ライフサイエンスコーパス: TSC2

1 in tuberous sclerosis complex genes (TSC1 or TSC2).

2 nizing tuberous sclerosis complex protein 2 (TSC2).

3 plicated in disease development are TSC1 and TSC2.

4 r genes tuberous sclerosis complex (TSC)1 or TSC2.

5 ugh direct phosphorylation and inhibition of TSC2.

6 Here, TSC1 functions independently of TSC2.

7 directly by phosphorylation of the regulator TSC2.

8 nd 24 as critical for pUL38 interaction with TSC2.

9 one of two tumor suppressor genes, TSC1 and TSC2.

10 sequence and structural similarity with Tsc1-Tsc2.

11 of the mTORC1-inhibitory proteins, TSC1 and TSC2.

12 of mTORC1, although none had loss of TSC1 or TSC2.

13 ne H3 acetylation levels in a mouse model of TSC2.

14 and cancers with mutations in either TSC1 or TSC2.

15 in 13 patients/families (6 in TSC1 and 7 in TSC2), 5 of which were novel.

16 Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in A

17 le inducing minor gene expression changes in TSC2 add-back cells.

18 a-derived TSC2-deficient cells compared with TSC2 add-back cells.

19 The lack of Tsc2 also delayed axonal development and caused aberrant

20 s that are rescued by additional knockout of TSC2, an inhibitor of mTOR.

21 PI3k, Akt; the target of rapamycin pathway: Tsc2 and 4EBP; the Wnt pathway: shaggy).

22 of ERK1/2, which promoted the inhibition of TSC2 and activation of S6K.

23 Therefore, biallelic mutations in TSC2 and associated molecular dysfunction, including mTO

24 n mediating the interaction between AMPK and TSC2 and facilitate TSC2 phosphorylation at Ser1387.

25 at PTX effects on mTORC1 were independent of TSC2 and p53 and that the activation of a p53 transcript

26 ls, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene d

27 A-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potenti

28 nt proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1.

29 are etiologically linked to mutations in the tsc2 and tsc1 genes in the case of LAM.

30 al mediator of TSC2-driven tumorigenesis, as Tsc2(+/-) and Tsc2f/f Ksp-CreERT2(+) mice crossed to p62

31 phorylation of tuberous sclerosis complex 2 (TSC2) and PRAS40, both negative regulators of mTOR activ

32 ly mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also

33 SC) protein complex (TSCC), comprising TSC1, TSC2, and TBC1D7, is widely recognised as a key integrat

34 by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regula

35 Both human TSC1 and TSC2 are important tumour suppressors, and mutations in

36 The tuberous sclerosis proteins TSC1 and TSC2 are key integrators of growth factor signaling.

37 uman neurons but that biallelic mutations in TSC2 are necessary to induce gene expression dysregulati

38 TOR activation; however, second hits to TSC1/TSC2 are not always observed.

39 ions in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated prot

40 In Tsc2 +/- ASD mice where mTOR is constitutively overactiv

41 tophagy) was also deficient in cells lacking TSC2, associated with altered expression of PTEN-induced

42 ma-derived Tsc2-deficient ELT3 cells, mutant Tsc2-associated mouse kidney tumors, and human lung lymp

43 g7(CKO) neuronal autophagy-deficient mice or Tsc2 +/- :Atg7(CKO) double mutants.

44 in (mTOR) signaling via the inhibitory REDD1/TSC2 axis.

45 c knock-out of tuberous sclerosis complex-2 (Tsc2) blocked the IL-4-dependent expression of Cox-1 and

46 UL3825-331 lost the ability to interact with TSC2 but retained the ability to activate mTORC1, althou

47 In summary, covalent modification of TSC2 by iNOS-derived NO is associated with impaired TSC2

48 r absent TSC2, we show that complete loss of TSC2 causes an increase in glycogen synthesis through mT

49 te that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activati

50 Inhibition of ERK1/2 in Tsc2 (-/-) cells-a model of TS-rescues GSK3beta activity

51 lls in vivo to a greater extent than control TSC2(+/+) cells.

52 reduced migration and invasion properties of TSC2(-/-) cells and attenuated lung colonization of intr

53 lung colonization of intravenously injected TSC2(-/-) cells in vivo to a greater extent than control

54 TSC2(-/-) cells show MTORC1-dependent impaired autophagi

55 cells lacking tuberous sclerosis complex 2 (TSC2(-/-) cells), which show constitutive MTORC1 activat

56 els of active Src kinase in LAM lungs and in TSC2(-/-) cells, caused by a reduction of autophagy.

