hôte ◽

W Kennedy ◽

D C Tomlinson ◽

M A Knowles

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Intracellular Signaling ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Cellular Transformation ◽

Fibroblast Growth ◽

Cell Type ◽

Specific Manner ◽

A Cell

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

The Journal of Cell Biology ◽

10.1083/jcb.200905118 ◽

2009 ◽

Vol 187 (2) ◽

pp. 265-277 ◽

Cited By ~ 31

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.

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Exon and intron sequences, respectively, repress and activate splicing of a fibroblast growth factor receptor 2 alternative exon.

Molecular and Cellular Biology ◽

10.1128/mcb.15.9.4825 ◽

1995 ◽

Vol 15 (9) ◽

pp. 4825-4834 ◽

Cited By ~ 65

Author(s):

F Del Gatto ◽

R Breathnach

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Splice Site ◽

Fibroblast Growth Factor Receptor ◽

Consensus Sequence ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Exon Sequence ◽

Sequence Elements ◽

A Cell

Two alternative exons, BEK and K-SAM, code for part of the ligand binding site of fibroblast growth factor receptor 2. Splicing of these exons is mutually exclusive, and the choice between them is made in a tissue-specific manner. We identify here pre-mRNA sequences involved in controlling splicing of the K-SAM exon. The short K-SAM exon sequence 5'-TAGGGCAGGC-3' inhibits splicing of the exon. This inhibition can be overcome by mutating either the exon's 5' or 3' splice site to make it correspond more closely to the relevant consensus sequence. Two separate sequence elements in the intron immediately downstream of the K-SAM exon, one of which is a sequence rich in pyrimidines, are both needed for efficient K-SAM exon splicing. This is no longer the case if either the exon's 5' or 3' splice site is reinforced. Furthermore, if the exon inhibitory sequence is removed, the intron sequences are not required for splicing of the K-SAM exon in a cell line which normally splices this exon. At least three elements are thus involved in controlling splicing of the K-SAM exon: suboptimal 5' and 3' splice sites, an exon inhibitory sequence, and intron activating sequences.

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Fibroblast Growth Factor Receptor 3 Associates with and Tyrosine Phosphorylates p90 RSK2, Leading to RSK2 Activation That Mediates Hematopoietic Transformation

Molecular and Cellular Biology ◽

10.1128/mcb.00998-08 ◽

2009 ◽

Vol 29 (8) ◽

pp. 2105-2117 ◽

Cited By ~ 39

Author(s):

Sumin Kang ◽

Shannon Elf ◽

Shaozhong Dong ◽

Taro Hitosugi ◽

Katherine Lythgoe ◽

...

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor Receptor ◽

Critical Role ◽

Ectopic Expression ◽

Growth Factor Receptor ◽

Marrow Transplant ◽

Fibroblast Growth ◽

Murine Bone Marrow

ABSTRACT Dysregulation of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) plays a pathogenic role in a number of human hematopoietic malignancies and solid tumors. These include t(4;14) multiple myeloma associated with ectopic expression of FGFR3 and t(4;12)(p16;p13) acute myeloid leukemia associated with expression of a constitutively activated fusion tyrosine kinase, TEL-FGFR3. We recently reported that FGFR3 directly tyrosine phosphorylates RSK2 at Y529, which consequently regulates RSK2 activation. Here we identified Y707 as an additional tyrosine in RSK2 that is phosphorylated by FGFR3. Phosphorylation at Y707 contributes to RSK2 activation, through a putative disruption of the autoinhibitory αL-helix on the C terminus of RSK2, unlike Y529 phosphorylation, which facilitates ERK binding. Moreover, we found that FGFR3 interacts with RSK2 through residue W332 in the linker region of RSK2 and that this association is required for FGFR3-dependent phosphorylation of RSK2 at Y529 and Y707, as well as the subsequent RSK2 activation. Furthermore, in a murine bone marrow transplant assay, genetic deficiency in RSK2 resulted in a significantly delayed and attenuated myeloproliferative syndrome induced by TEL-FGFR3 as compared with wild-type cells, suggesting a critical role of RSK2 in FGFR3-induced hematopoietic transformation. Our current and previous findings represent a paradigm for tyrosine phosphorylation-dependent regulation of serine-threonine kinases.

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