ライフサイエンスコーパス: sortilin

1 anism involving NTR1 and NTR3 (also known as sortilin).

2 R) receptors and cell death via p75(NTR) and Sortilin.

3 her ATZ levels and secretion are affected by sortilin.

4 he common neurotrophin receptor (p75NTR) and sortilin.

5 nt mannose-6-phosphate receptor (CI-MPR) and sortilin.

6 ortilin that impair lysosomal degradation of sortilin.

7 ation of proNGF interactions with p75NTR and sortilin.

8 nsulin-responsive aminopeptidase (IRAP), and sortilin.

9 and required both p75NTR and its coreceptor sortilin.

10 ng to p75 neurotrophin receptor (p75NTR) and sortilin.

11 ed neurons, and recombinant proBDNF binds to sortilin.

12 ed cells by double transfection of Glut4 and sortilin.

13 er receptors macrophage mannose receptor and sortilin.

14 se 2-dependent C-terminal phosphorylation of sortilin.

15 at was independent of the endocytic receptor sortilin.

16 on, indicating a primary role of SMC-derived sortilin.

17 found that the cellular trafficking receptor sortilin 1 (Sort1) inhibits hepatic apolipoprotein B sec

18 Sortilin 1 (SORT1) is a lysosomal trafficking receptor t

19 The cellular trafficking receptor sortilin 1 (Sort1) was recently identified to transport

20 tional TDP-43 was measured by monitoring the sortilin 1 mRNA splicing activity.

21 Sortilin 1 regulates the levels of brain progranulin (PG

22 nd markedly increased expression of the gene sortilin-1 (SORT1) in liver.

23 sclerotic cardiovascular disease is the 1p13 sortilin-1 (SORT1) locus.

24 ssociated with altered expression of hepatic sortilin-1 (SORT1), which encodes a protein thought to b

25 led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride

26 icamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemi

27 ray identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity

28 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride se

29 et models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and a

30 mice reduced ER stress and increased hepatic sortilin-1 levels.

31 Furthermore, we identify sortilin-1(Sort1), a known regulator of circulating low-

32 orebrain-derived inhibitors, one of which is sortilin, a lysosomal sorting receptor.

33 This revealed that the protein is sortilin, a novel membrane protein that was cloned in an

34 n component of Glut4-containing vesicles, is sortilin, a novel type I receptor-like protein recently

35 Here we investigated whether sortilin, a Vps10p domain-sorting receptor believed to p

36 Understanding the mechanism by which sortilin affects LDL cholesterol will increase our under

37 Here we demonstrated that sortilin also directly affects atherogenesis, independen

38 bind beta-amyloid effector proteins such as sortilin and 14-3-3.

39 significantly reduces cell surface-expressed sortilin and abolishes proneurotrophin-induced neuronal

40 Both sortilin and BDNF are trafficked to and degraded by the

41 rotein consisting of the cytoplasmic tail of sortilin and EGFP is co-localized with ectopically expre

42 ilin and the cytoplasmic interaction between sortilin and GGA adaptors play an important role in recr

43 lin signaling but decreases the stability of sortilin and Glut4 and blocks their entry into the small

44 However, double expression of sortilin and Glut4 reconstitutes functional GSVs that in

45 Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2.

46 hypothesized that overexpression of proNGF, sortilin and p75(NTR) play a role in ts1-induced neurode

47 We found that complex formation between sortilin and p75(NTR) relies on contact points in the ex

48 To identify the interaction site between sortilin and p75(NTR), we analyzed binding between chime

49 l apoptosis using a dual receptor complex of sortilin and p75(NTR).

50 Here, we explore the expression of pro-NGF, sortilin and p75NTR in the mouse lumbar dorsal root gang

51 induce apoptosis of cells coexpressing both sortilin and p75NTR, suggesting that interaction of proB

52 In sympathetic neurons coexpressing sortilin and p75NTR, we found that proBDNF is an apoptot

53 that a subpopulation of neurons coexpresses sortilin and p75NTR.

