ライフサイエンスコーパス: FGFR4

1 FGF19 uniquely binds to FGF receptor 4 (FGFR4).

2 receptor 3 (FGFR3) but not FGFR1, FGFR2, or FGFR4.

3 ctively blocks the interaction of FGF19 with FGFR4.

4 increased the interactions between FGF19 and FGFR4.

5 ignancies involving interaction of FGF19 and FGFR4.

6 ever, only FGF19 signals efficiently through FGFR4.

7 that is also present in FGFR1c, FGFR3c, and FGFR4.

8 is unique in binding solely to one receptor, FGFR4.

9 s HCC development in a process that requires FGFR4.

10 t activity in PC lines expressing endogenous FGFR4.

11 lice forms of FGFR1 to -3 as well as towards FGFR4.

12 mutation was generated in FGFR1, FGFR3, and FGFR4.

13 embers of the FGF family, including Fgf6 and Fgfr4.

14 of FGF23 on aortic relaxation do not require FGFR4.

15 iation is modulated by 2 genetic variants in FGFR4.

16 able to activate FGFRs 1c, 2c and 3c but not FGFR4.

17 -regulated in human and mouse hepatomas than FGFR4.

18 nes expressing the empty vector or wild-type FGFR4.

19 FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1.

20 38-42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation

21 n were abolished, and betaKlotho-independent FGFR4 activation was preserved; therefore, FGF19dCTD is

22 FGFR4 activity in hepatocytes that normally serves to pr

23 ults demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe

24 The results show that FGFR4 acts by promotion of processes that restore hepato

25 Our findings highlight the importance of the FGFR4 allele in pNET progression and identify a predicti

26 nation for the unusual affinity of FGF19 for FGFR4 alone.

27 Ablation of FGFR4 also failed to correct hypophosphatemia in Hyp mic

28 The objective was to determine the role of FGFR4, an isotype that has been proposed to mediate an i

29 Factors required for FGF19 signaling (i.e., FGFR4 and betaKlotho) are expressed in mucosal epithelia

30 lesterol 7alpha-hydroxylase transcription by FGFR4 and cholate.

31 s-regulatory elements at promoter regions of Fgfr4 and Hes1, and regulates their expression.

32 also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR.

33 ax3 in head ectoderm is sufficient to induce FGFR4 and Ngn2 expression, but neurons do not differenti

34 ls for expression of the opV placode markers FGFR4 and Ngn2, maintenance of the preplacodal marker Ey

35 naling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes t

36 studies using TCGA data (e.g., SYNE1, KLF6, FGFR4, and EPHB4).

37 into C2C12 myotubes showed Tead2 to activate Fgfr4, and mutation of the M-CAT motif in the Fgfr4 prom

38 hate transporter, alphaKlotho, FGFR1, FGFR3, FGFR4, and the PTH receptor.

39 overexpressing constitutively active hepatic FGFR4--and FGFR4(-/-) with constitutively active hepatic

40 The results described herein suggest that FGFR4 antagonists alone, or in combination with other ag

41 eatment of diet-induce obese (DIO) mice with FGFR4 antisense oligonucleotides (ASO) specifically redu

42 Although Fgfr3 and Fgfr4 are expressed in the mesenchyme and epithelium, in

43 ced in myocardium, while receptors fgfr2 and fgfr4 are induced in adjacent epicardial-derived cells.

44 ates that unique sequences in both FGF19 and FGFR4 are key to the formation of the complex.

45 We show that aging mice lacking FGFR4 are protected from LVH.

46 F19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and

47 as no correlation between the presence of an FGFR4(arg) allele and CRC or polyp risk in 3,471 partici

48 erns to overexpress either the FGFR4(gly) or FGFR4(arg) alleles.

49 he stronger inducer of tumor growth, whereas FGFR4(arg) was the stronger inducer of migration.

50 mportant implication of our findings is that FGFR4(arg)-carriers are at a higher risk for more aggres

51 However, among 182 patients with CRC, FGFR4(arg)-carriers had a fivefold higher risk of tumors

52 streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation.

