ライフサイエンスコーパス: HJV

1 ly attenuated in the absence of hemojuvelin (Hjv).

2 g in hh are hepcidin (HAMP) and hemojuvelin (HJV).

3 It interacts with hemojuvelin (HJV).

4 modulated by the BMP coreceptor hemojuvelin (HJV).

5 e examined the trafficking and processing of HJV.

6 presses hepcidin expression independently of HJV.

7 uscle and liver could be the source of serum HJV.

8 We suggest that it be designated HJV.

9 critical for the iron regulatory function of HJV.

10 r of hepatic hepcidin expression and cleaves HJV.

11 gosaccharides to complex oligosaccharides on HJV.

12 8), which produces one major soluble form of HJV.

13 s HJV, leading to a decrease in cell surface HJV.

14 exerts its inhibitory effect by inactivating HJV.

15 deficient for both Tmprss6 and hemojuvelin (Hjv), a BMP coreceptor that augments hepcidin expression

16 It interacts with hemojuvelin (HJV), a BMP coreceptor that plays a pivotal role in hepa

17 hepcidin production by cleaving Hemojuvelin (Hjv), a key modulator of hepcidin expression, from the h

18 dies demonstrate that neogenin may stabilize HJV, a glycosylphosphatidylinositol-anchored protein tha

19 not Mt2S762A, had reduced interactions with Hjv, ActRIIA, and Hfe.

20 Cellular HJV acts as a BMP co-receptor to enhance the transcripti

21 Membrane-anchored HJV acts as a coreceptor for bone morphogenetic proteins

22 of the hepcidin-induction pathway, including Hjv, Alk3, ActRIIA, and Hfe, when overexpressed in hepat

23 iron overload similar to mice deficient for Hjv alone.

24 eficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2.

25 HJV also binds neogenin, a membrane protein widely expre

26 HJV also interacts with neogenin, a ubiquitously express

27 Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C,

28 ons in the recently cloned hemojuvelin gene (HJV; also called HFE2), whereas Type 2B HH is caused by

29 Hemojuvelin (HJV; also called repulsive guidance molecule c, RGMC) is

30 iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signa

31 neogenin interacted with MT2 as well as with HJV and facilitated the cleavage of HJV by MT2.

32 mplished by the binding of Mt2 ectodomain to Hjv and Hfe.

33 93 cells and characterized the processing of HJV and its effect on iron homeostasis.

34 Both HJV and neogenin were expressed in liver hepatocytes.

35 ctRIIA, Bmpr2, Hfe, and, to a lesser extent, Hjv and Tfr2.

36 independently of each other, we intercrossed Hjv(-/-) and Bmp6(-/-) mice and compared the phenotype o

37 Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential

38 Cells co-transfected with hemojuvelin (HJV) and matriptase-2 (MT-2) were used as a model to inv

39 Hemojuvelin (HJV) and matriptase-2 (MT2) are co-expressed in hepatocy

40 m iron challenge in iron-depleted Hfe, Tfr2, Hjv, and Bmp6 mutant mice.

41 Mutations in HFE, HJV, and TfR2 cause autosomal-recessive forms of hemochr

42 ic BMP6 expression by iron is independent of HJV, and that expression of HJV in hepatocytes plays an

43 Soluble HJV antagonizes bone morphogenetic protein signaling and

44 Mutations in HJV are implicated in the majority of diagnosed juvenile

45 rine hepcidin, because these molecules, like Hjv, are known to be involved in hepcidin signaling.

46 gh a receptor complex requiring hemojuvelin (HJV) as a co-receptor.

47 BMPs), apparently by binding to hemojuvelin (Hjv) as a coreceptor and signaling through Smad4.

48 sent work, we show that matriptase-2 cleaves HJV at Arg(288), which produces one major soluble form o

49 in forms a ternary complex with both MT2 and HJV at the plasma membrane.

50 ntrations transmitted through HFE, TfR2, and HJV augment BMP receptor sensitivity to BMPs.

51 ng complex oligosaccharides, indicating that HJV avoided Golgi processing.

52 t a model in which retrograde trafficking of HJV before cleavage is the predominant processing pathwa

53 Further analyses suggest that the Hjv binding triggered the cleavage of the Neo1 cytoplasm

54 nal studies revealed that in addition to the Hjv-binding domains, the function of Neo1 also required

55 HJV binds BMP6 and increases hepcidin expression presuma

56 vivo studies validated the important role of HJV-BMP interaction for Hjv stimulation of BMP signaling

57 mechanism underlying neogenin regulation of HJV-BMP signaling.

