ライフサイエンスコーパス: MEKK3

1 lar signal-regulated kinase kinase kinase 3 (MEKK3).

2 d CCM2 cooperate to regulate the activity of MEKK3.

3 which TAK1 regulates autophosphorylation of MEKK3.

4 anscriptional program that are downstream of MEKK3.

5 of p38 upstream kinases, including ASK1 and MEKK3.

6 iated via p38 MAPK, a downstream effector of MEKK3.

7 ing with the N-terminal regulatory domain of MEKK3.

8 regulatory and C-terminal kinase domains of MEKK3.

9 n agreement with a previous report on murine MEKK3.

10 We have isolated a cDNA encoding human MEKK3.

11 substrate targeting by the MAP3Ks, MEKK2 and MEKK3.

12 ion, and that this surface is conserved with MEKK3.

13 ndemly duplicated gene family with MEKK2 and MEKK3.

14 CDK2, -5, and -7, CALM3, MAPAKP5, and MAP3K/MEKK3.

15 n through dephosphorylating and inactivating MEKK3.

16 end basic region of the MAPK kinase kinase, MEKK3.

17 equired to dampen the activity of the kinase MEKK3(1-4).

18 Our evidence also indicates that Ras and MEKK3, a MEK5 kinase in non-neuronal cells, do not play

19 Map3k3 (also known as Mekk3), which encodes Mekk3, a member of the Mekk/Ste11 family, in mice.

20 expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM

21 Moreover, Mekk3 activated myocyte-specific enhancer factor 2C (Mef

22 We now demonstrate that MEKK3 activates SEK and MEK, the known kinases targeting

23 Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5,

24 However, the precise regulation for MEKK3 activation at the molecular level is still not ful

25 Finally, we found that MEKK3 activation by TCR stimulation requires Rac1/2.

26 irpin RNA knockdown of p62 inhibits IL-1 and MEKK3 activation of NF-kappaB.

27 negative charge at Ser526 was necessary for MEKK3 activity and implicating Ser526 as a phosphorylati

28 Moreover, we demonstrate that MEKK3 activity is required for growth factor mediated ce

29 ve mutations in MEKK2 and seven mutations in MEKK3, all located within 20 kb of the mekk1-1 T-DNA ins

30 on of dominant negative mutants of MEKK2 and MEKK3 also blocked activation of ERK5 by WNK1.

31 nscription factor NFkappaB, we now show that MEKK3 also enhances transcription from an NFkappaB-depen

32 Finally, the association between MEKK3 and 14-3-3 was dependent on Ser526 and prevented d

33 ast, small interference RNA directed against MEKK3 and a dominant negative form of MEKK3 caused the r

34 Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for t

35 Of the four MEKKs tested, only MEKK3 and MEKK4 are involved in arsenate-mediated activa

36 nite-mediated JNK activation requires MEKK2, MEKK3 and MEKK4.

37 We found that both MEKK3 and NIK exert effects on IKKalpha/beta activation,

38 TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activa

39 ith a fusion protein composed of full-length MEKK3 and the death domain of RIP (MEKK3-DD).

40 c associates with the phosphorylated form of MEKK3 and the interaction between PP2Ac and MEKK3 is ind

41 Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibi

42 homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 A cocrystal structure.

43 in, we analyze the functional role of MEKK2, MEKK3, and MEK5 PB1 domains in the ERK5 activation pathw

44 oded within the N-terminal portion of MEKK2, MEKK3, and MEK5.

45 ted protein kinase kinase kinases, MEKK2 and MEKK3, and this interaction may in part be mediated thro

46 CCM2 binds to MEKK3, and we have recently shown that CCM complex regul

47 ults established that elevated expression of MEKK3 appears to be a frequent occurrence in breast and

48 MEKK2 and MEKK3 are differentially associated with signaling from

49 MEKK2 and MEKK3 are MAPK kinase kinases that activate the ERK5 pat

50 The kinase domains of MEKK2 and MEKK3 are nearly identical, although their N-terminal re

51 MEKK2 and MEKK3 are two closely related mitogen-activated protein

52 We identify MEKK3 as a critical signaling molecule during endocardia

53 Taken together, these results identify MEKK3 as a kinase that regulates the activity of MEK5 an

54 yeast two-hybrid screen, we have identified MEKK3 as a molecule that physically interacts with MEK5.