53 In addition, combination treatment with FGFR4 ASO and rimonabant showed additive reduction in BW

54 FGFR4 ASO treatment increased basal metabolic rate durin

55 tudies indicated that anti-obesity effect of FGFR4 ASO was mediated at least in part through an induc

56 Specific blockade of FGFR4 attenuates established LVH in the 5/6 nephrectomy

57 d to mediate an ileal FGF15/19 to hepatocyte FGFR4 axis in cholesterol homeostasis, in metabolic home

58 that FGF19 acts through the receptor complex FGFR4-beta-Klotho (KLB) to regulate bile acid metabolism

59 ll-free complexes of heparin and recombinant FGFR4 bound FGF-1 and FGF-2 equally.

60 filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explai

61 ion of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a

62 reted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase.

63 both FGF19 and FGF21 bind to the betaKlotho-FGFR4 complex; however, only FGF19 signals efficiently t

64 that the kinase domains of FGFR1, FGFR3, and FGFR4 containing the activation loop mutation, when targ

65 These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific funct

66 Therefore, FGFR4 could be a potential novel target and antisense re

67 These findings highlight that FGF19/FGFR4 cross-talk with beta-catenin and that pathway inte

68 Surprisingly, the FGFR4 deficiency alleviated high-fat diet-induced fatty

69 Here, we show that FGFR4 deficiency in mice leads to improvement in glucose

70 of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular

71 ure resulted in severe fibrosis in livers of FGFR4-deficient mice compared to normal mice.

72 Following acute CCl(4) exposure, the FGFR4-deficient mice exhibited accelerated liver injury,

73 protein levels indicated an 8-hour delay in FGFR4-deficient mice in the down-regulation of cytochrom

74 FGFR4-deficient mice on a normal diet exhibited features

75 Mechanism of action studies in FGFR4-deficient mice suggest that the effects are mediat

76 ion of FGFR4, specifically in hepatocytes of FGFR4-deficient mice, decreased plasma lipid levels and

77 both acute and chronic exposure to CCl(4) in FGFR4-deficient mice.

78 A model for the complex of FGF19 with FGFR4 demonstrates that unique sequences in both FGF19 a

79 unique FGF19 molecule specifically activated FGFR4-dependent signaling in liver and suppressed CYP7A1

80 nally, we demonstrate that FGFR1, FGFR3, and FGFR4 derivatives can stimulate PI-3 kinase activity.

81 supports the unique intersection of KLB and FGFR4 distribution in liver.

82 Conclusion: The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of S

83 sults established that both allelic forms of FGFR4 exert an oncogenic impact and may serve equally we

84 Here we show that livers of mice lacking FGFR4 exhibited normal morphology and regenerated normal

85 el target and antisense reduction of hepatic FGFR4 expression could be an efficacious therapy as an a

86 ude that HNF1alpha is a major determinant of FGFR4 expression in PC.

87 Higher FGFR4 expression in RMS tumors was associated with advan

88 nable to activate signaling in adipose where FGFR4 expression is very low.

89 nucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in b

90 ed with FGFR1 expression being lost, whereas FGFR4 expression was expanded beyond its normal expressi

91 F15 level resulted from reduction of hepatic FGFR4 expression.

92 xpression of various markers including Pax3, FGFR4, Eya2, and the neuronal differentiation markers Is

93 Here we show that in Fgfr3;Fgfr4 (Fgfr3;4) global mutant mice, alveolar simplificat

94 equally well to complexes of both FGFR1 and FGFR4 formed with endothelial cell-derived HSPG, but the

95 Fibroblast growth factor receptor 4 (FGFR4), Frizzled 9 (Fz9), and SRY box-containing gene 2

96 inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin.

97 BON1 cells and transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of a

98 Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished

99 examined the chromatin structure around the FGFR4 gene in a panel of expressing and non-expressing P

100 We established the FGFR4 genotype of 71 patients with pNETs and correlated

101 xpression patterns to overexpress either the FGFR4(gly) or FGFR4(arg) alleles.