54 , addition of preformed complexes of soluble sortilin and proBDNF failed to induce apoptosis of cells

55 levels of p75(NTR) and its interaction with sortilin and proNGF set the dependency on BDNF for survi

56 nd direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors t

57 Also, sortilin and SorLA both bind and mediate internalization

58 replicated the interaction between PGRN and sortilin and that between TNF and TNFRI/II, but not the

59 at the lumenal interaction between Glut4 and sortilin and the cytoplasmic interaction between sortili

60 mote apoptosis by engaging in a complex with sortilin and the p75 neurotrophin receptor (p75(NTR)).

61 The data provide a link between sortilin and the pathological findings of microglia and

62 a to disrupted interactions between PGRN and Sortilin and/or other binding partners yet to be identif

63 SORT1 encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism

64 liver is independent of mannose 6-phosphate, sortilin, and Limp2.

65 ized storage vesicles containing IRAP, LRP1, sortilin, and VAMP2, which are sequestered by TUG, Ubc9,

66 We suggest that sortilin- and retromer-mediated Glut4 retrieval from end

67 In addition, sortilins are required for delivery of a key protease in

68 Our studies suggest a new function for sortilin as a modulator of BACE1 retrograde trafficking

69 We here identify sortilin as a novel APP interaction partner.

70 Together, our findings identified sortilin as an essential neuronal pathway for APOE-conta

71 we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APO

72 ether, these data reveal TrkA, p75(NTR), and sortilin as potential therapeutic targets in thyroid can

73 the non-neuronal isoforms, leaving SorLA and sortilin as the only receptors for sAPP generated by neu

74 Together, our findings establish sortilin, as a novel APP interaction partner that influe

75 caused a 1.7-fold increase in the amount of sortilin at the plasma membranes of 3T3-L1 adipocytes, a

76 he life span of the Tg mice, suggesting that sortilin, at least in part, inhibits forebrain tau prion

77 on cellular coexpression of both p75NTR and sortilin, because neurons deficient in p75NTR are resist

78 as biosynthetic analysis, we discovered that sortilin binds and stabilizes APLP2, and hence could reg

79 Sortilin binds APOE with high affinity.

80 tent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles i

81 However, sortilin binds to numerous ligands and plays a major rol

82 l loop of Glut4, and the cytoplasmic tail of sortilin binds to retromer.

83 ed apoptosis, and competitive antagonists of sortilin block sympathetic neuron death.

84 of the LDLR independently of either APLP2 or sortilin both ex vivo and in mice.

85 eriments reveal that the cytoplasmic tail of sortilin, but not those from other VPS10p domain recepto

86 Sortilin can impact the intracellular response to brain-

87 A truncated form of sortilin causes BDNF missorting to the constitutive secr

88 Furthermore, sortilin co-localizes with, and enhances accumulation of

89 njury; however, the majority of small p75NTR-sortilin coexpressing neurons are lost 25 days after sci

90 for the p75 neurotrophin receptor (p75(NTR))-sortilin complex.

91 hat sortilin interacts with BACE1 and that a sortilin construct lacking its cytoplasmic domain, which

92 e in neurons, and this is dependent upon the sortilin cytoplasmic tail.

93 found that siRNA against TrkA, p75(NTR), and sortilin decreased cell survival and cell migration thro

94 Knockdown of sortilin decreases both formation of GSVs and insulin-re

95 duced atherosclerosis, we found no effect of sortilin deficiency on macrophage recruitment or lipopol

96 Macrophage sortilin deficiency protects against atherosclerosis by

97 etermine the mechanism by which hematopoetic sortilin deficiency reduced atherosclerosis, we found no

98 ether this effect was a result of macrophage sortilin deficiency, we transplanted Sort1(-/-);LDLR(-/-

99 espite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain li

100 Additionally, transfer of sortilin-deficient BM cells to irradiated atheroscleroti

101 Transfer of sortilin-deficient BM into irradiated atherosclerotic mi

102 In contrast, sortilin-deficient macrophages had significantly reduced

103 Altogether, sortilin defines a pathway required for optimal intracel

104 ficking switch to impair lysosomal-dependant sortilin degradation and to redistribute sortilin to the

105 ontrast, the tagged luminal Vps10p domain of sortilin demonstrates partial co-localization with Glut4