58 as a scaffold to facilitate assembly of the HJV.BMP.BMP receptor complex to induce hepcidin expressi

59 TfR2, HJV, BMP6, and, to a lesser extent, HFE are required for

60 Surprisingly, although cleavage of HJV by furin has been implicated in the regulation of HJ

61 lso been shown to facilitate the cleavage of HJV by furin in transfected cells.

62 as with HJV and facilitated the cleavage of HJV by MT2.

63 HJV can be cleaved by the furin family of proprotein con

64 Crystallography studies indicate that HJV can simultaneously bind to both BMP2 and the ubiquit

65 While HJV can use all 3 BMP type I receptors (ALK2, ALK3, and

66 These studies confirm that mutations in HJV cause juvenile hemochromatosis.

67 ne encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low h

68 Mutations in hemojuvelin (HJV) cause severe, early-onset juvenile hemochromatosis.

69 In this study, we stably transfected HJV cDNA into human embryonic kidney 293 cells and chara

70 The complex facilitates HJV cleavage by MT2, and release of the cleaved HJV from

71 HJV co-immunoprecipitated with neogenin, a receptor invo

72 nistration of a recombinant, soluble form of HJV decreased hepcidin expression and increased serum ir

73 Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or

74 We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammati

75 Hemojuvelin (HJV), encoded by the gene HFE2, is a critical upstream r

76 cholesterol depletion by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-me

77 of cellular HJV release, and stimulation of HJV-enhanced hepcidin expression.

78 ors ActRIIA and BMPRII, but not ActRIIB, and HJV enhances utilization of ActRIIA by BMP-2 and BMP-4.

79 4-induced hepcidin mRNA levels by 16-fold in HJV-expressing HepG2 cells but only by about 2-fold in c

80 In contrast to MT2, increased Hjv expression caused no significant changes in wild-typ

81 HJV expression is detected in hepatocytes, as well as in

82 e demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidi

83 pression in vitro and that administration of HJV.Fc decreases hepcidin expression, increases ferropor

84 In vivo, HJV.Fc or a neutralizing antibody to BMP6 inhibits hepci

85 We also show that soluble hemojuvelin (HJV.Fc) selectively inhibits BMP induction of hepcidin e

86 show that compared with soluble hemojuvelin (HJV.Fc), the homologous DRAGON.Fc is a more potent inhib

87 These data suggest that, in Hjv(-/-) females, Bmp6 can provide a signal adequate to

88 cting as a decoy that competes with membrane HJV for BMP ligands.

89 s required for the processing and release of HJV from cells.

90 nizes hepcidin induction by BMPs by cleaving HJV from the cell membrane.

91 cleavage by MT2, and release of the cleaved HJV from the cell occurs after a retrograde trafficking

92 rin has been implicated in the regulation of HJV function in cell culture models and furin-cleaved so

93 In addition, the HJV G320V mutant implicated in Type 2A HH did not co-imm

94 We have disrupted the murine Hjv gene and shown that Hjv-/- mice have markedly increa

95 nsferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes.

96 We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associa

97 HJV has also been demonstrated to bind to neogenin, but

98 This shed form of HJV has decreased ability to bind BMP6 and does not supp

99 Patients with HJV hemochromatosis have low urinary levels of hepcidin,

100 e three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and Tf

101 The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphat

102 Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate

103 in as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for th

104 ad in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes

105 MT2 regulates the levels of membrane-bound HJV in hepatocytes by binding to and cleaving HJV into a

106 Expression of HJV in hepatocytes of Hjv(-/-) mice using an AAV2/8 vect

107 s independent of HJV, and that expression of HJV in hepatocytes plays an essential role in hepcidin e

108 BMP-4, and BMP-6 are endogenous ligands for HJV in hepatoma-derived cell lines, and that all 3 of th

109 er the stimulation of hepcidin expression by Hjv in mice.

110 Expression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuate

111 We characterized the role of hepatocyte HJV in the regulation of BMP6 and hepcidin expression.

112 6 (BMP6) or the BMP coreceptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin

113 Secreted HJV, in contrast, has complex oligosaccharides and can b

114 pound heterozygous mutations in hemojuvelin (HJV), including a termination codon, in a patient with j

115 Finally, we show that HJV-induced BMP signaling and hepcidin expression are no

116 55Fe accumulation studies indicated that the HJV-induced increase in intracellular iron levels in hum

117 monstrated that this process depends on Neo1-Hjv interaction and showed that the Hjv-mediated hepcidi

118 However, the role of the neogenin-HJV interaction in the function of HJV is unknown.

119 These observations indicate that Neo1-Hjv interaction is essential for hepcidin expression.

120 ue to the inhibition of cell surface MT2 and HJV internalization.

