ライフサイエンスコーパス: JAK3

1 protein kinase (prkdc), and janus kinase 3 (jak3).

2 mains of Shc were responsible for binding to Jak3.

3 d PTP1B to Jak3 and thereby dephosphorylated Jak3.

4 ta-catenin facilitated its interactions with Jak3.

5 e residues on beta-catenin phosphorylated by Jak3.

6 ne phosphorylate and functionally inactivate Jak3.

7 esin) domain and induced gain of function in JAK3.

8 trols and found 4 patients with mutations in JAK3.

9 romote the ubiquitination and degradation of JAK3.

10 inhibition of JAK1/JAK2 and no inhibition of JAK3.

11 therapeutic strategy that involves targeting Jak3.

12 r further phosphorylation of beta-catenin by Jak3.

13 via a direct interaction with phosphorylated JAK3.

14 xploit a unique cysteine (Cys909) residue in JAK3.

15 ovided exceptional selectivity for JAK2 over JAK3 (23).

16 We screened our compound library against JAK3, a key signaling kinase in immune cells, and identi

17 amma) as a critical growth determinant for a JAK3(A572V) mutation-positive acute myeloid leukemia cel

18 letely abrogated the clonogenic potential of JAK3(A572V), as well as the transforming potential of ad

19 JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors

20 as the transforming potential of additional JAK3-activating mutations such as JAK3(M511I).

21 e trans-molecular mechanism of regulation of Jak3 activation by Shc.

22 e mechanism of trans-molecular regulation of Jak3 activation is not known.

23 lar mechanism of intracellular regulation of Jak3 activation where Jak3 interactions with Shc acted a

24 beta and gammac chain, consequently blocking Jak3 activation.

25 than previously determined is necessary for JAK3 activation/gammaC-mediated signaling in response to

26 ses and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays.

27 Thus, pharmacological inhibition of JAK3 activity may provide a promising treatment option f

28 suggesting that Fsk can negatively regulate Jak3 activity possibly mediated through PKA.

29 Inhibition of JAK3 activity reduced the phosphorylation of cPLA2 and C

30 by chemokines is also dependent on JAK2 and JAK3 activity.

31 tion of an additional mutation in the mutant JAK3 allele.

32 Lack of Jak3 also resulted in exaggerated symptoms of metabolic

33 n to regulate lymphopoiesis, Janus kinase 3 (JAK3) also plays a critical role in promoting lymphocyte

34 nants that regulate the interactions between Jak3 and cytoskeletal proteins of the villin/gelsolin fa

35 molecular mechanism of interactions between Jak3 and cytoskeletal proteins where tyrosine phosphoryl

36 olecular switch for the interactions between Jak3 and cytoskeletal proteins.

37 te-limiting step during interactions between Jak3 and cytoskeletal proteins.

38 wn of IL2Rgamma abrogates phosphorylation of JAK3 and downstream signaling molecules, JAK1, STAT5, MA

39 onstrate the negative regulatory function of JAK3 and elucidate the signaling pathway by which JAK3 d

40 Whereas JAK3 and Fes marginally activate PLD2 in non-transformed

41 Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflamm

42 ib, a Janus kinase (JAK) inhibitor targeting JAK3 and JAK1.

43 rylation of the signaling molecules Jak1 and Jak3 and negative regulation of signaling via Jak and th

44 highlights a unique signaling axis in which JAK3 and p38 MAPK regulate the activity of multiple enzy

45 are especially sensitive to a combination of JAK3 and PLD2 enzymatic activity inhibitors (30nM apigen

46 We also consistently found that JAK3 and PLD2 pathways are utilized at the maximum effic

47 nants that regulate the interactions between Jak3 and Shc and demonstrate the trans-molecular mechani

48 Direct interactions between mutants of Jak3 and Shc showed that although FERM domain of Jak3 wa

49 ulation that exists between the two kinases (JAK3 and the oncogene Fes) and between these two kinases

50 ated by PLD2 under direct regulation of both JAK3 and the tyrosine kinase, epidermal growth factor re

51 ited tyrosine phosphatases SHP2 and PTP1B to Jak3 and thereby dephosphorylated Jak3.