57 Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a

58 The tuberous sclerosis 1 (TSC1)/TSC2 complex negatively regulates the activity of an mTO

59 l kinase is an upstream effector of the TSC1/TSC2 complex that regulates mTOR signaling.

60 po, Ubiquitin-proteasome system (ERK5), Tsc1/Tsc2 complex, FoxO1, wnt/beta-catenine signaling pathway

61 DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTOR pathwa

62 on in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR-

63 TSC2 constitutively inhibits mTORC1; however, this activ

64 Moreover, on TSC2 correction, AML cells mature into adult lymphatic e

65 ration, invasion and apoptotic resistance of Tsc2-defective cells.

66 TSC2 deficiency leads to hyperactivation of mTOR Complex

67 KL protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitocho

68 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.

69 These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potenti

70 bited potent antiproliferative activities in TSC2-deficient cells and an immunodeficient mouse xenogr

71 and activation of the tyrosine kinase Syk in TSC2-deficient cells and pulmonary nodules from lymphang

72 Lgals3 encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKO(Prrx1)-cre mic

73 ctively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells.

74 ulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells.

75 ther delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of t

76 ontent, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690.

77 ING4 inhibited the migration and invasion of Tsc2-deficient cells while silencing of ING4 reversed th

78 lar amino acids and glucose, suggesting that TSC2-deficient cells would be hypersensitive to ceramide

79 way that regulates tumorigenic properties of Tsc2-deficient cells, and that may serve as a potential

80 proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1

81 In TSC2-deficient cells, Syk signaling increased the expres

82 which we determined to mediate cell death in Tsc2-deficient cells.

83 90) inhibitors selectively triggers death of TSC2-deficient cells.

84 n vitro and in vivo and induced apoptosis in TSC2-deficient cells.

85 d that miR-29b acts as an oncogenic miRNA in Tsc2-deficient cells: inhibition of miR-29b suppressed c

86 roblasts, Eker rat uterine leiomyoma-derived Tsc2-deficient ELT3 cells, mutant Tsc2-associated mouse

87 c2/mTORC1 expression signature identified in Tsc2-deficient fibroblasts was also increased in bladder

88 ial subsets of cells observed in mesenchymal Tsc2-deficient lungs.

89 TSC2-deficient macrophages formed mTORC1-dependent granu

90 Our results demonstrate Tsc2-deficient mesenchymal progenitors cause aberrant mo

91 nd completely resolved granulomas in myeloid TSC2-deficient mice.

92 e we show that unlike in non-neuronal cells, Tsc2-deficient neurons have increased autolysosome accum

93 pling protein-2 (Ucp2) are highly induced in Tsc2-deficient neurons, as well as in a neuron-specific

94 protein, and rescues spine deficits found in Tsc2-deficient neurons.

95 of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells.

96 cell migration, invasion, and the growth of Tsc2-deficient tumors in vivo.

97 r, without in-depth functional analysis, the Tsc2-deficient zebrafish line cannot be used for studies

98 d as a rapamycin-induced microRNA (miRNA) in Tsc2-deficient, mTORC1-hyperactive cells.

99 roglia and hypomyelination seen with Tsc1 or Tsc2 deletion in the oligodendrocyte lineage during CNS

100 er, only neurons with biallelic mutations of TSC2 demonstrated hyperactivity and transcriptional dysr

101 ith either a single or biallelic mutation in TSC2 demonstrated hypersynchrony and downregulation of F

102 rated that pUL38 can activate mTORC1 in both TSC2-dependent and -independent manners.

103 was activated by HCMV protein pUL38 in both TSC2-dependent and TSC2-independent manners.

104 While AMPK normally stimulates TSC2-dependent inactivation of mTORC1 signaling, mTORC1

105 iquitination of TSC1, thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization.

106 In general, TSC2 disease was more severe than TSC1, with more subepe

107 we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2(+/-) and Tsc2f/f Ksp-

108 ienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe ph

109 1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%).

110 phorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wirin

111 oss of tuberous sclerosis complex subunit 2 (TSC2) exploit the PLD-PA pathway and thereby sustain mTO

112 ecimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indic

113 oteins suppresses mTOR activity by promoting Tsc2 expression, which is necessary for the nuclei clear

114 ls (Fmr1(-/y), Cntnap2(-/-), 16p11.2(del/+), Tsc2(+/-)), focusing on somatosensory cortex.

115 The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regula

116 aling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1.

117 sistance exercise led to the dissociation of TSC2 from Rheb and increased in the co-localisation of m

118 nsient transfection-based approach to rescue TSC2 function in muscles of the iTSC2KO mice, we demonst

119 The TSC2 GAP domain is found abutting the centre of the body

120 roteins are repressed in neurons missing the Tsc2 gene expression.