102 importance for both polymorphic alleles, but FGFR4(gly) was the stronger inducer of tumor growth, whe

103 Fgfr4 has been shown to be important for appropriate mus

104 The deletion of FGFR4 has no effect on the proliferative response of hep

105 fically assess the impact of the polymorphic FGFR4 in colorectal cancer (CRC), we engineered CRC cell

106 The structures of FGFR4 in complex with the type I inhibitor Dovitinib and

107 we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation an

108 We also show that expression of FGFR4 in liver was decreased by fasting, increased by in

109 st that pericellular matrix-controlled liver FGFR4 in particular may ensure adequate cholesterol for

110 pport the potential therapeutic targeting of FGFR4 in RMS.

111 but FGF19 was able to interact directly with FGFR4 in the absence of betaKlotho in a heparin-dependen

112 osine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes.

113 FGFR type 4 (FGFR4) in liver parenchymal cells binds only FGF-1, wher

114 tion of fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues.

115 role of fibroblast growth factor receptor 4 (FGFR4) in regulating bile acid synthesis has been well d

116 s the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellul

117 sent four structures of the kinase domain of FGFR4, in its apo-form and in complex with different typ

118 Because the ablation of neither FGFR3 nor FGFR4 inhibited the renal effects of excess FGF23, the k

119 activation, Taqman analyses show that FGF19/FGFR4 inhibition reduced beta-catenin target gene (cycli

120 erated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design.

121 may assist in the design and development of FGFR4 inhibitors.

122 ponse to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of b

123 ce that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulatio

124 Coordinate expression of betaklotho and FGFR4 is a property of mature hepatocytes.

125 FGF signaling through receptors Fgfr3 and Fgfr4 is crucial for alveologenesis, but the mechanisms

126 inition of liver from foregut endoderm where FGFR4 is expressed and stimulation of hepatocyte DNA syn

127 r FGF receptor (FGFR) tyrosine kinases, only FGFR4 is expressed in mature hepatocytes.

128 GF) receptor genes expressed in adult liver, FGFR4 is expressed specifically in mature hepatocytes.

129 The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a ro

130 FGFR4 is involved in myogenesis and muscle regeneration.

131 the endoderm implies that signaling through FGFR4 is involved in specifying lung versus liver.

132 comes highly abnormal at the time point when Fgfr4 is normally expressed.

133 lated transmembrane tyrosine kinase receptor FGFR4 is the major FGFR isotype in mature hepatocytes.

134 FGFR4 is the major hepatic FGF receptor isoform and is r

135 These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepato

136 In summary, neither FGFR3 nor FGFR4 is the principal mediator of FGF23 effects in the

137 We have shown that FGFR4 is widely distributed in mouse, whereas KLB distri

138 in of the fibroblast growth factor receptor (FGFR4) is associated with increased risk, staging, and m

139 Fibroblast growth factor receptor 4 (FGFR4) is expressed in 50-70% of pancreatic carcinomas (

140 cturally characterized, the structure of the FGFR4 kinase domain has not yet been reported.

141 The two apo-FGFR4 kinase domain structures show an activation segmen

142 ther endocrine FGF19 or cellular FGF1 of the FGFR4 kinase in a complex with betaklotho restricts cell

143 The FGF19-FGFR4-KLB pathway links regulation of BA synthesis to co

144 vanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor g

145 number of ki67-positive nuclei is reduced in FGFR4 knockdown tumor xenograft tissues.

146 FGFR4 knockdown using inducible short hairpin RNA signif

147 of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5.

148 Mutations affecting the kinase domain of FGFR4 may cause cancer, for example, breast cancer or rh

149 The mechanism underlying the FGFR4-mediated hepatoma suppression has not been address

150 ate that FGF signalling, via FGF receptor 4 (Fgfr4), mediates a signal-transduction pathway between W

151 However, the FGFR4 (-/-) mice exhibited depleted gallbladders, an ele

152 ent, cholesterol-induced hepatomegaly in the FGFR4 (-/-) mice suggested that activation of receptor i

153 FGFR4(-/-) mice-mice overexpressing constitutively activ

154 RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apo

155 inically actionable genes including gains of FGFR4 (n = 6 [30%]), FLT1 (n = 4 [20%]), AURKA (n = 2 [1

156 t exogenous expression of HNF1 factors in an FGFR4 non-expressing line led to an induction of enhance

157 t staged induction of muscle regeneration in Fgfr4 null mice becomes highly abnormal at the time poin

158 cle development in chick limb buds; however, Fgfr4 null mice show no phenotype.

