The roles of the FGF signal in zebrafish embryos analyzed using constitutive activation and dominant-negative suppression of different FGF receptors

Ota, Satoshi; Tonou-Fujimori, Noriko; Yamasu, Kyo

doi:10.1016/j.mod.2008.10.008

Cited by 38 publications

(42 citation statements)

References 86 publications

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“…Treatment of fish in the embryonic state with either FIIN-2 or FIIN-3 caused defects to the posterior mesoderm similar to the phenotypes reported following genetic knockdown of FGFR or treatment with other reported FGFR inhibitors (9,67). FIIN-2 and FIIN-3 caused mild or severe phenotypes to the tail morphogenesis in all treated embryonic zebrafish.…”

Section: Significancesupporting

confidence: 70%

“…(5,6). The fundamental importance of FGFR to development is well proven by gain-of-function mutations that result in dwarfism in model organisms and in humans (7)(8)(9)(10). Deregulation of FGFR signaling through mutation, chromosomal translocation, and gene amplification or overexpression has been documented abundantly in numerous cancers (11).…”

Section: Significancementioning

confidence: 99%

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Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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Section: Significancesupporting

confidence: 70%

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

169

132

View full text Add to dashboard Cite

show abstract

“…We first investigated whether mFGFR1 is functional in zebrafish. Transient overexpression of the constitutively active mFGFR1‐IgG caused developmental malformations such as caudalization of the brain and the formation of a secondary axis, similar to a previously described constitutively active zebrafish FGFR115a (Figure 3 a, b). We next confirmed that injection of AdoCbl and mFGFR1‐MxCBD alone did not negatively impact animal development (Figure 3 c, d).…”

supporting

confidence: 80%

Green‐Light‐Induced Inactivation of Receptor Signaling Using Cobalamin‐Binding Domains

Kainrath

Stadler²,

Reichhart

et al. 2017

Angew Chem Int Ed

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Optogenetics and photopharmacology provide spatiotemporally precise control over protein interactions and protein function in cells and animals. Optogenetic methods that are sensitive to green light and can be used to break protein complexes are not broadly available but would enable multichromatic experiments with previously inaccessible biological targets. Herein, we repurposed cobalamin (vitamin B12) binding domains of bacterial CarH transcription factors for green‐light‐induced receptor dissociation. In cultured cells, we observed oligomerization‐induced cell signaling for the fibroblast growth factor receptor 1 fused to cobalamin‐binding domains in the dark that was rapidly eliminated upon illumination. In zebrafish embryos expressing fusion receptors, green light endowed control over aberrant fibroblast growth factor signaling during development. Green‐light‐induced domain dissociation and light‐inactivated receptors will critically expand the optogenetic toolbox for control of biological processes.

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“…6c-f), suggesting that fgfr1 and fgfr2 expression is essentially independent of the FGF signal during epiboly. The deformation of the fgfr2 domain in the paraxial mesoderm could be due to abnormal gastrulation caused by disruption of the FGF signaling, which was observed previously (Ota et al, 2009; cf. Fig.…”

Section: Regulation Of the Fgfr Genes By The Fgf Signalmentioning

confidence: 55%

“…Interestingly, when the FGF signal was disrupted by the overexpression of mdn-R3, a membrane-bound dominant-negative form of FGFR3c that strongly suppresses the entire FGF signal (Ota et al, 2009), fgfr1 and fgfr2 expression in the paraxial mesoderm was repressed, whereas their expression was largely unaffected in the anterior neuroepithelium (Fig. 7a,b,d,e).…”

Section: Regulation Of the Fgfr Genes By The Fgf Signalmentioning

confidence: 99%

FGF receptor gene expression and its regulation by FGF signaling during early zebrafish development

Ota¹,

Tonou-Fujimori²,

Nakayama³

et al. 2010

Genesis

Self Cite

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The expression of all four fgfr genes was extensively examined throughout early embryogenesis of the zebrafish (Danio rerio). fgfr1 alone was expressed maternally throughout the blastoderm, and then zygotically in the anterior neural plate and presomitic mesoderm. fgfr4 expression was first detected in late blastulae and was gradually restricted to the brain. fgfr2 and fgfr3 expression were initiated in early and late gastrulae, respectively; fgfr2 was expressed in the anterior neural plate and somitic mesoderm, whereas fgfr3 was activated in the axial mesoderm and then in the midbrain and somitic mesoderm. During somitogenesis, each of these fgfr genes was expressed in a characteristic manner in the brain. Using an FGF signal inhibitor, dominant-negative FGF receptors and fgf8.1/fgf8a mutants, we found that fgfr expression is directly or indirectly regulated by FGF signaling during epiboly and at the end of somitogenesis, revealing the presence of an autoregulatory mechanism.

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The roles of the FGF signal in zebrafish embryos analyzed using constitutive activation and dominant-negative suppression of different FGF receptors

Cited by 38 publications

References 86 publications

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Green‐Light‐Induced Inactivation of Receptor Signaling Using Cobalamin‐Binding Domains

FGF receptor gene expression and its regulation by FGF signaling during early zebrafish development

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