121 a mouse model of TSC (Tsc2-RG) in which the Tsc2 gene is deleted in radial glial precursors and thei

122 isorder arising from mutation in the TSC1 or TSC2 gene, characterized by the development of hamartoma

123 esence of a large pathogenic deletion in the TSC2 gene, covering exons 2 to 16 and including the init

124 thout TSC, owing to somatic mutations in the TSC2 gene.

125 ch develops as a result of mutations in TSC1/TSC2 genes in TSC patients, because we observed the reac

126 that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mec

127 ns in tuberous sclerosis complex 1 (TSC1) or TSC2 genes, causes protein synthesis dysregulation, incr

128 rom inactivating variants within the TSC1 or TSC2 genes, leading to constitutive activation of mechan

129 of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity.

130 utations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic ta

131 The mammalian Tsc1-Tsc2 GTPase activating protein (GAP) heterodimer is a cr

132 -63 with alanine impaired both intrinsic and TSC2 GTPase-activating protein (GAP)-mediated GTP hydrol

133 The "body" is composed of a flexible TSC2 HEAT repeat dimer, along the surface of which runs

134 e results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pat

135 Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells

136 Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains el

137 nesis was investigated through disruption of Tsc2 in craniofacial and limb bud mesenchymal progenitor

138 For example, mice lacking TSC2 in developing SCs displayed hyperproliferation of u

139 next-generation sequencing (NGS) analysis of TSC2 in five tumors (four from the left kidney, one from

140 We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53

141 Here, we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and de

142 only establish a critical role for Rheb and TSC2 in the mechanical activation of mTOR signaling, but

143 Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonar

144 eveal any genomic rearrangements in TSC1 and TSC2 in the samples with no mutations identified.

145 bnormalities by loss of the second allele of TSC2 in TSC2 (-/-) neurons.

146 NGS analysis of TSC2 in two of these tumors identified a second hit muta

147 In this study, we found that the lack of Tsc2 in zebrafish resulted in heterotopias and hyperacti

148 onditional deletion of the mTORC1 inhibitor, TSC2, in alpha-cells (alphaTSC2(KO)).

149 ng Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity.

150 Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tuberous

151 CMV protein pUL38 in both TSC2-dependent and TSC2-independent manners.

152 Tsc2 induction inhibits mTORC1 to suppress cellular meta

153 mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased.

154 Overexpression of InRDN or Tsc2 inhibits lifespan extension by Met restriction, sug

155 y depletion of tuberous sclerosis complex 2 (TSC2) inhibits lipophagy induction in DENV-infected cell

156 identified the residues important for pUL38-TSC2 interaction and demonstrated that pUL38 can activat

157 gesting an MOI-dependent importance of pUL38-TSC2 interaction in supporting virus propagation.

158 acterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mutatio

159 atient with TSC with one or two mutations in TSC2 into neurons using induced expression of NGN2 to ex

160 Biallelic loss of TSC1 or TSC2 is a known genetic driver of angiomyolipoma develop

161 data demonstrate that loss of one allele of TSC2 is sufficient to cause some morphological and physi

162 Tuberin (TSC2) is a GTPase-activating protein and prominent intri

163 ecific knock-out mice for Rheb (iRhebKO) and TSC2 (iTSC2KO) and mechanically stimulated muscles from

164 Thus, in Tsc2-knockdown neurons AMPK activation is the dominant r

165 caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation.

166 Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation,

167 x 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to uncontrolled cell growth yet increased a

168 As expected, the knock-out of TSC2 led to an elevation in the basal level of mTOR sign

169 epletion of Atg9 caused a marked decrease in TSC2 levels.

170 cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrate

171 ng the autophagy dysfunction associated with Tsc2 loss in neurons, our work sheds light on a previous

172 To see whether TSC1/TSC2 loss was a common genetic event in human mesothelio

173 Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatid

174 a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-d

175 cally developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo a

176 Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1

177 that the tuberous sclerosis complex (TSC) 1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-

178 ggest that loss of heterozygosity of TSC1 or TSC2 may play an important role in the development of co

179 itor, the GTPase-activating protein tuberin (TSC2), may play a role in this pathway.

180 ng SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1.