106 Thus sortilin-dependent as well as sortilin-independent sorti

107 mpathetic neuron death that is p75(NTR)- and sortilin-dependent, with hallmark features of apoptosis

108 multiple cytokines including IFN-alpha, and sortilin depletion in plasmacytoid dendritic cells (pDCs

109 Furthermore, mice deficient in APLP2 or sortilin do not exhibit significant changes in liver LDL

110 Thus, although the intracellular domain of sortilin does not contribute to p75(NTR) binding, it doe

111 ted the role of the proneurotrophin receptor sortilin during phagosome maturation and mycobacterial k

112 stalk region, to release the ligand binding sortilin ectodomain from the transmembrane and cytoplasm

113 ding and identify a novel mechanism by which sortilin ectodomain shedding acts as a regulatory switch

114 Indeed, expression of the sortilin ectodomain, which corresponds to the domain rel

115 Sortilin ectopically expressed in undifferentiated cells

116 lesterol transport and metabolism, including sortilin, endoplasmic reticulum-Golgi intermediate compa

117 Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/A

118 er element that regulates the inclusion of a sortilin exon cassette (termed Ex17b) not normally prese

119 strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in h

120 evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion

121 n through the posttranscriptional control of sortilin expression by TLR signals.

122 Conversely, down-regulation of sortilin expression in HeLa cells leads to an up-regulat

123 e previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels.

124 We also show that sortilin expression is higher in the forebrain than the

125 and alterations of intracellular zinc affect sortilin expression.

126 n export, whereas other studies suggest that sortilin facilitates lipoprotein export.

127 SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) d

128 As hypothesized, sortilin function impacts the levels of secreted ATZ in

129 Yet, sortilin gene-targeted mice (Sort1(-/-)) and chimeras de

130 In dendritic cells, sortilin had an impact on Ag processing.

131 te atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-gamma, bu

132 The overexpression of both proNGF and sortilin has been associated with several neurodegenerat

133 Previous characterization of sortilin has led to the suggestion that it functions to

134 Mice lacking Sortilin have elevations in brain and serum PGRN levels

135 corresponding to vertebrate Trk, p75(NTR) or Sortilin have not been identified in Drosophila, thus it

136 The expression of sortilin in 3T3-L1 cells occurred only upon differentiat

137 r study was to elucidate the distribution of sortilin in different immune cell types in mice and huma

138 contrast, little is known about the role of sortilin in immune cells and inflammatory diseases.

139 uences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and red

140 Studies by several groups support a role for sortilin in inhibiting lipoprotein export, whereas other

141 several groups support an important role for sortilin in lipoprotein metabolism; however, the directi

142 initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and

143 ), neurotrophin receptor p75 (p75(NTR)), and sortilin in the areas showing spongiform changes.

144 lpha secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-alpha in pDC

145 t ADAM10 is the preferred protease to cleave sortilin in the extracellular stalk region, to release t

146 mice (Sort1(-/-)) and chimeras deficient in sortilin in the immune system were as susceptible as wil

147 Forced expression of sortilin in undifferentiated cells does not recruit IRAP

148 am of VPS35, suggesting a potential role for sortilins in PD.

149 n studies implicate the human Vps10 homolog, sortilin, in cardiovascular disease, and because hepatic

150 novel function for a Vps10p domain protein, sortilin, in controlling BDNF sorting to the regulated s

151 Coexpression of sortilin increased targeting of myc7-Glut4 to the IRVs,

152 f the transporter, whereas overexpression of sortilin increases formation of GSVs and stimulates insu

153 the Golgi protein galactosyltransferase was sortilin independent and occurred even in the absence of

154 Thus sortilin-dependent as well as sortilin-independent sorting mechanisms target aggregate

155 Together, these data demonstrate that sortilin influences cytokine secretion and that targetin

156 ysosomes is mediated by the sorting receptor sortilin interacting with the lumenal stem domain of GPP

157 Sortilin interacts specifically with BDNF in a region en

158 rLA mainly colocalizes with APP in the soma, sortilin interacts with APP in neurites.

