ライフサイエンスコーパス: JAK1

1 JAK1 activity was required for IFN-beta to activate PI3K

2 JAK1 and JAK2 truncating mutations resulted in a lack of

3 JAK1 and JAK3 are recurrently mutated in acute lymphobla

4 JAK1 and STAT3 gain-of-function mutations were found in

5 JAK1 and STAT3 were required for proliferation and survi

6 JAK1 is a critical effector of pro-inflammatory cytokine

7 JAK1 is critical for the signal transduction of many typ

8 JAK1 is designed to be unstructured in buffered saline s

9 JAK1 mediates interferon (IFN)-gamma-regulated tumor imm

10 JAK1 regulated the expression of nearly 3,000 genes in A

11 JAK1/2 inhibitors (such as ruxolitinib and JAK inhibitor

12 2-33C (adjusted odds ratio, 2.09; P = 0.02); JAK1 IVS22+112T (adjusted odds ratio, 1.66; P = 0.04); a

13 hat miR-373 directly targets Janus kinase 1 (JAK1) and IFN-regulating factor 9 (IRF9), important fact

14 24 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor.

15 cumulation of phosphorylated Janus kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2).

16 H2-like domains of the human Janus kinase 1 (JAK1) bound to a fragment of the intracellular domain of

17 activation of the Janus-activated kinase 1 (JAK1) in cells.

18 H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas

19 terferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion

20 ding activating mutations of Janus kinase 1 (JAK1), in 9.1% of patients and provides a path toward th

21 ling antagonist by targeting Janus kinase 1 (JAK1).

22 protein (RLTPR); moesin; and Janus kinase 1 (JAK1).

23 e treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MM

24 he development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myelo

25 its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the

26 results on the use of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib in murine models of hemoph

27 or, or with ruxolitinib, a Janus kinase 1/2 (JAK1/2) inhibitor.

28 Recently, several Janus kinase 1/2 (JAK1/2) inhibitors, such as ruxolitinib, have been devel

29 stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-depen

30 lation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS.

31 We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumor

32 bination with activating mutations in IL-7R, JAK1, or LCK, and down-regulation of CD45 expression cau

33 We have used AZD1480, a JAK1/2 inhibitor, to investigate the therapeutic potenti

34 the mutants can be partially inhibited by a JAK1/2 inhibitor.

35 It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but s

36 eliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 s

37 y program involving activation of STAT3 in a JAK1-dependent fashion.

38 In addition, administration of a JAK1/2 kinase inhibitor alleviated the Vhlh knockout phe

39 AK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.

40 Drug Administration approved ruxolitinib (a JAK1 and JAK2 inhibitor) for use in the treatment of hig

41 Importantly, Ruxolitinib, a JAK1 inhibitor, could rescue the phenotypic changes indu

42 Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had n

43 Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft A

44 Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors

45 Furthermore, we found that a JAK1 inhibitor dose dependently reduced IFN-gamma-contro

46 ant roles in immune function, while abnormal JAK1 activity has been linked to immunological and neopl

47 ns indicated that IL15RA signaling activated JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 in the absen

48 Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently

49 AK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM).

50 s, the compound library was screened against JAK1, resulting in the identification of a triazolopyrid

51 Although JAK1/2 inhibitor therapy is effective in decreasing the

52 itch is dependent on neuronal IL-4Ralpha and JAK1 signaling.

53 Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR show

54 and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signa

55 -function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total approximate

56 nine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets.

57 The results indicate that, through Gi and JAK1 and 2 kinases activation, CXCL12 signaling cooperat

58 PNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not

59 Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro.

60 eterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in tran

61 with dose dependent effects on both JAK2 and JAK1 suggests that it is likely that multiple pathways a

62 Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflammation of

63 us kinase (JAK) inhibitor targeting JAK3 and JAK1.

64 correlated with inhibition of Src kinase and JAK1 and JAK2 kinases.

65 that mdig directly interacts with c-myc and JAK1 in MM cell lines, which contributes to hyperactivat

66 hibited the RET receptor (EC(50), 42 nM) and JAK1/2/3 kinases (EC(50), 780 nM).

67 of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3.

68 mpared with wild-type JAK1, JAK1(T478S), and JAK1(V623A) expression was associated with increased STA

69 scoveries that the tyrosine kinases TYK2 and JAK1 and the transcription factors STAT1, STAT2, and IRF

70 K3A, MAP3K, MEK, RSK2, RSK4, PLK4, ULK1, and JAK1.

71 oundwork for repurposing clinically approved JAK1/JAK2 inhibitors for type 1 diabetes.