159 Genetic deletion of FGFR4 or betaklotho in mice disrupts hepatic cholesterol

160 ll four tyrosine kinase FGF receptors (FGFR1-FGFR4), other members demonstrate a higher degree of sel

161 The betaklotho-FGFR4 partnership caused a depression of activated AKT a

162 Thus the same betaklotho-heparan sulfate-FGFR4 partnership that mediates endocrine control of hep

163 Our data suggest a novel MyoD-Tead2-Fgfr4 pathway important for effective muscle regeneratio

164 suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve

165 To determine whether FGFR4 plays a broader role in liver-specific metabolic f

166 FGFR4 plays essential roles in systemic lipid and glucos

167 gfr4, and mutation of the M-CAT motif in the Fgfr4 promoter abolished these effects.

168 The Fgfr4 promoter region contained a Tead protein binding s

169 Co-transfection of Tead2 and Fgfr4 promoter reporter constructs into C2C12 myotubes s

170 These results show that hepatocyte FGFR4 protects against acute and chronic insult to the l

171 Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished responsivene

172 FGFR4-R388 is associated with more aggressive clinical b

173 thotopic mouse xenograft model, we show that FGFR4-R388 promotes tumor progression by increasing intr

174 d transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of action and to e

175 n in response to everolimus in patients with FGFR4-R388.

176 Chimeric FGFR1c/FGFR4 receptors were constructed to identify domains tha

177 uction during regeneration commensurate with Fgfr4 regulation.

178 GFR4(-/-) with constitutively active hepatic FGFR4 restored in the liver were subjected to a normal a

179 from liver cells in cell-free complexes with FGFR4 restored the specificity for FGF-1 and supported t

180 SNPs of fibroblast growth factor receptor 4 (FGFR4) revealed that rs1966265 (Val10Ile) and rs351855 (

181 2E1 rs6413432, ERCC1 rs11615, ERCC2 rs13181, FGFR4 rs351855, HYKK rs931794, MIR146A rs2910164, MIR196

182 Further, FGF19 activated FGFR4 signaling in the presence or absence of betaKlotho

183 together, our data highlight a role of FGF23/FGFR4 signaling in the regulation of cardiac remodeling

184 rmacological interference with cardiac FGF23/FGFR4 signaling might protect from CKD- and age-related

185 in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis a

186 on was preserved; therefore, FGF19dCTD is an FGFR4-specific activator.

187 Restoration of FGFR4, specifically in hepatocytes of FGFR4-deficient mi

188 n of Wnt target GLUL, pharmacological target FGFR4, stemness markers EPCAM and KRT19 and immune check

189 d hepatocellular carcinomas, indicating that FGFR4 suppresses hepatoma proliferation.

190 (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver.

191 otho not only interacts with heparan sulfate-FGFR4 to form a complex with high affinity for endocrine

192 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7alpha hydroxylase (CYP7A1

193 Here we determine the sites of FGFR4 transcriptional initiation which show a pattern ch

194 nine (R) for glycine (G) in codon 388 of the FGFR4 transmembrane domain.

195 Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among

196 Recently, we showed that mice in which FGFR4 was ablated from the germline exhibited elevated c

197 Genetic variation in FGFR4 was associated with AC t((1/2)) in response to CDC

198 found that posterior expression of FGFR1 and FGFR4 was dependent on the expression of RARalpha2.

199 ever, in contrast to FGFR1, when recombinant FGFR4 was expressed back in epithelial cells by transfec

200 aluation of clinical specimens revealed that FGFR4 was upregulated in 20/71 patients independent of g

201 to dissect the molecular pathways involving Fgfr4, we queried the promoter sequences for transcripti

202 Fgfr4, which encodes the likely receptor for both FGF19

203 y, FGF23 increases cardiac contractility via FGFR4, while known effects of FGF23 on aortic relaxation

204 ing constitutively active hepatic FGFR4--and FGFR4(-/-) with constitutively active hepatic FGFR4 rest