159 We also found that sortilin interacts with BACE1 and that a sortilin constr

160 nd the yeast two-hybrid system, we show that sortilin interacts with Glut4 and IRAP in the vesicular

161 echanistically, the luminal Vps10p domain of sortilin interacts with the first luminal loop of Glut4,

162 aled an important regulatory function of the sortilin intracellular domain in p75(NTR)-regulated intr

163 We determined that sortilin is a high-affinity receptor for the proinflamma

164 Here, we have demonstrated that sortilin is a key regulator of smooth muscle cell (SMC)

165 Sortilin is a lysosomal sorting protein that binds ligan

166 Sortilin is a multiligand sorting receptor responsible f

167 The proneurotrophin receptor sortilin is a protein with dual functions, being involve

168 Sortilin is also expressed in macrophages, but its role

169 Here we demonstrate that sortilin is also involved in retrograde protein traffic.

170 Sortilin is an intracellular chaperone that binds to the

171 Interestingly, the phagosomal association of sortilin is critical for the delivery of acid sphingomye

172 In the CNS, Sortilin is expressed by neurons and PGRN is most strong

173 Like the related APP receptor SorLA, sortilin is highly expressed in the CNS, but whereas Sor

174 Sortilin is modified by ectodomain shedding, although th

175 Thus, sortilin is not only essential, but also sufficient for

176 e and accessible to proneurotrophin ligands, sortilin is primarily localized to intracellular membran

177 In Xenopus embryos, overexpression of sortilin leads to a decrease in phospho-Smad2 levels and

178 ue of AD patients and that overexpression of sortilin leads to increased BACE1-mediated cleavage of A

179 ed expression of Glut4 prior to induction of sortilin leads to rapid degradation of the transporter,

180 We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multipl

181 ovel function of the endolysosomal T. gondii sortilin-like receptor (TgSORTLR), which mediates traffi

182 Sortilin localized to calcifying vessels in human and mo

183 hese results propose pro-NGF-induced, p75NTR-sortilin-mediated neuronal death as a critical aspect of

184 Sortilin-mediated PGRN endocytosis is likely to play a c

185 Sortilin-mediated uptake of native LDL into macrophages

186 codes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apolipopr

187 contrast to mice, the inclusion of Ex17b in sortilin mRNA generates a truncated, nonfunctional, extr

188 Moreover, sortilin mRNA was degraded posttranscriptionally upon st

189 ed the C-rich element (CRE) in the 3' UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degra

190 ed Ex17b) not normally present in the mature sortilin mRNA.

191 gulatory inhibitor, Ex17b is included in the sortilin mRNA.

192 We found that proNGF and p75(NTR), but not sortilin, mRNA and protein were significantly elevated i

193 Our results suggest that sortilin negatively regulates TGF-beta signaling by dive

194 , a kinase-dead TrkA, and siRNA against TrkA sortilin, neurotensin, whereas siRNA against p75(NTR) an

195 Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB

196 ntiating 3T3-L1 adipocytes upon induction of sortilin on day 2 of differentiation.

197 however, the directionality of the effect of sortilin on plasma cholesterol and its role in the secre

198 NRH2 critically regulates the expression of sortilin on the neuronal cell surface and promotes p75(N

199 his hypothesis, we have studied targeting of sortilin, one of the major IRV constituents.

200 Secreted PGRN is incorporated into cells via sortilin or cation-independent mannose 6-phosphate recep

201 n demonstrate that mRNA knockdowns of APLP2, sortilin, or both in the human hepatocyte cell lines Hep

202 reduced foam cell formation in vivo, whereas sortilin overexpression in macrophages resulted in incre

203 NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be tran

204 Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with AS

205 mation of a stable ternary complex of proNGF-sortilin-p75NTR.

206 Together, the results of this study identify sortilin phosphorylation as a potential therapeutic targ

207 Here we report that the sorting receptor sortilin plays a key role in cytokine production.

208 e conclude that the proneurotrophin receptor sortilin plays a role in innate, rather than in adaptive

209 TRKB with the intracellular sorting protein sortilin, prevented TRKB degradation, and promoted its a

210 The presence of sortilin promotes alpha-secretase cleavage of APP, unlik

211 Expression of a sortilin protein rescues these defects, downstream of VP

212 Sortilin rapidly endocytoses and delivers PGRN to lysoso

213 ronal cell surface and promotes p75(NTR) and sortilin receptor complex formation, rendering cells res

214 be dependent upon membrane expression of the sortilin receptor, which interacts with p75NTR to promot

215 a the neurotrophin receptor p75(NTR) and the sortilin receptor.