181 These effects are dependent on TSC2-mediated mechanistic target of rapamycin inactivati

182 mits access to both amino acids and glucose, TSC2(-/-) MEFs also had a survival advantage when extrac

183 enic Ras abrogated the survival advantage of TSC2(-/-) MEFs upon ceramide treatment most likely by in

184 -like behaviors and spine pruning defects in Tsc2 +/- mice, but not in Atg7(CKO) neuronal autophagy-d

185 Treatment of both Tsc2(+/) (-) mice and a TSC1-null bladder cancer xenogra

186 We describe a novel seizure phenotype in TSC2(+/-) mice that is also normalized with HDAC inhibit

187 s and ameliorates the aberrant plasticity in TSC2(+/-) mice.

188 Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition

189 f HMGA2 in the pathogenesis of TSC using the TSC2(+/-) mouse model that similarly mirrors human disea

190 Tsc1(-/-) and Tsc2(-/-) mouse embryonic fibroblasts expressed higher u

191 rast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one me

192 GF-A levels, in renal cystadenoma cells in a Tsc2+/- mouse model.

193 haB-crystallin was upregulated in Tsc1-/- or Tsc2-/- mouse embryonic fibroblasts, Eker rat uterine le

194 is, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement.

195 translation initiation via alteration of the Tsc2-mTor-Eif4e axis was further validated across MIA ro

196 ch of signaling events that can regulate the TSC2/mTOR pathway.

197 A Tsc2/mTORC1 expression signature identified in Tsc2-defi

198 Young Tsc2 mutant mice demonstrate hypoglycemia with increased

199 Removal of a single mTOR allele from the Tsc2 mutant mice largely normalizes the bone and metabol

200 However, with age, Tsc2 mutants develop metabolic features similar to mice

201 C1 mutation, 65% (11 of 17) of patients with TSC2 mutation, and 12% (one of eight) of patients with T

202 ust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with bo

203 ons that retained a patient-specific genomic TSC2(+/-) mutation and recapitulated the molecular and f

204 ge, this is the first comprehensive TSC1 and TSC2 mutational analysis carried out in TSC patients in

205 also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database.

206 Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type al

207 milar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin fo

208 ally caused by tuberous sclerosis complex 2 (TSC2) mutations resulting in mTORC1 activation in prolif

209 Here we show that the TSC2 N terminus interacts with the TSC1 C terminus to me

210 The structure of the TSC2 N-terminal domain from Chaetomium thermophilum and

211 We observed that TSC2 (+/-) neurons show mTOR complex 1 (mTORC1) hyperact

212 ties by loss of the second allele of TSC2 in TSC2 (-/-) neurons.

213 on in TSC2-null tumor cells and immortalized TSC2-null angiomyolipoma cells, but not in cells with in

214 Disruption of alphaB-crystallin suppressed Tsc2-null cell proliferation and tumorigenesis.

215 profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, gluta

216 Inhibition of uPA expression in Tsc2-null cells reduced the growth and invasiveness and

217 Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhi

218 Moreover, rapamycin-enhanced migration of TSC2-null cells was inhibited by the uPA inhibitor UK122

219 We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterp

220 ter Slc1a5 and increased glutamine uptake in Tsc2-null cells.

221 mitochondrial damage and promoted growth of Tsc2-null cells.

222 ble of further increasing mTORC1 activity in TSC2-null cells.

223 A-knock-out mice developed fewer and smaller TSC2-null lung tumors, and introduction of uPA shRNA in

224 We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which

225 apamycin further increased uPA expression in TSC2-null tumor cells and immortalized TSC2-null angiomy

226 We also created TSC2-null U373-MG cell lines by CRISPR genome editing an

227 , and 1 culture showed biallelic mutation in TSC2, one of which was germline and the second acquired

228 ryonic fibroblasts with genetic ablations of TSC2 or 4E-BP1/2 express less Egr1 mRNA but more Egr1 pr

229 ereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are assoc

230 ted negative regulators of mTORC1, including TSC2 or TSC1, in developing SCs of mutant mice.

231 clerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response

232 mors, each of whom had the germline mutation TSC2 p.R905Q.

233 Specific TSC2 pathogenic mutations, however, result in elevated g

234 etic disorder caused by mutations in TSC1 or TSC2 Patients frequently have epilepsy, autism spectrum

235 CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity.

236 presses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC

237 raction between AMPK and TSC2 and facilitate TSC2 phosphorylation at Ser1387.

238 Therefore, TSC2 phosphorylation is both required and sufficient for

239 autophagy in cardiomyocytes by PKG1 requires TSC2 phosphorylation.