55 It was 94% homologous with human and murine MEKK3 at the catalytic domains and 60% homologous at the

56 beta-isoform results in dephosphorylation of MEKK3 at Thr-516 and Ser-520 and termination of MEKK3-me

57 iption factor KLF4 (a downstream effector of MEKK3) augment mTOR signalling in endothelial cells.

58 The PB1 domains of MEKK2 and MEKK3 bind the PB1 domain of MEK5 but do not significant

59 at specifically recognized phospho-Ser526 of MEKK3 but did not recognize the S526A point mutant.

60 ed c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4.

61 noreactive MEKK2, TAK1, and trace amounts of MEKK3 but not MEKK1 or apoptosis-signal regulating kinas

62 Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF.

63 Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventr

64 We now show that MEKK2 and MEKK3 can in vivo activate IKK-alpha and IKK-beta, induc

65 Endothelial cells that lack the MEK kinase MEKK3 cannot form vessels.

66 gainst MEKK3 and a dominant negative form of MEKK3 caused the reduction of NFAT activation in respons

67 Rho-ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular le

68 evidenced by the fact that cellular MEK5 and MEKK3 co-immunoprecipitate.

69 p62 and MEKK3 co-localize in speckles or aggregates that are cen

70 Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cel

71 The p62-MEKK3 complex binds TRAF6, which regulates the ubiquitin

72 aggregates or speckles-associated TRAF6-p62-MEKK3 complex for control of NF-kappaB activation.

73 Constitutively active mutants of MEKK3, consisting of S526D and S526E, were capable of ac

74 as replacement with acidic residues rendered MEKK3 constitutively active.

75 tems to examine whether stable expression of MEKK3 could lead to increased NFkappaB activity and conf

76 MEKK3 critically blocks mitogen-driven expression of cyc

77 d NF-kappaB activation was fully restored by MEKK3-DD in these cells.

78 In these cells, MEKK3-DD substitutes for RIP and directly associates wit

79 ll-length MEKK3 and the death domain of RIP (MEKK3-DD).

80 ree of homology with MEKK3, MEKK2-DD, unlike MEKK3-DD, also fails to restore TNF-alpha-induced NF-kap

81 We find Mekk3 deficiency impairs neurovascular integrity, which

82 ably, under a nonpolarizing condition (Th0), Mekk3 deficiency led to a significant reduction of IFN-g

83 en-activated protein kinase kinase kinase 3 (MEKK3)-deficient fibroblast cells, we found that MEKK3 p

84 d p38 MAPKs activation was also defective in Mekk3-deficient CD4 T cells.

85 cially IFN-gamma production, was impaired in Mekk3-deficient CD4 T cells.

86 Conversely, restoring MEKK3 to the MEKK3-deficient cells restored angiotensin II-mediated c

87 Bone marrow cells (BM) from LacZ(+) Mekk3-deficient conditional knockout mice (Mekk3(Deltafl

88 emodeling increases EHT by wild-type but not MEKK3-deficient endothelium.

89 Genetic studies showed that MEKK3-deficient mouse embryo fibroblasts failed to activ

90 IFN-gamma production and MAPK activation in Mekk3-deficient T cells was not affected suggesting that

91 density compared with mice transplanted with Mekk3(Deltaflox/+) BM cells.

92 Because the grafted Mekk3(Deltaflox/-) BM cells cannot contribute to vessel

93 Strikingly, chimeric mice transplanted with Mekk3(Deltaflox/-) BM exhibited a reduction in tumor gro

94 nfirmed that chimeric mice transplanted with Mekk3(Deltaflox/-) BM were impaired for tumor vessel for

95 Mekk3(Deltaflox/-) cells that were LacZ positive were vi

96 ) Mekk3-deficient conditional knockout mice (Mekk3(Deltaflox/-) mice) were transplanted into irradiat

97 MEKK3-dependent activation of an NF-kappaB reporter gene

98 We postulate that TLR8-mediated MEKK3-dependent IKKgamma phosphorylation might play an i

99 interferon-gamma increase RUNX1+ HECs in an MEKK3-dependent manner.