216 ins, combined with prior work on the role of sortilin receptors in mucocyst biogenesis, suggests that

217 tes p75 neurotrophin receptor (p75(NTR)) and sortilin receptors to mediate proapoptotic responses.

218 However, expression of this truncated sortilin redistributes BACE1 from the trans-Golgi networ

219 The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine

220 Sortilin regulated the loading of the calcification prot

221 d as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism.

222 s have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of

223 In humans, genetic variation of sortilin-related receptor, L(DLR class) A repeats contai

224 xplored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SOR

225 In contrast, RNAi suppression of sortilin results in decreased BACE1-mediated cleavage of

226 enhancer element is consistently present in sortilin RNA of mice and other species but absent in pri

227 The current studies show that sortilin selectively co-immunoprecipitates with the clea

228 Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo

229 hese findings characterize the regulation of sortilin shedding and identify a novel mechanism by whic

230 We identify sortilin shedding at the cell surface and in an intracel

231 hermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination.

232 In addition, sortilin small interfering RNA introduced into primary n

233 x (Vps35, Vps26) and its putative receptors (sortilin, SorL1, SorCS1)] have been implicated in the mo

234 ng 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiot

235 the vesicular sorting of the retromer cargo, sortilin, SorLA and cation-independent mannose 6-phospha

236 , and unbiased expression cloning identifies Sortilin (Sort1) as a binding site.

237 issue of Neuron, Hu and colleagues identify Sortilin (SORT1) as a key neuronal receptor for PGRN tha

238 The gene encoding sortilin (SORT1) has been implicated as the causative ge

239 Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocyt

240 SNP rs646776 is located near sortilin (SORT1), and the minor C allele of rs646776 was

241 potential mechanism linking misregulation of sortilin splicing with altered PGRN metabolism.

242 between the cytoplasmic domains of NRH2 and sortilin that impair lysosomal degradation of sortilin.

243 splicing events were detected (including in sortilin, the receptor for progranulin) following deplet

244 ant sortilin degradation and to redistribute sortilin to the cell surface, rendering p75(NTR)-express

245 In cultured 3T3-L1 adipocytes, sortilin together with retromer rescues Glut4 from degra

246 PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc level

247 pletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a

248 an act as a trans-acting factor to stabilize sortilin transcripts.

249 red the binding characteristics of proNGF to sortilin using surface plasmon resonance and cell-based

250 proteins requires classical receptors of the sortilin/VPS10 family, which indicates that dual mechani

251 Sortilin was expressed most profoundly in murine and hum

252 Accordingly, sortilin was highly expressed by infiltrated perivascula

253 Sortilin was overexpressed in thyroid cancers compared w

254 er with GLUT4 vesicle isolation, showed that sortilin was primarily located in the low density micros

255 is after binding to p75NTR and a coreceptor, sortilin, we asked whether the precursor of BDNF (proBDN

256 death after binding to co-receptors p75(NTR)/sortilin, we hypothesized that overexpression of proNGF,

257 r p75(NTR), and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a co

258 ines that stably express wild-type or mutant sortilin were recently established, we examined whether

259 Amyloid precursor-like protein 2 (APLP2) and sortilin were reported to individually bind the proprote

260 when co-expressed with PCSK9, both APLP2 and sortilin were targeted for lysosomal degradation.

261 ds on the expression of the sorting receptor sortilin, which interacts with the unique amino acid res

262 Another NTSR, sortilin, which is common to neurotensin and neurotrophi

263 We observed interactions of sortilin with multiple cytokines including IFN-alpha, an

264 Co-expression of sortilin with TGF-beta family members leads to decreased

265 timulated by proNGF and mediated by TrkA and sortilin, with the activation of Akt and Src, for the st

266 atherosclerosis in mice lacking hematopoetic sortilin without an effect on plasma LDL-C levels.