52 e genes encoding two of the four human JAKs (JAK3 and TYK2) and three of the six human STATs (STAT1,

53 through direct interactions of Shc with both Jak3 and tyrosine phosphatases.

54 f cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphop

55 on of cell invasion by two kinases (EGFR and JAK3) and a phospholipase (PLD2) provides regulatory fle

56 Phosphorylation of Janus kinase 3 (JAK3) and signal transducers and activator of transcript

57 ting IL-2R complex formation, recruitment of JAK3, and activation of AKT and ERK1/2 and a transcripti

58 icate that HuR is tyrosine-phosphorylated by JAK3, and link this modification to HuR subcytoplasmic l

59 t expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML.

60 tro-epidermal growth factor receptor (EGFR), JAK3, and Src (with JAK3 reported for the first time in

61 Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multipl

62 ctive sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within

63 these kinases as Y(296) for EGFR, Y(415) for JAK3, and Y(511) for Src.

64 JAK1 and JAK3 are recurrently mutated in acute lymphoblastic leuk

65 The products of the oncogene Fes and JAK3 are tyrosine kinases, whose expressions are elevate

66 Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, b

67 Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved i

68 lin and that tyrosine autophosphorylation of Jak3 at the SH2 domain decreased these intramolecular in

69 We show that Jak3 autophosphorylation was the rate-limiting step duri

70 villin/gelsolin-wt as substrate showed that Jak3 autophosphorylation was the rate-limiting step duri

71 We demonstrate that Jak3 autophosphorylation was the rate-limiting step duri

72 ful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune

73 action studies indicated that phosphorylated Jak3 bound to phosphorylated beta-catenin with a dissoci

74 sulted in elevated serine phosphorylation of Jak3 but not Stat5, suggesting that Fsk can negatively r

75 in NP (FOXP3, TGFB1, IL10, SMAD3, IL2RA, and JAK3), but transcription factors associated with Th2 (GA

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

77 ed through the activation of Janus kinase 3 (JAK3) by the vitamin K3 analog menadione.

78 ctivity, the Y(415) is a prominent site, and JAK3 compensates the negative modulation by EGFR on Y(29

79 Our data suggest that wild-type JAK3 competes with mutant JAK3 (M511I) for binding to th

80 ssion of IL2Rgamma, indicating IL2Rgamma and JAK3 contribute to constitutive JAK/STAT signaling throu

81 e combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype,

82 es from SCID patients with IL-2RG (n = 3) or JAK3 deficiency (n = 2), which produce similar "T-NK-B+"

83 impaired B-cell responses after HCT in IL2RG/JAK3 deficiency results from poor donor B-cell engraftme

84 studied 28 transplanted patients with IL2RG/JAK3 deficiency.

85 y and to restore antibody responses in IL2RG/JAK3-deficient patients after HCT.

86 ruiting the E2 enzymes, were able to prevent JAK3 degradation induced by both ASB2/SKP2 and NOTCH sig

87 ral Janus kinase inhibitor that targets Jak1/Jak3 dependent Stat activation, has been assessed as a s

88 gamma chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocke

89 lymphocyte-specific protein tyrosine kinase/JAK3-dependent activation of the PI3K/AKT pathway with l

90 seful tools to pharmacologically interrogate JAK3-dependent biology.

91 on through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), dem

92 interactions with Shc acted as regulators of Jak3 dephosphorylation through direct interactions of Sh

93 and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory

94 trans-phosphorylation of beta-catenin, where Jak3 directly phosphorylated three tyrosine residues, vi

95 ring Jak3 trans-phosphorylation of Shc where Jak3 directly phosphorylated two tyrosine residues in Sr

96 ive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro.

97 tor, CEP-33779 (JAK2 enzyme IC(50) = 1.3 nM; JAK3 enzyme IC(50)/JAK2 enzyme IC(50) = 65-fold), was te

98 The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design o

99 Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas

100 Interestingly, the R980W mutant of JAK3 exhibited diminished interaction with SKP2 and resi

101 titutive JAK3 mutant signaling by increasing JAK3 expression and phosphorylation.