72 -treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserv

73 bitors of JAK1/2 resulting in first approved JAK1/2 inhibitor, ruxolitinib, for the treatment of pati

74 We also show that just as JAK1 interacts with IL-7Ralpha, JAK2 is associated with

75 rgets that do not contain mutations, such as JAK1 and the focal adhesion kinases (FAK), that are cruc

76 rs of downstream signaling molecules such as JAK1 inhibitors.

77 servations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and repre

78 accurate picture of the interactions between JAK1 and IFNLR1 than those given in earlier reports, ill

79 on to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.

80 NCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1

81 er, ruxolitinib, which preferentially blocks JAK1 and JAK2, abolished the proliferation of cells tran

82 Both JAK1/3 inhibitors and Tac were similarly effective in re

83 s(467)) whose presence was required for both JAK1/2 binding to betac and receptor ubiquitination.

84 model correlated with the inhibition of both JAK1 and JAK3 signaling pathways.

85 ibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival.

86 her, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effec

87 After heart transplantation, both JAK1/3 inhibitors reduced early mononuclear graft infilt

88 e X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated.

89 2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein inter

90 ->STAT3 pathway by forming adducts with both JAK1 and STAT3.

91 ied by H3Y41-P marks that were diminished by JAK1 inhibition.

92 response, which we show is phosphorylated by JAK1.

93 cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in

94 These findings clarify JAK1 signalling mechanisms and demonstrate a critical fu

95 Consequently, JAK1-deficient mice exhibit impaired apoptosis and a sig

96 Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encycl

97 itutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFN-gamma-initiate

98 JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib.

99 he IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth.

100 ed through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 leve

101 hang et al. report that TJP1 suppresses EGFR/JAK1/STAT3-mediated signaling and increases the proteaso

102 knockdown of miR-373 in hepatocytes enhanced JAK1 and IRF9 expression and reduced HCV RNA replication

103 owing JAK1 inhibition, suggesting epigenetic JAK1 action.

104 silencing of two members of the JAK family (JAK1 and JAK2) increased the susceptibility of a variety

105 drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3).

106 not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action.

107 d a selectivity of approximately 30-fold for JAK1- over JAK2-dependent signaling.

108 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described.

109 ma effects suggesting a predominant role for JAK1-STAT1.

110 consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of J

111 mall molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family

112 ovo protein synthesis, and contribution from JAK1.

113 nes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 pati

114 prising GATA1, the miR-23a cluster and gp130-JAK1-Stat3 pathway, that synergistically facilitates apo

115 rget multiple members of the oncogenic gp130-JAK1-Stat3 pathway, and thus reinforce their inhibition

116 nts with favorable pharmacokinetics and high JAK1/3 selectivity, but only R507 synergistically intera

117 culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral b

118 ibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergi

119 Having identified JAK1 as a possible new target for arthritis at Galapagos

120 utually exclusive mutations affecting IL2RG, JAK1, JAK3, or STAT5B in 38 of 50 T-PLL genomes (76.0%).

121 Functionally, IL2RG-JAK1-JAK3-STAT5B mutations led to signal transducer and

122 frequency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL.

123 eficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of th

124 uted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but al

125 e reporter gene construct was not altered in JAK1- and STAT-1-deficient cells following exposure to I

126 rostate cancer cells, which are deficient in JAK1 and RNase L, were resistant to the effects of IFN-b

127 results from activating mutations either in JAK1, JAK3, or in both kinases.

128 by acquiring another activating mutation in JAK1.

129 nation of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the des

130 aracterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK

131 several tyrosine kinase proteins - including JAK1 and EPHA4 - did not depend on KIT activation.

132 rms of various signaling proteins, including JAK1, JAK2, STAT1, STAT3, STAT5, and ERK1/2.

133 aft inhibitors delay and reduce IL-7-induced JAK1 and JAK3 phosphorylation.

134 ine kinase 3 inhibitor that does not inhibit JAK1.

135 347 dose dependently (1 nM-10 muM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-

136 In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhi

137 substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1, 2, 3, 6, and 10 with IC50 values of le

138 Cys(1077) in the kinase domain and inhibits JAK1 activity.

139 rimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomola

140 his regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being aff

141 Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in

142 rd assays, but compared with wild-type JAK1, JAK1(T478S), and JAK1(V623A) expression was associated w

143 L7 receptor (IL7R) and signals through JAK2, JAK1, and STAT5 to drive proliferation and suppress apop

144 (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting h

145 ctional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/

146 gly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JA

147 rmined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibro

148 rt activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.

149 oring somatic mutations in the Janus kinases JAK1 and JAK2.

150 Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signalin

151 Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are invo

152 ng MESCM through transient activation of LIF-JAK1-STAT3 signaling that delays eventual nuclear transl

153 These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of in

154 vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the disco

155 core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibit

156 A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutin

157 of JAK3 and downstream signaling molecules, JAK1, STAT5, MAPK and pS6 ribosomal protein.

