ライフサイエンスコーパス: TSC2

1 nizing tuberous sclerosis complex protein 2 (TSC2).

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

3 ugh direct phosphorylation and inhibition of TSC2.

4 Here, TSC1 functions independently of TSC2.

5 directly by phosphorylation of the regulator TSC2.

6 nd 24 as critical for pUL38 interaction with TSC2.

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

8 sequence and structural similarity with Tsc1-Tsc2.

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

10 identified by the loss of heterozygosity for TSC2.

11 etely abolished the lysosomal association of TSC2.

12 bstrates FoxO, GSK-3beta, PRAS40, AS160, and Tsc2.

13 enesis due to inherited mutations in Tsc1 or Tsc2.

14 estations due to mutations in either TSC1 or TSC2.

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

16 plicated in disease development are TSC1 and TSC2.

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

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

19 stant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechani

20 We identify TSC2, a negative regulator of mTOR-C1, as a novel Pim2 s

21 expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA.

22 Cells mutant for the tuberous sclerosis gene Tsc2 also had extra cilia and diluted ciliary protein.

23 rosurvival autophagy, which was dependent on TSC2/AMPK-mediated mTOR inhibition but not on beclin-1.

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

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

26 Tsc2 mutants, leading to the hypothesis that Tsc2 and Akt might work via the same genetic pathway to

27 Indeed, transheterozygous analysis of Tsc2 and Akt mutants confirmed this hypothesis.

28 ed that ECs induced hyper-phosphorylation of TSC2 and at least part of this increase occurred on resi

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

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

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

32 rosis complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic target of rapa

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

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

35 Tuberous sclerosis complex 2 (TSC2) and phosphatase and tensin homolog deleted on chro

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

37 phorylation of tuberous sclerosis complex-2 (TSC2) and targeting of mTOR and TSC2 to the lysosome.

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

39 te hydratase, succinate dehydrogenase, TSC1, TSC2, and TFE3 genes, have significantly altered the way

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

41 control muscles, we found that both mTOR and TSC2 are highly enriched at the lysosome.

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

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

44 Tuberous sclerosis complex 1 (TSC1) and TSC2 are suppressors of mechanistic target of rapamycin

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

46 Following TSC2(-/-) ASM cell administration, lymphangiogenesis inc

47 This study shows that TSC2(-/-) ASM cells can migrate and invade lungs and lym

48 TSC2(-/-) ASM cells infiltrated lymph nodes and alveolar

49 TSC2(-/-) ASM cells, derived from a human renal angiomyo

50 TSC2(-/-) ASM cells, previously labeled with PKH26-GL dy

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

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

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

54 mTOR is associated with the translocation of TSC2 away from the lysosome.

55 results suggest a role for the NFATc3/REDD1/TSC2 axis in the regulation of intestinal cell different

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

57 c basis for the difference between TSC1- and TSC2-based disease is unclear.

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

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

60 LKB1 and TSC2, but not TSC1, are required for PERK-mediated inhib

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

62 homozygous conditional hypomorphic alleles (Tsc2(c-del3/c-del3)SynICre(+)) and heterozygote null/con

63 ent of epileptiform bursting activity in the TSC2(+/-) CA3 region of the hippocampus.

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

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

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

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

68 , and inhibition of E-cadherin expression in TSC2(-/-) cells by upregulating the transcription factor

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

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

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

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

73 conditional hypomorphic and null alleles of Tsc2 combined with the neuron-specific synapsin I cre (S

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

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

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

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

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

79 omplex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to po

80 nd ubiquitous third core subunit of the TSC1-TSC2 complex.

81 The TSC proteins Tsc1 and Tsc2 control the mTORC1 signaling pathway in diverse cel

82 Loss of Tsc1 or Tsc2 copies the progressive Lkb1(cko) phenotype, suggest

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

84 sion of NFATc3 increased, while knockdown of TSC2 decreased, MUC2 expression.

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

86 TSC2 deficiency induces constitutive activation of mTOR,

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

88 bed an alternative mechanism showing that in TSC2 deficiency, enhanced PTEN expression contributes to

89 nced prostaglandin biosynthesis signature in Tsc2-deficient (TSC(-)) cells, both in vitro and in vivo

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

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

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

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

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

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

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

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

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

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

100 TORC1 inhibition may promote the survival of TSC2-deficient cells.

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

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

103 TSC2-deficient macrophages formed mTORC1-dependent granu

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

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

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

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

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

109 ltiple miRs, including pro-survival miRs, in TSC2-deficient patient-derived cells.

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

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

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

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

114 fibronectin expression in both wild-type and TSC2(+/-) diabetic rats.

115 ntly greater in partially tuberin-deficient (TSC2(+/-) ) diabetic rats than wild-type diabetic rats.

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

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

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

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

120 e proportional to the extent of reduction in Tsc2 expression in neurons.

121 Using Tsc1 and Tsc2 floxed alleles and a radial glial transgenic Cre dr

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

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

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

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

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

127 s a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiation anti

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

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

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

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

132 is caused by the loss of either the TSC1 or TSC2 genes that normally regulate the mammalian target o

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

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

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

136 -63 with alanine impaired both intrinsic and TSC2 GTPase-activating protein (GAP)-mediated GTP hydrol

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

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

139 ostnatally in a well-established neuroglial (Tsc2-hGFAP) model of TSC would rescue brain developmenta

140 gnificantly reduces epileptiform bursting in TSC2(+/-) hippocampal slices.