102 Jak3 expression in these cells was essential for AJ loca

103 nt growth and were not affected by wild-type JAK3 expression.

104 In summary, the JAK3, Fes and PLD2 interactions in transformed cells mai

105 A new JAK3-Fes-PLD2 axis is responsible for the highly prolife

106 Modulating this new JAK3-Fes-PLD2 pathway could be important to control the

107 domains of nonphosphorylated Jak3 prevented Jak3 from binding to villin and that tyrosine autophosph

108 l maturation/differentiation requires intact JAK3 function, even if partially functioning T lymphocyt

109 Although mutations that abrogate Jak3 functions cause different immunological disorders,

110 ibitors or specific small interfering RNA or JAK3 gene knockout resulted in an increase in TLR-mediat

111 also identified, including in the PDGFRA and JAK3 genes.

112 NOTCH signaling leads to the degradation of JAK3 in B lineage cells, suggesting that NOTCH signaling

113 Investigating JAK3 in cancer cells led to an important discovery as ex

114 A 2.9 A cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction

115 res of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4

116 reviously, we characterized the functions of Jak3 in cytoskeletal remodeling, epithelial wound healin

117 rome, present studies determined the role of Jak3 in development of such conditions.

118 Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD.

119 of PI3K enhanced this regulatory ability of JAK3 in LPS-stimulated monocytes.

120 However, the role of Jak3 in mucosal differentiation and inflammatory bowel d

121 In this report, we characterize the role of Jak3 in mucosal differentiation, basal colonic inflammat

122 requirement for signaling through IL-2RG and JAK3 in normal development of human lymphoid progenitors

123 se results demonstrate the essential role of Jak3 in promoting mucosal tolerance through suppressed e

124 results in loss of mature T and B cells and jak3 in T and putative Natural Killer cells.

125 se results demonstrate the essential role of Jak3 in the colon where it facilitated mucosal different

126 ely, we found that mutant, but not wild-type JAK3, increased the expression of IL2Rgamma, indicating

127 Specifically, JAK3 inhibition by pharmacological inhibitors or specifi

128 Moreover, JAK3 inhibition correlated with an increased CD4(+) T ce

129 In this study, we found that JAK3 inhibition enhanced TLR-mediated immune responses b

130 JAK3 inhibition exhibited a GSK3 activity-dependent abil

131 rstood, although the suppressive function of JAK3 inhibition in adaptive immune response has been wel

132 tion of GSK3beta abrogated the capability of JAK3 inhibition to enhance proinflammatory cytokines and

133 e risk of immune suppression associated with JAK3 inhibition was undertaken.

134 se studies support further evaluation of the Jak3 inhibitor CP-690,550 in the treatment of select pat

135 herein are the first studies on the use of a JAK3 inhibitor in lentivirus infected NHP.

136 Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival.

137 Recent findings show that the JAK3 inhibitor utilized in the studies reported herein h

138 ing our unique FLT3 substrate and identified JAK3 inhibitor VI (designated JI6 hereafter) as a novel

139 Consistently, JAK3 inhibitor was able to significantly reduce the grow

140 ecernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo

141 and blocked by tofacitinib, a clinical-grade JAK3 inhibitor.

142 infection, use was made of a Janus kinase 3 (JAK3) inhibitor that has previously been shown to be eff

143 esults warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.

144 decades, identification of highly selective JAK3 inhibitors has eluded the scientific community.

145 n of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909)

146 ned and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the

147 nted with neutralizing anti-IL-2 Ab or STAT5/JAK3 inhibitors, indicating that STAT5 signaling drives

148 Previously, we demonstrated that Jak3 interacted with actin-binding protein villin, there

149 and human intestinal epithelial cells where Jak3 interacted with and activated p85, the regulatory s

150 d 41, ezrin, radixin, and moesin) domains of Jak3 interacted with beta-catenin, the NTD domain of bet

151 Thus, we not only characterize Jak3 interaction with beta-catenin but also demonstrate

152 Thus we not only characterize Jak3 interaction with Shc, but also demonstrate the mole

153 Previously we reported that Jak3 interactions with adapter protein p52ShcA (Shc) fac

154 the structural determinants responsible for Jak3 interactions with beta-catenin and determine the fu