121 JV in hepatocytes by binding to and cleaving HJV into an inactive soluble form that is released from

122 HJV is a bone morphogenetic protein (BMP) coreceptor and

123 is is consistent with the current views that HJV is a coreceptor for BMP6 in hepatocytes.

124 HJV is a glycosylphosphatidylinositol-linked membrane pr

125 Our results indicate that HJV is a glycosylphosphatidylinositol-linked protein and

126 Previous studies demonstrated that HJV is a GPI-anchored protein, binds the proteins neogen

127 ell culture models and furin-cleaved soluble Hjv is detectable in the serum of mice, mutating the fur

128 smembrane domains of Hfe are sufficient, and Hjv is essential, for Hfe-mediated induction of hepcidin

129 diated induction of hepcidin expression when HJV is expressed.

130 HJV is highly expressed in both skeletal muscle and live

131 t changes in wild-type mice, suggesting that Hjv is not a limiting factor for hepcidin expression.

132 The normal function of HJV is unknown.

133 neogenin-HJV interaction in the function of HJV is unknown.

134 Hemojuvelin (HJV) is a coreceptor for bone morphogenetic protein (BMP

135 Hemojuvelin (HJV) is a glycosylphosphatidylinositol-linked protein an

136 Hemojuvelin (HJV) is an important regulator of iron metabolism.

137 Its encoded protein, hemojuvelin (HJV), is a co-receptor for the bone morphogenetic protei

138 RGMc, also called hemojuvelin (HJV), is essential for iron homeostasis.

139 Similarly, RPE cells from hemojuvelin (Hjv)-knockout mice, another model of hemochromatosis, al

140 ndicate that matriptase-2 binds and degrades HJV, leading to a decrease in cell surface HJV.

141 favor a model in which Neo1 interaction with Hjv leads to accumulation of cleaved Neo1 on the plasma

142 To determine whether BMP6 and HJV may also signal to hepcidin independently of each ot

143 These results demonstrate that recombinant HJV may be a useful therapeutic agent for treatment of t

144 Thus, HJV-mediated BMP signaling and hepcidin regulation occur

145 on Neo1-Hjv interaction and showed that the Hjv-mediated hepcidin expression is correlated with the

146 Furthermore, iron depletion in Hjv(-/-) mice decreased hepatic BMP6 mRNA.

147 Unlike wild-type mice, Hjv(-/-) mice developed lethal plague when challenged wi

148 These results indicate that Hjv(-/-) mice do not lack BMP6.

149 xpression of this mutant Hjv in the liver of Hjv(-/-) mice dramatically attenuated its induction of B

150 ling and hepcidin expression in the liver of Hjv(-/-) mice of both sexes, and led to iron accumulatio

151 decreased hepatic and splenic ferroportin in Hjv(-/-) mice on standard or iron-deficient diet, but on

152 Expression of HJV in hepatocytes of Hjv(-/-) mice using an AAV2/8 vector, increased hepatic

153 Immunization of Hjv(-/-) mice with a subunit vaccine that blocks Y. pest

154 In Hjv(-/-) mice, increased expression of exogenous MT2 in

155 y decreased serum iron in hepcidin-deficient Hjv(-/-) mice, model of hemochromatosis.

156 crease of hepcidin was seen in Bmp6(-/-) and Hjv(-/-) mice.

157 In HJV-null (Hjv(-/-)) mice that have severe iron overload and marked

158 We used hemojuvelin-knockout (Hjv(-/-)) mice to examine whether iron-storage disease r

159 disrupted the murine Hjv gene and shown that Hjv-/- mice have markedly increased iron deposition in l

160 In Hjv-/- mice, expression of HjvA183R mutant that has redu

161 Hepcidin mRNA expression was decreased in Hjv-/- mice.

162 mice showed nearly no increase, and Tfr2 and Hjv mutant mice showed no increase in hepcidin expressio

163 e morphogenetic protein (BMP) coreceptor and HJV mutants have impaired BMP signaling.

164 ase of the cytoplasmic domain of Neo1 in the Hjv-Neo1 complex.

165 ogenin-mediated HJV release occurs after the HJV-neogenin complex is internalized from the cell surfa

166 Together, these results suggest that the HJV-neogenin interaction is required for the BMP-mediate

167 her studies indicated that disruption of the HJV-neogenin interaction is responsible for a marked sup

168 meostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2)

169 In HJV-null (Hjv(-/-)) mice that have severe iron overload

170 odels of hemochromatosis (HFE-null mouse and HJV-null mouse) and in two nongenetic models of iron ove

171 n with siRNA increased the amount of MT2 and HJV on the plasma membrane, suggesting a lack of neogeni

172 involved either in retrograde trafficking of HJV or in cleavage leading to HJV release.

173 usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP).