100 The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylatio

101 The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylatio

102 ated NFkappaB activation: TAK1-dependent and MEKK3-dependent pathways, respectively.

103 Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFkappaB activation to produ

104 orm IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFkappaB activation, which i

105 n is believed to be a critical component for MEKK3-dependent signal transduction, but little is known

106 for NFkappaB activation, TAK1-dependent and MEKK3-dependent, respectively.

107 Utilizing an estrogen ligand-activated MEKK3 derivative, we furthermore demonstrate that MEKK3

108 MEKK3-driven mesenchyme production is further substantia

109 sis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully exa

110 in (RIP) was found to interact strongly with MEKK3 during oltipraz-induced NF-kappaB signaling, imply

111 kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3) negatively regulated transform

112 ssel development in the same way as the host Mekk3(+/+) endothelial cells, angiogenesis is normal in

113 Stimulation of the conditional mutant Delta MEKK3:ER* in asynchronous hamster (CCl39) and rat (Rat-1

114 Activation of Delta MEKK3:ER* inhibited cell proliferation through a combina

115 colin and then released, activation of Delta MEKK3:ER* resulted in the up-regulation of p21(CIP1) and

116 Delta MEKK3:ER*-mediated CDK inhibition and G2 arrest did not

117 igated in breast and ovarian cancers whether MEKK3 expression may be altered and correlated with aber

118 Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates

119 MEKK3 forms a complex with TRAF6 in response to IL-1 and

120 Thus, MEKK3 functions downstream of the AT1 receptor and is es

121 The free PB1 domain of MEKK2 or MEKK3 functions effectively to inhibit the ERK5 pathway

122 yed mice with hematopoietic deletions of the Mekk3 gene to evaluate the importance of vasculogenesis

123 Transfected MEKK3 has the ability to activate both SAPK and ERK path

124 racellular-regulated kinase kinase kinase-3 (MEKK3) has been shown to participate in the activation o

125 In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1.

126 g MAP kinase 1 (BMK1) function downstream of MEKK3 in a signaling cascade that induces calcineurin ac

127 nstrating that CCM1 associates with CCM2 and MEKK3 in a ternary complex.

128 d ovarian cancers and that overexpression of MEKK3 in cells leads to increased NFkappaB activity and

129 gether, our study reveals a specific role of MEKK3 in mediating the TCR signals for IFN-gamma product

130 In contrast, siRNA-mediated knockdown of Mekk3 in TC71 Ewing's sarcoma cells had no effect on tum

131 ion, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling.

132 ting cross-talk between the CCM proteins and MEKK3 in vivo.

133 The MEKK3-induced block of cyclin D1 expression and of cell

134 MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB tr

135 knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardi

136 Although TAK1-MEKK3 interaction is not affected by overexpressed TAB1,

137 se-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formatio

138 We have also shown that MEKK3 interacts with RIP and directly phosphorylates IKK

139 MEKK3 is a central intermediate signaling component in l

140 MEKK3 is a conserved Ser/Thr protein kinase belonging to

141 In summary, Ser526 of MEKK3 is an autophosphorylation site within the T-loop t

142 MEKK3 is both necessary and sufficient for expression of

143 We previously showed that active MEKK3 is capable of stimulating calcineurin/nuclear fact

144 MEKK3 is constitutively expressed in T cells, but its fu

145 Furthermore, MEKK3 is crucial for IL-1- and LPS-induced activation of

146 These data demonstrate that MEKK3 is crucial for IL-1R and TLR4 signaling through th

147 ecently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development.

148 Our results show that MEKK3 is essential in the regulation of rapid activation

149 MEKK3 and the interaction between PP2Ac and MEKK3 is induced by LPA in a transient fashion in the ce

150 MEKK3 is involved in the formation of the IkappaBalpha:N

151 We conclude that Mekk3 is necessary for blood vessel development and may

152 In vitro, MEKK3 is not required for Th1 and Th2 cell differentiati

153 MEKK3 is observed to endocardial cells of the cardiac cu

154 The kinase activity of MEKK3 is pivotal to its function and, therefore, MEKK3 l

155 We have shown that MEKK3 is required for IKK activation and functions downs

156 ditional knockout (T-cKO) mice, we show that MEKK3 is required for T cell immunity in vivo.