155 cellular regulation of Jak3 activation where Jak3 interactions with Shc acted as regulators of Jak3 d

156 JAK3 is a tyrosine kinase that associates with the commo

157 JAK1 is appended to the specific chain, and JAK3 is appended to the common gamma chain.

158 SCID resulting from mutations in IL2RG or JAK3 is characterized by lack of T and natural killer ce

159 ak3 knock-out (KO) mouse model, we show that Jak3 is expressed in colonic mucosa of mice, and the los

160 Numerous studies have demonstrated that Jak3 is widely involved in the activation cascade and fu

161 Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase expressed in both

162 Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase expressed in both

163 JAK2 and JAK3 isoforms, but not JAK1, mediate CXCL12-induced LFA-

164 imilarities between the TYK2, JAK1, JAK2 and JAK3 isozymes.

165 lling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrup

166 d functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/

167 /paracrine systems that in turn activate the Jak3 (Janus kinase 3)/STAT5 (signal transducers and acti

168 ity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak

169 Using the Jak3 knock-out (KO) mouse model, we show that Jak3 is ex

170 JAK3 knockdown abrogated lipase activity and epidermal-g

171 At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of S

172 testinal epithelium erosion were observed in JAK3 knockout mice.

173 Jak3 KO mice showed reduced expression of colonic villin

174 shed JAK-receptor interaction did not affect JAK3(L857P) activity, whereas it inhibited the other rec

175 In contrast, transduction with JAK3(L857P) induced various types of lymphoid and myeloi

176 e same cytokine receptor independence as for JAK3(L857P) was observed for homologous Leu(857) mutatio

177 or complex to constitutively activate STAT5, JAK3(L857P) was unexpectedly found to not depend on such

178 proved much less potent on cells expressing JAK3(L857P).

179 Leu(857) mutations of JAK1 and JAK2 and for JAK3(L875H).

180 h constitutive activation of Janus kinase 3 (Jak3) leads to different cancers, the mechanism of trans

181 l effect on lymphopoiesis through modulating JAK3 levels.

182 We demonstrate that JAK3 (M511I) can increase its limited oncogenic potentia

183 est that wild-type JAK3 competes with mutant JAK3 (M511I) for binding to the common gamma chain and t

184 additional JAK3-activating mutations such as JAK3(M511I).

185 domain of JAK3 (Y100C) completely abrogated JAK3-mediated leukemic transformation.

186 lar interplay between AJ dynamics and EMT by Jak3-mediated NTD phosphorylation of beta-catenin.

187 Physiologically, Jak3-mediated phosphorylation of beta-catenin suppressed

188 Moreover, loss of Jak3-mediated phosphorylation sites in beta-catenin abro

189 found IL2Rgamma contributes to constitutive JAK3 mutant signaling by increasing JAK3 expression and

190 provide an explanation of why progression of JAK3-mutant T-ALL cases can be associated with the accum

191 Surprisingly, we observed that one third of JAK3-mutant T-ALL cases harbor 2 JAK3 mutations, some of

192 Pairwise binding between Jak3 mutants and P-villin-wt showed that the FERM domain

193 with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-A

194 s underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a ne

195 JAK3 mutants induce constitutive JAK/STAT signaling and

196 though JAK3(V674A) and the majority of other JAK3 mutants needed to bind to a functional cytokine rec

197 signaling complex in 293T cells showed that JAK3 mutants required receptor binding to mediate downst

198 These double JAK3 mutants show increased STAT5 activation and increas

199 ansient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activa

200 Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOH

201 lexes in mediating the oncogenic activity of JAK3 mutants.

202 n potentiating oncogenesis in the setting of JAK3-mutation-positive leukemia.