158 amples and pave the way toward multitargeted JAK1 and JAK3 therapy in T-ALL.

159 Overexpression of mutant JAK1 did not transform primary murine cells in standard

160 uencies and found 4 novel somatic mutations, JAK1(V623A), JAK1(T478S), DDR1(A803V), and NTRK1(S677N),

161 ng RNA sequencing, we identified several new JAK1 target genes that are upregulated during involution

162 ctively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosp

163 Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-7

164 JAK2 and JAK3 isoforms, but not JAK1, mediate CXCL12-induced LFA-1 triggering to a high

165 to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in bioche

166 be involved in leukemogenesis (ETV6, NOTCH1, JAK1, and NF1), we identified novel recurrent mutations

167 ells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7.

168 -2-dependent proliferation and activation of JAK1 and STAT-5A/B.

169 ch leading to the constitutive activation of JAK1/STAT3 signalling, which results in sustained proinv

170 other pathogenic JAK2 mutants, as well as of JAK1 V658F, and prevents induction of erythrocytosis in

171 Both domains of JAK1 are generally well ordered, with regions not seen i

172 aneously to the FERM and SH2-like domains of JAK1.

173 Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces

174 exposure to IFN-gamma, whereas expression of JAK1 or STAT-1 protein restored the IFN-gamma inhibitory

175 nisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and p

176 Specific functions of JAK1 in the context of hematopoiesis, and specifically w

177 The importance of JAK1/3 signaling on TH2 differentiation and development

178 Inclusion of JAK1/2 inhibitor therapy in future transplant conditioni

179 Pharmacological inhibition of JAK1 also delayed disease onset.

180 e data suggest that fractional inhibition of JAK1 and JAK2 is sufficient for significant activity in

181 We observed that inhibition of JAK1/2 signaling resulted in reduced proliferation of ef

182 enzyme assays showed selective inhibition of JAK1/3-dependent pathways with 20-fold or greater select

183 viding partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3.

184 eated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth with

185 of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic

186 c effect of AZD1480, a specific inhibitor of JAK1/2, in suppressing neuroinflammation and neurodegene

187 aling by anti-IL-2Ralpha Ab or inhibitors of JAK1 and JAK3 significantly reduced IFN-gamma production

188 Inhibitors of JAK1/2 improve symptoms and prolong life in myelofibrosi

189 development of small molecule inhibitors of JAK1/2 resulting in first approved JAK1/2 inhibitor, rux

190 on of IFNgammaR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNgammaR signaling, r

191 ese results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.

192 interfering RNA confirms the involvement of JAK1 and TYK2, as well of IFN-stimulated gene factor 3 (

193 JH2 of JAK1, JAK2, and TYK2 all bind ATP, but the significance

194 The loss of JAK1 uncouples interleukin-6-class ligands from their do

195 bserved for homologous Leu(857) mutations of JAK1 and JAK2 and for JAK3(L875H).

196 We identified activating mutations of JAK1 and/or STAT3 genes in approximately 20% of 88 [corr

197 ntly associated with activating mutations of JAK1 or JAK2, deletion or mutation of IKZF1, and Hispani

198 leukin-6) consistent with our observation of JAK1 hyperactivation.

199 d results in constitutive phosphorylation of JAK1.

200 Increased phosphorylation of JAK1/2 after IL-17A treatment was detected in primary no

201 forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations.

202 We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA sam

203 We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in

204 reveal a phosphorylation-independent role of JAK1 in signal transduction.

205 Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment

206 JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors.

207 ar to that observed in crystal structures of JAK1 and JAK2.

208 ized how the gene structures of the oncogene JAK1 and the tumor suppressors KDM6A and RB1 are affecte

209 ivity, which was induced without receptor or JAK1 co-expression.

210 NCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic.

211 alterations activating the JAK-STAT pathway (JAK1, JAK2, IL7R) identified in 63 patients (50.8% of th

212 racterization of a de novo designed peptide, JAK1, which undergoes surface-induced folding at the hyd

213 Together, this work describes a new PERK/JAK1/STAT3 signaling pathway that elicits a feed-forward

214 the synergistic action of these proapoptotic JAK1 targets is obligatory for the remodeling of the mam

215 CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been

216 These findings identify recurrent JAK1 truncating mutations that could contribute to tumor

217 Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimula

218 : four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implic

219 s a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET

220 lates with interleukin-13 (IL-13) secretion, JAK1/2 tyrosine phosphorylation, and reduced expression

221 on of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA

222 We sought to examine a selective JAK1/3 inhibitor (R256) on differentiation of TH subsets

223 A selective JAK1/3 inhibitor was used to assay the importance of thi

224 we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPN

225 other JAK-STAT signaling genes (IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6

226 ession profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a s

227 s is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations m

228 Using a novel mammary gland-specific JAK1 knockout model, we demonstrate here that this tyros

229 inated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell

230 type I IFN signaling pathway by suppressing JAK1 and IRF9.