157 Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart.

158 MAPK/ERK kinase kinase 3 (MEKK3) is a mitogen-activated protein kinase kinase kina

159 Here we show that MAPK-ERK kinase kinase (MEKK3) is an essential signal transducer of the MyD88-IR

160 The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developm

161 that recapitulates in vivo EMT and show that MEKK3(KI) attenuates mesenchyme formation.

162 We used a kinase inactive form of MEKK3 (MEKK3(KI)) in an in vitro assay that recapitulates in vi

163 rylation, which is associated with decreased MEKK3 kinase activity and down-regulation of MKK3/6 and

164 the precise mechanism for the termination of MEKK3 kinase activity is not fully understood.

165 these results suggest an involvement of the MEKK3 kinase in negative regulation of cell cycle progre

166 It is demonstrated here that the MEKK3 kinase inhibits cell proliferation, a biologic res

167 ne/threonine kinase similar to the mammalian MEKK3 kinase.

168 elial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation,

169 Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid sh

170 an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but

171 Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multipl

172 3 is pivotal to its function and, therefore, MEKK3 links RIP and IKK in TNF-induced NF-kappaB activat

173 fy mutations in the closely linked MEKK2 and MEKK3 loci.

174 The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis i

175 ir upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3).

176 These observations suggest that MEKK3 may function during production of cushion mesenchy

177 ent T cells was not affected suggesting that MEKK3 may selectively mediate the TCR-induced MAPK signa

178 As such, MEKK3 may serve as a therapeutic target to control cance

179 Finally, we determined that MEKK3-mediated activation of calcineurin/NFAT signaling

180 experiments indicated that TRAF7 potentiated MEKK3-mediated AP1 and CHOP activation and induced apopt

181 epletion of TRAF7 by antisense RNA inhibited MEKK3-mediated AP1 and CHOP activation.

182 ically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation.

183 The MEKK3-mediated block of proliferation also reverses Ras-

184 own of PP2Ac expression enhances LPA-induced MEKK3-mediated IkappaB kinase beta (IKKbeta) phosphoryla

185 kinase activation loop that is essential for MEKK3-mediated IkappaB kinase beta (IKKbeta)/NF-kappaB a

186 K3 at Thr-516 and Ser-520 and termination of MEKK3-mediated NF-kappaB activation.

187 We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required

188 d JNK activation are completely abolished in MEKK3(-/-) MEFs, whereas IL-1-mediated signaling was onl

189 teractions, including p62-p62, p62-NBR1, and MEKK3-MEK5 interactions.

190 in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.

191 Compared with MEKK3, MEKK2 activated BMK1/ERK5 to a greater extent, wh

192 ugh MEKK2 has a high degree of homology with MEKK3, MEKK2-DD, unlike MEKK3-DD, also fails to restore

193 We used a kinase inactive form of MEKK3 (MEKK3(KI)) in an in vitro assay that recapitulate

194 was completely blocked by a kinase-inactive MEKK3 (MEKK3kin(-)), whereas MEKK2kin(-) had no effect.

195 gene expression while only trace amounts of MEKK3, MEKK4, and MLK3 mRNA were detected.

196 y, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)

197 t hypertonicity activates p38 via a Rac1-OSM-MEKK3-MKK3-p38 pathway and that p38alpha contributes to

198 ery that root growth in a triple mekk1 mekk2 mekk3 mutant (mekk1/2/3), defective in a set of three ta

199 The binding affinity of 14-3-3 for the MEKK3 N terminus was 90 nM, demonstrating a high affinit

200 MEKK3 neither binds Lad/RIBP nor is recruited to the T c

201 e show that stable cell lines overexpressing MEKK3 not only had elevated levels of NFkappaB binding a

202 siRNA knockdown of osmosensing scaffold for MEKK3 (OSM) also reduces high NaCl-dependent TonEBP/OREB

203 ly characterized as osmosensing scaffold for MEKK3 (OSM).

204 ctivated by nuclear factor kappaB via a CCM2-MEKK3 pathway that has been implicated in hyperosmotic s

205 ific and unique requirement of the MEKK2 and MEKK3 PB1 domain in regulating ERK5 activation.