203 our insight into the oncogenic properties of JAK3 mutations and provide an explanation of why progres

204 Our data show that JAK3 mutations are drivers of T-ALL and require the cyto

205 -cell engraftment can occur in patients with JAK3 mutations despite the presence of autologous T cell

206 rt the transforming potential of a series of JAK3 mutations identified in primary T-cell acute lympho

207 ltogether, our results showed that different JAK3 mutations induce constitutive activation through di

208 The study of 3 patients with hypomorphic JAK3 mutations suggests that terminal B-cell maturation/

209 ne third of JAK3-mutant T-ALL cases harbor 2 JAK3 mutations, some of which are monoallelic and others

210 sed the transforming potential of activating JAK3 mutations, whereas absence of IL2Rgamma completely

211 and function of 3 patients with hypomorphic JAK3 mutations.

212 sociated with the accumulation of additional JAK3 mutations.

213 ations, including activating Janus kinase 3 (JAK3) mutations, were detected.

214 rposes of activating PLD2 for cell invasion, JAK3 operates via an alternative pathway that is indepen

215 ts from activating mutations either in JAK1, JAK3, or in both kinases.

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

217 JAK3 phosphorylated HuR at tyrosine 200, in turn inhibit

218 d EGFR colocalized at the cell membrane, and JAK3 phosphorylation at Tyr980/Tyr981 followed receptor

219 IRS-2, STAT6, and JAK3 phosphorylation was observed in CHO cells expressin

220 itors delay and reduce IL-7-induced JAK1 and JAK3 phosphorylation.

221 analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation.

222 ate that conserved IL-2Rgammac signaling via JAK3 plays a key role during early zebrafish lymphopoies

223 xplained for the first time by combined high JAK3/PLD2 phosphorylation and activity involving PLD2's

224 ed cells in culture show an upregulated EGFR/JAK3/PLD2-PA system and are especially sensitive to a co

225 he FERM and SH2 domains of nonphosphorylated Jak3 prevented Jak3 from binding to villin and that tyro

226 However, the SH2 domain of Jak3 prevented P-villin-wt from binding to the FERM doma

227 el, we found that phosphorylation of EZH2 by JAK3 promotes the dissociation of the PRC2 complex leadi

228 interleukin-2 beta receptor (IL-2Rbeta) and JAK3 proteins; however, the association of Lyn with the

229 We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vit

230 JAK3 pseudokinase mutants were dependent on Jak1 kinase

231 t has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the respo

232 fferentiated human colonic epithelial cells, Jak3 redistributed to basolateral surfaces and interacte

233 In addition, JAK3 regulates cPLA2 phosphorylation independent of tran

234 factor receptor (EGFR), JAK3, and Src (with JAK3 reported for the first time in this study)-that pho

235 y through covalent interaction with a unique JAK3 residue Cys-909.

236 , or its direct downstream signaling partner JAK3, result in T and NK cell deficiency, an associated

237 Our data show that loss of Jak3 resulted in increased body weight, basal systemic C

238 mice, and the loss of mucosal expression of Jak3 resulted in reduced expression of differentiation m

239 was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimid

240 can predict in vivo B-cell immunity in IL2RG/JAK3 SCID after transplantation.

241 himerism, and quality of life (QoL) of IL2RG/JAK3 SCID patients >2 years post-HSCT at our center.

242 IL2RG/JAK3 SCID survivors free from immunoglobulin replacement

243 In both IL-2RG- and JAK3-SCID patients, the early stages of lymphoid commitm

244 In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white b

245 All of these events were blocked by the JAK3-selective inhibitor, PF-956980.

246 n interleukin-2 gamma-chain receptor (IL2RG)/JAK3 severe combined immunodeficiency (SCID).

247 related with the inhibition of both JAK1 and JAK3 signaling pathways.

248 d protein kinase (MAPK), and Janus kinase 3 (JAK3) signaling are necessary for F. tularensis-induced

249 anti-IL-2Ralpha Ab or inhibitors of JAK1 and JAK3 significantly reduced IFN-gamma production of the T

250 he identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform spec

251 avorable efficacy and safety profile of this JAK3-specific inhibitor 11 led to its evaluation in seve

252 r cells were, in contrast, more sensitive to JAK3-specific inhibitors.