240 ylation sites are required for the role that TSC2 plays in the EC-induced activation of mTOR signalin

241 erozygosity in one tumor, and four different TSC2 point mutations (p.E1351*, p.R1032*, p.R1713H, c.41

242 horylation of four bona fide Akt substrates (TSC2, PRAS40, FOXO1/3a, and AS160) was reduced by ~50% i

243 In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with

244 om 6 patients with TSC all exhibited reduced TSC2 protein expression, and 1 culture showed biallelic

245 ed the function of the tuberous sclerosis 2 (Tsc2) protein, a key target important in coordinating nu

246 by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersens

247 n AML-derived cell line to determine whether TSC2 restitution brings about the cell type from which A

248 However, only biallelic mutations in TSC2 resulted in elevated neuronal activity and upregula

249 tor of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic a

250 Our data demonstrate that loss of Tsc2 results in autophagic activity via AMPK-dependent a

251 nd found that loss of one or both alleles of TSC2 results in mTORC1 hyperactivation and specific neur

252 easing ODC activity and putrescine levels in Tsc2-RG mice worsened many of the neurodevelopmental phe

253 genetic approaches to reduce ODC activity in Tsc2-RG mice, followed by histologic assessment of brain

254 tribute to the neurodevelopmental defects of Tsc2-RG mice, we used pharmacologic and genetic approach

255 t modify the phenotype in this developmental Tsc2-RG model.

256 Using a mouse model of TSC (Tsc2-RG) in which the Tsc2 gene is deleted in radial gli

257 rowth factor-responsive pathway mediated via TSC2/Rheb and an amino acid-responsive pathway mediated

258 ion of REDD1-mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor-sensitive ovarian can

259 utated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the cor

260 at either of two adjacent serine residues in TSC2 (S1365 and S1366 in mice; S1364 and S1365 in humans

261 ease is reduced and survival of heterozygote Tsc2(S1365A) knock-in mice subjected to the same stress

262 phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have highe

263 ion of a phosphorylation-mimicking mutation (TSC2(S1365E)).

264 s available from this patient had one of the TSC2 second hit mutations identified.

265 Together, these findings suggest that Tsc2 serves as a key checkpoint in the osteoblast that i

266 rotein kinase G1 (PKG1) phosphorylates these TSC2 sites.

267 thereby promoting TSC1-TSC2 dimerization and TSC2 stabilization.

268 ed the growth of renal lesions in Eker rats (Tsc2+/-) subjected to a ketogenic diet for 4, 6 and 8 mo

269 PI3K/Akt-mediated activation of Rheb-GTP via TSC2 suppression.

270 activation of the MEK-ERK pathway in a TSC1/TSC2/TBC1D7 protein complex and mTORC1-independent manne

271 g a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, inclu

272 o search for SS/L interactions with TSC1 and TSC2, the two tumor suppressors underlying tuberous scle

273 g of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteas

274 SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1.

275 requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is cri

276 nction protein (Patj), which associates with TSC2 to regulate TOR activity.

277 iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and pro

278 ress a phosphorylation-silencing mutation in TSC2 (TSC2(S1365A)) develop worse heart disease and have

279 ation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is implicated in the induc

280 provide the first structural information on TSC2/tuberin with novel insight into the molecular funct

281 t stem cells with two, one, or no functional TSC2 (tuberous sclerosis complex 2) alleles and found th

282 d with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes.

283 (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes.

284 a, the mTOR pathway was not activated in all TSC2(+/-) tumors and was elevated in only 50% of human m

285 used by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the pre

286 ed germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing.

287 neurin activates DAPK1, which interacts with TSC2 via its death domain and phosphorylates TSC2 via it

288 TSC2 via its death domain and phosphorylates TSC2 via its kinase domain to mediate mTORC1 activation

289 n of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and prolifera

290 Transcription of p53 target genes, including TSC2, was activated by AICAR but not by PTX.

291 man and mouse cells with defective or absent TSC2, we show that complete loss of TSC2 causes an incre

292 s, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently.

293 murine embryonic fibroblasts (MEFs) lacking TSC2 were highly resistant to ceramide-induced death.

294 CCLs with inactivating mutations in TSC1 and TSC2 were sensitive to the mammalian target of rapamycin

295 teins tuberous sclerosis complex (TSC)-1 and TSC2, which are directly involved in suppressing the mec

296 plex (TSC) is caused by mutations in TSC1 or TSC2, which encode negative regulators of the mTOR signa

297 ntal disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTO

298 TOR2 complex controls the phosphorylation of TSC2, which is essential for TSC exchange.

299 ependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFE

300 ass spectrometry, we identified six sites on TSC2 whose phosphorylation was significantly altered by

301 mplex (TSC) 2, and inhibited dimerization of TSC2 with its inhibitory partner TSC1, enhancing GTPase