174 transferrin receptor 2 (Tfr2), hemojuvelin (HJV), or bone morphogenetic protein 6 (BMP6) prevent app

175 e to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand c

176 Both NEO1 and HJV play pivotal roles in iron homeostasis by inducing h

177 Cellular HJV reached the plasma membrane without obtaining comple

178 ng that knock-down of endogenous neogenin, a HJV receptor, in C2C12 cells suppresses HJV shedding and

179 udy we characterized the role of neogenin in HJV-regulated hepcidin expression.

180 Hemojuvelin (HJV) regulates iron homeostasis by direct interaction wi

181 n of endogenous neogenin markedly suppresses HJV release but has no evident effect on HJV trafficking

182 The additional findings that HJV release is coupled to lysosomal degradation of neoge

183 d HJV release suggest that neogenin-mediated HJV release occurs after the HJV-neogenin complex is int

184 n by filipin blocks both HJV endocytosis and HJV release suggest that neogenin-mediated HJV release o

185 ssesses two functions, mediation of cellular HJV release, and stimulation of HJV-enhanced hepcidin ex

186 ogenin ectodomain to cells markedly inhibits HJV release, indicating that the HJV shedding is not pro

187 trafficking of HJV or in cleavage leading to HJV release.

188 Earlier studies suggest that the function of HJV relies on its interaction with NEO1.

189 nations of BMP ligands and receptors used by HJV remain unknown.

190 Release of HJV requires it to bind to the transmembrane receptor ne

191 FE2), which encodes the protein hemojuvelin (HJV), result in the absence of hepcidin and an early-ons

192 n hemojuvelin/repulsive guidance molecule c (HJV/RGMc) cause juvenile hemochromatosis (JH), a rapidly

193 are seen in Hfe(-/-) RPE cells as well as in Hjv(-/-) RPE cells, providing a molecular basis for the

194 hyperproliferative phenotype of Hfe(-/-) and Hjv(-/-) RPE cells.

195 al role in iron homeostasis by regulation of HJV secretion and bone morphogenetic protein (BMP) signa

196 We demonstrate in vitro that HJV selectively uses the BMP type II receptors ActRIIA a

197 up-regulation of TMPRSS6 increases membrane HJV shedding and decreases hepcidin promoter responsiven

198 n, a HJV receptor, in C2C12 cells suppresses HJV shedding and that overexpression of neogenin in HEK2

199 ot support that Neo1 functions by inhibiting Hjv shedding as previously proposed.

200 ith the observations in iron-deficient rats, HJV shedding in these cell lines was down-regulated by h

201 nhances this process, suggests that membrane HJV shedding is mediated by neogenin.

202 ly inhibits HJV release, indicating that the HJV shedding is not processed before trafficking to the

203 or its antagonist, noggin, was able to alter HJV shedding support the lack of involvement of BMP sign

204 uman hepatoma cell line) cells showed active HJV shedding, implying that both skeletal muscle and liv

205 significance and the underlying mechanism of HJV shedding.

206 he important role of HJV-BMP interaction for Hjv stimulation of BMP signaling and hepcidin expression

207 y associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the m

208 cted with either empty vector or G99V mutant HJV that does not bind BMPs.

209 Here we identify a mutation in HJV that specifically lowers its interaction with neogen

210 onvertases, which releases a soluble form of HJV that suppresses BMP signaling and hepcidin expressio

211 results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intra

212 Neogenin does not, however, play a role in HJV trafficking to the cell surface, suggesting that it

213 ses HJV release but has no evident effect on HJV trafficking to the plasma membrane.

214 The role that neogenin plays in HJV trafficking was investigated, using HepG2 cells, a h

215 Membrane-anchored HJV up-regulates expression of the iron regulatory hormo

216 The increase in MT2 and HJV upon neogenin knockdown was likely due to the inhibi

217 ucing bone morphogenetic protein co-receptor HJV via inhibition of the membrane-bound serine protease

218 des showed that MT2 cleavage of cell surface HJV was coupled to a transition from high mannose oligos

219 Hemojuvelin (HJV) was recently identified as a critical regulator of

220 eo1L1046E mutant that does not interact with Hjv, was unable to correct the decreased hepcidin expres

221 Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE

222 nship, 2 previously undescribed mutations of HJV were identified, c.238T>C (C80R) and c.302T>C (L101P

223 of their interaction and the interaction of HJV with BMP-2.

224 ly suppressed by blocking the interaction of HJV with full-length neogenin with a soluble fragment of

225 lex oligosaccharides and can be derived from HJV with high-mannose oligosaccharides at the plasma mem

226 we detected an early phase increase of serum HJV with no significant change of either HFE2 mRNA or pr