253 ion mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total approximately 11%

254 Here we show that IL-2-JAK3-STAT5 signaling is required for Th9 differentiation

255 Inhibition of IL-2 signaling via Jak3-Stat5 was required during this step to generate CD4

256 els that include IL-2R complex formation and Jak3/Stat5 activation.

257 between at least two signaling pathways: the Jak3/Stat5 and cAMP-mediated cascades.

258 proximal signaling through the IL-7R-coupled JAK3/STAT5 pathway.

259 L6 in Th9 cells is under the control of IL-2/JAK3/STAT5 signaling pathway.

260 tion is thought to be driven by constitutive Jak3/Stat5 signaling, mostly due to autocrine production

261 ency mutational activation of the IL2RG-JAK1-JAK3-STAT5B axis in the pathogenesis of T-PLL.

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

263 tations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mu

264 Most importantly, activation of the JAK3-STAT6 pathway, downstream of IL-4, is required for

265 Effects of IL-4 were mediated via JAK3/STAT6 and we propose a potential role for JAK inhib

266 fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist.

267 Inhibition of JAK3 suppressed phosphorylation of PI3K downstream effec

268 wever, in 2-h or 16-h starved cell cultures, JAK3 switches to a PLD2-enhancing role, consistent with

269 Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD.

270 kinases (PKC, FES, EGF receptor (EGFR), and JAK3) that are activated by it, or PLD becomes the targe

271 In this study, we focused on JAK3, the nonreceptor tyrosine kinase that signals from

272 d pave the way toward multitargeted JAK1 and JAK3 therapy in T-ALL.

273 Both ASB2 and SKP2 can interact with JAK3 through different domains; the FERM and pseudo-kina

274 ve and metastatic, did not substantially use JAK3 to activate PLD2.

275 horylation was the rate-limiting step during Jak3 trans-phosphorylation of beta-catenin, where Jak3 d

276 horylation was the rate-limiting step during Jak3 trans-phosphorylation of Shc where Jak3 directly ph

277 he biological significance of NOTCH-mediated JAK3 turnover.

278 degree of allelic heterogeneity at the human JAK3, TYK2, STAT1, and STAT3 loci has revealed highly di

279 nd humans carrying biallelic null alleles of JAK3, TYK2, STAT1, or STAT5B.

280 The Janus kinase 3 (JAK3) tyrosine kinase is mutated in 10% to 16% of T-cell

281 hemical mechanisms involved in NOTCH-induced JAK3 ubiquitination and degradation.

282 Together, these results suggest that JAK3 ubiquitination involves the non-canonical dimeric E

283 ase activity by recombinant full-length (wt) Jak3 using Jak3-wt or villin/gelsolin-wt as substrate sh

284 Although JAK3(V674A) and the majority of other JAK3 mutants neede

285 nsduction of murine hematopoietic cells with JAK3(V674A) led homogenously to lymphoblastic leukemias

286 cells transformed by the receptor-dependent JAK3(V674A), yet proved much less potent on cells expres

287 y three mutations, which encoded NRAS(A18T), JAK3(V722I) and MET(R970C) in three specimens.

288 inome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties.

289 Functionally Jak3 was autophosphorylated under IL-2 stimulation in ep

290 Previously, we reported that Jak3 was essential for mucosal differentiation and enhan

291 Mechanistically, Jak3 was essential for reduced expression and activation

292 d P-villin-wt showed that the FERM domain of Jak3 was sufficient for binding to P-villin-wt with a K(

293 and Shc showed that although FERM domain of Jak3 was sufficient for binding to Shc, CH1 and PID doma

294 by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activa

295 2 (PLD2) is under control of Janus kinase 3 (JAK3), which mediates chemotaxis.

296 d CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding.

297 PLD2 is under the control of Janus kinase 3 (JAK3), with the kinase phosphorylating PLD2 at the Y415

298 ic parameters showed that phosphorylated (P) Jak3-wt binds to P-villin-wt with a dissociation constan

299 y by recombinant full-length (wt) Jak3 using Jak3-wt or villin/gelsolin-wt as substrate showed that J

300 gamma interaction site in the FERM domain of JAK3 (Y100C) completely abrogated JAK3-mediated leukemic