231 Sustained JAK1/STAT3 signalling is maintained by DNA methyltransfe

232 t miR-373 impairs IFN signaling by targeting JAK1/IRF9 molecules.

233 Together, these findings indicate that JAK1-mediated signaling cascades in skin regulate the ex

234 Here, we report that JAK1 is a constitutive TGFbetaRI binding protein and is

235 Functional assays show that JAK1 deficient cancer cells are defective in IFN-gamma-i

236 and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells.

237 Further analysis showed that JAK1 V658F cooperated in vivo with PML-RARA, causing a r

238 ollective results of this study suggest that JAK1 has nonredundant roles in the activation of particu

239 h the adsorption isotherm data suggests that JAK1 binds to HA, forming a self-limiting monolayer.

240 atic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutatio

241 The JAK1 and JAK2 mutations involved highly conserved residu

242 The JAK1/JAK2 inhibitor AZD1480 blocked the effect of cytoki

243 The JAK1/JAK2 inhibitor ruxolitinib produced significant red

244 Increased HIF-1alpha activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self

245 timulates IL-10 production by activating the JAK1- and PI3K-signaling pathways.

246 ha (HIF-1alpha) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and A

247 ferentiation by inhibiting the Notch and the JAK1/STAT1/STAT3 pathways, respectively.

248 llate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of

249 eukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib.

250 In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel t

251 rs, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somat

252 duces cancer progression by deactivating the JAK1/STAT3 pathway.

253 AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein

254 esult from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors.

255 over, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT

256 edisposition to moderate selectivity for the JAK1 isoform over JAK2.

257 germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cyto

258 t results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, th

259 Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1

260 Moreover, the JAK1/2 inhibitor ruxolitinib restored sensitivity to the

261 omatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib.

262 utations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and con

263 arthritis (RA), by specific targeting of the JAK1 pathway.

264 cate that CDDO-Me inhibits activation of the JAK1-->STAT3 pathway by forming adducts with both JAK1 a

265 miR-23a cluster-mediated-inactivation of the JAK1-Stat3 pathway promotes the expression and activity

266 strate that clinically relevant doses of the JAK1/2 inhibitor ruxolitinib suppresses the harmful cons

267 improvement after the administration of the JAK1/2 inhibitor ruxolitinib.

268 ne whether pharmacological inhibition of the JAK1/2 not only prevents the onset of HLH immunopatholog

269 There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcr

270 Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticip

271 ER stress-induced activation of the JAK1/STAT3 axis leads to expression of interleukin 6 (IL

272 In the present study the JAK1/2 inhibitor ruxolitinib reduced phosphorylation of

273 This mutation was identical to the JAK1 V658F mutation previously found in human APL and ac

274 emcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus

275 of inhibiting the JAK/STAT pathway using the JAK1/2 inhibitor, AZD1480.

276 stem/progenitor cells were treated with the JAK1/2 inhibitor ruxolitinib (RUX).

277 ly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased poly

278 Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3

279 Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood cou

280 In both models, treatment with the JAK1/2 inhibitor ruxolitinib significantly lessened the

281 d peripheral blood MF CD34(+) cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number

282 These JAK1 epigenetic target genes encode important regulators

283 lly, IFNG activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a

284 and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes.

285 JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in

286 standard assays, but compared with wild-type JAK1, JAK1(T478S), and JAK1(V623A) expression was associ

287 d provide an example wherein a cytokine uses JAK1 and JAK2 to mediate the activation of STAT5.

288 ound 4 novel somatic mutations, JAK1(V623A), JAK1(T478S), DDR1(A803V), and NTRK1(S677N), once each in

289 ivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties.

290 Stat3 is phosphorylated via JAK1 and acts as a critical ALK5 (activin receptor-like

291 vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray st

292 as IL-7 receptor or IL-9 receptor, in which JAK1 is appended to the specific chain, and JAK3 is appe

293 direct mechanism, CDDO-Me forms adducts with JAK1 at Cys(1077) in the kinase domain and inhibits JAK1

294 ibutes of an X-ray structure in complex with JAK1.

295 receptor abolishes stable interactions with JAK1, although it was previously shown that box2 alone i

296 We show that APLNR interacts with JAK1, modulating interferon-gamma responses in tumours,

297 mechanisms of thrombocytopenia observed with JAK1/2 inhibition.

298 rmed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation.

299 Within JAK1 the K142, P430, and K860 frame-shift mutations were

300 se (ROS1 or TYK2) were also discovered in WT JAK1/STAT3 ALK(-) ALCL.