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

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

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

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

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

146 achieves a graded reduction in expression of Tsc2 in neurons in vivo.

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

148 Tg(GFAP-cre)25Mes/J), we deleted Tsc1 and/or Tsc2 in radial glial progenitor cells.

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

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

151 tes with a graded reduction in expression of Tsc2 in the two sets of mice.

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

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

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

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

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

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

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

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

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

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

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

163 zygote null/conditional hypomorphic alleles (Tsc2(k/c-del3)SynICre(+)) achieves a graded reduction in

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

165 ckdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without eff

166 RK promotes the activation of LKB1, AMPK and TSC2, leading to the rapid induction of detachment-induc

167 tive regulator tuberous sclerosis complex 2 (TSC2) leads to hypersensitivity to glucose deprivation.

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

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

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

171 Tsc2 lies upstream of mammalian target of rapamycin (mTO

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

173 Unexpectedly, we also found that Tsc1-Tsc2 loss activated RalA/B independently of Rheb-mTOR si

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

175 nsistent with these observations, cells with TSC2 loss of heterozygosity expressed the OPG receptors,

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

177 Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1

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

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 As TSC2(-/-) MEFs were resistant to nutrient stress despite

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

186 We also report that adult TSC2(+/-) mice exhibit a subtle perseverative behavioral

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

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

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

190 We found that in TSC2(-/-) mouse embryonic fibroblasts expression of a ki

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 peutic target for MM and define a novel Pim2-TSC2-mTOR-C1 pathway that drives MM proliferation.

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 Double Tsc1/Tsc2 mutants died earlier than single mutants, and singl

202 Furthermore, Tsc2 mutants showed a dramatic decrease in the levels of

203 ons (NMJs) in Drosophila, we identified that Tsc2 mutants showed increased synaptic growth.

204 , and interestingly, Akt mutants phenocopied Tsc2 mutants, leading to the hypothesis that Tsc2 and Ak

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

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

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

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

209 Genotype-phenotype studies suggest that TSC2 mutations are associated with a more severe neurolo

210 TSC2 mutations are more frequent in patients with retina

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

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

213 r, age at TSC diagnosis, presence of TSC1 or TSC2 mutations, detailed ophthalmic examination findings

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

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

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

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

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

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

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

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

222 protein levels enhanced by mTORC1 sensitized TSC2-null cells to iron deprivation due to constitutive

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

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

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

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

227 ORC1 plays a key role in determining whether TSC2-null Elt3 rat leiomyoma cells apoptose in response

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

229 Moreover, inhibition of deregulated TORC1 in TSC2-null mouse embryonic fibroblasts or in 293 cells by

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

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

232 on Ser-1798 and relieves the suppression of TSC2 on mTOR-C1.

233 e and show that Pim2 directly phosphorylates TSC2 on Ser-1798 and relieves the suppression of TSC2 on

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

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

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

237 Tsc2 or Pten deficiency in progenitors increases TOR sig

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

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

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

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

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

243 in response to insulin requires Akt-mediated TSC2 phosphorylation.

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

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

246 the tumor suppressors Folliculin (Flcn) and Tsc2 prevent ESC commitment.

247 h glucose enhanced fibronectin expression in TSC2(+/-) primary proximal tubular epithelial cells; bot

248 tial clinical benefit of strategies to raise TSC2 protein expression from the wild-type allele by eve

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

250 n and learning assays, which correlated with Tsc2 protein levels as well.

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

252 odimeric TSC complex, consisting of Tsc1 and Tsc2 proteins, regulates the activity of the TOR (target

253 Furthermore, TSC2(+/-) rats exhibited significant increases in the ba

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

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

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

257 etic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian target

258 he tuberous sclerosis complex genes (TSC1 or TSC2), resulting in hyperactive mammalian Target of Rapa

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

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

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

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

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

264 nd contrast the brain phenotypes of Tsc1 and Tsc2 single and double mutants.

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

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

267 We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex

268 he PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn on Rheb, a

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

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

271 lerosis complex tumor-suppressor genes (TSC1/TSC2) that cause LAM, a multisystem disease characterize

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 large number of signalling pathways rely on TSC2 to control mTOR signalling, our results have potent

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

277 s complex-2 (TSC2) and targeting of mTOR and TSC2 to the lysosome.

278 vity, without effects on the localization of TSC2 to the lysosome.

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

280 tations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene.

281 s in either of two genes, TSC1 (hamartin) or TSC2 (tuberin), are responsible for most cases.

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

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

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

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

286 ng pathway that engages ATM and the LKB1 and TSC2 tumor suppressors to repress mTORC1 and regulate au

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

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

289 Inactive mutation of either TSC1 or TSC2 unleashes mTOR signaling and consequently causes TS

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

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

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

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

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

295 the CCF-TSCP and TSC-A groups, mutations in TSC2 were more frequent than in TSC1, 3.3 times and 5.8

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

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

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

299 that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively reg

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