206 Expression in cells of the MEKK2 or MEKK3 PB1 domain inhibits ERK5 activation, whereas expre

207 phatase, protein phosphatase 2A (PP2A), as a MEKK3 phosphatase.

208 tion-deficient Akt decreases VEGF-stimulated MEKK3 phosphorylation and increases MKK/p38 activation.

209 The TAK1-mediated regulation of MEKK3 phosphorylation is dependent on the kinase activit

210 te that lipopolysaccharide induced MEKK2 and MEKK3 phosphorylation on their regulatory serine.

211 expressing constitutively active Akt causes MEKK3 phosphorylation, which is associated with decrease

212 required for TAK1 activation and subsequent MEKK3 phosphorylation.

213 We determined that angiotensin II induced MEKK3 phosphorylation.

214 These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammat

215 3)-deficient fibroblast cells, we found that MEKK3 plays a critical role in TNF-induced NF-kappaB act

216 indicating that RIP-dependent recruitment of MEKK3 plays a specific role in TNF-alpha signaling.

217 Here we report that Mekk3 plays an intrinsic role in embryonic vascular deve

218 cant fraction of these samples have elevated MEKK3 protein levels with corresponding increases in NFk

219 derivative, we furthermore demonstrate that MEKK3 regulates the SAPK and the ERK pathway directly.

220 pression of these genes, and partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos.

221 Silencing of mekk3 rescues the big heart and body axis phenotype, sug

222 erine 519 and serine 526, in MAP3K MEKK2 and MEKK3, respectively.

223 MEKK3 serves as a critical intermediate signaling molecu

224 novel TRAF family member that is involved in MEKK3 signaling and apoptosis.

225 ecognized novel essential regulatory role of MEKK3 signaling in calcineurin/NFAT activation.

226 These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanism

227 increased expression of cell survival genes, MEKK3 stable cells showed reduced activation of caspases

228 A conditionally activated form of MEKK3 stably expressed in fibroblasts arrests these cell

229 tion, we show that a dominant active form of MEKK3 stimulates BMK1 activity through MEK5.

230 Furthermore, we show that MEKK3 stimulates EMT via a TGFbeta(2)-dependent mechanis

231 Using Mekk3 T cell conditional knockout (T-cKO) mice, we show

232 Mekk3 T-cKO mice had reduced T cell response to bacteria

233 CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADA

234 Unlike MEKK2 and MEKK3, the C-terminal kinase domain of MEKK1 demonstrate

235 ish NF-kappaB activation induced by MEKK2 or MEKK3, thereby providing evidence that these IKKs mediat

236 sidues with alanine abolished the ability of MEKK3 to activate IKKbeta/NF-kappaB, whereas replacement

237 1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappaB in TNF-alpha signaling.

238 sidues with alanine abolished the ability of MEKK3 to mediate lysophosphatidic acid-induced optimal I

239 protein kinases that function downstream of MEKK3 to mediate MCIP1 phosphorylation and the mechanism

240 The ability of MEKK3 to simultaneously activate the SAPK and ERK pathwa

241 Conversely, restoring MEKK3 to the MEKK3-deficient cells restored angiotensin

242 t the role of RIP is to specifically recruit MEKK3 to the TNF-alpha receptor complex, whereas the for

243 We report the detection of MEKK3 transcripts to embryonic hearts before, during, an

244 Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular end

245 osphorylated both MEKK2 and -3 in vitro, and MEKK3 was activated by WNK1 in 293 cells.

246 We determined that active MEKK3 was capable of activating calcineurin/nuclear fact

247 The catalytically inactive (K391M) mutant of MEKK3 was not phosphorylated at Ser526, indicating that

248 Endogenous MEKK3 was phosphorylated on Ser526 in response to osmoti

249 We disrupted Map3k3 (also known as Mekk3), which encodes Mekk3, a member of the Mekk/Ste11

250 PRK2 did not bind MEKK3, which is closely related to MEKK2.

251 domain mediates the association of MEKK2 and MEKK3 with MEK5 and that the respective PB1 domains of t

252 p62 is required for the association of MEKK3 with TRAF6 and short hairpin RNA knockdown of p62