ライフサイエンスコーパス: MEKK

1 MEKK 2 and 3 encode proteins of 69.7 and 71 kDa, respect

2 MEKK-1 also played an essential role in myosin light cha

3 he association of PKCbeta with MEK kinase 1 (MEKK-1), an upstream effector of the SAPK/ERK kinase 1 (

4 nuclear c-Abl associates with MEK kinase 1 (MEKK-1), an upstream effector of the SEK1-->SAPK pathway

5 d mitogen-activated protein kinase kinase-1 (MEKK-1) were activated in response to TNF-alpha.

6 en-activated protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated p

7 acellular signal-regulated kinase) kinase-1 (MEKK-1), and Raf-B were not present.

8 required for activation of the MEK kinase-1 (MEKK-1)--> SAPK pathway.

9 overexpression constitutively active MEKK-1 (MEKK-1COOH), a protein that strongly activates extracell

10 tivation in the MEKK1 (MAPK kinase kinase 1)/MEKKs-MKK4/5-MPK3/6 cascade, HopF2 targets additional co

11 main, a small GTP-binding (ras) domain and a MEKK domain.

12 and oxidative stress activate Spc1/StyI by a MEKK-dependent process, whereas heat shock activates Spc

13 Our findings define a MEKK-regulated JNK pathway activated by FcepsilonRI that

14 gulator of thymocyte apoptosis while MINK, a MEKK kinase, is required for negative selection.

15 Our findings also suggest that a MEKK cascade diverges to regulate effectors other than t

16 ed that PKCbeta phosphorylated and activated MEKK-1 in vitro.

17 n Swiss 3T3 and REF52 fibroblasts, activated MEKK induces cell death involving cytoplasmic shrinkage,

18 Expression of activated MEKK enhanced the apoptotic response to ultraviolet irra

19 Inducible expression of activated MEKK stimulated the transactivation of c-Myc and Elk-1.

20 Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage.

21 caspases can induce apoptosis by activating MEKK-1, which in turn activates more caspase activity, c

22 ase (JNK), along with its upstream activator MEKK-1, is typically thought of as a stress-activated ki

23 Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuc

24 II alpha regulation, a constitutively active MEKK that stimulates these two kinases simultaneously wa

25 ycin or overexpression constitutively active MEKK-1 (MEKK-1COOH), a protein that strongly activates e

26 Transfection of constitutively active MEKK-1, an upstream activator of the mitogen-activated p

27 dependent scaffolding complex that amplifies MEKK-MEK5-ERK5 signaling.

28 K and JNK cascades at the level of Raf-1 and MEKK-1 could account for the inhibitory action of dexame

29 Activated forms of Ras, RacI, Cdc42Hs, and MEKK increased expression of the c-jun promoter, while d

30 e catalytically inactive mutants of JNK1 and MEKK, also partially inhibited the shear-induced lucifer

31 2 (42 kDa), a 54-kDa ERK, MEK1 (45 kDa), and MEKK (78 kDa).

32 JNK(K-R) and MEKK(K-M), the respective catalytically inactive mutants

33 Activated forms of H-Ras and MEKK stimulate signals that result in nuclear translocat

34 phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IkappaKalp

35 ediators, including c-Src, TRAF2, TRAF6, and MEKK-1, levels of which were notably reduced in TNFr1 kn

36 athway, whereas that between G alpha(13) and MEKKs is not known.

37 binds to endogenous ERK2, MEK1, and another MEKK level kinase, Raf-1, suggesting that it can assembl

38 ulators of JNK activity (MLK, LZK, TAK, ASK, MEKK, and TPL); however, the specificity underlying whic

39 by MEKK appears to be cell-specific, because MEKK did not activate the TPH promoter in nonneuronal ce

40 a dominant-negative fragment of ECSIT blocks MEKK-1 processing and activation of NF-kappaB.

41 of the small GTPase Rho, also inhibited both MEKK- and phenylephrine-induced ANF expression, indicati

42 0 bp in PAI-1 promoter that was activated by MEKK-1 and selectively blocked by the MEK1,2 inhibitor P

43 The activation by MEKK appears to be cell-specific, because MEKK did not a

44 which was previously shown to be mediated by MEKK.

45 ntly transfected wild-type MMP-9 promoter by MEKK-1, a specific c-Jun NH2-terminal kinase activator,

46 Phosphorylation of SMRT by MEKK-1 and, to a lesser extent, MEK-1 inhibits the abili

47 uct expression constitutively activated (ca) MEKK-1 increases levels of phospho-dependent neurofilame

48 n the c-Jun N-terminal kinase (JNK) cascade, MEKK-1 (mitogen-activated protein kinase/ERK kinase), is

49 t from those of the previously characterized MEKKs.

50 t a DEVD motif-specific caspase that cleaves MEKK-1 specifically is activated when cells lose matrix

51 e sequence homology to the previously cloned MEKK proteins.

52 Whereas expression of DA-MEKK-1 resulted in the constitutive activation of JNK al

53 Differential MEKK subcellular distribution and interaction with small

54 scopy of COS cells demonstrated differential MEKK subcellular localization: MEKK1 was nuclear and in

55 minant active (DA) or dominant negative (DN) MEKK-1.

56 ng CD3/CD28-induced IL-2 mRNA expression, DN-MEKK-1 abrogated the transcriptional activation of the I

57 transformants expressing IkappaBalphaM or DN-MEKK, respectively.

58 he minimal interleukin-2 (IL-2) promoter, DN-MEKK-1 inhibited JNK responsiveness during CD3/CD28 co-s

59 by EGF, and kinase-inactive mutants of each MEKK partially inhibited EGF-stimulated JNK activity.

60 hear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad

61 Overexpression of Sp1 enhanced MEKK-1-induced MRE promoter activity and a dominant-nega

62 MEK6 is only a poor substrate for MEKK, a mitogen-activated protein kinase kinase kinase t

63 Of the four MEKKs tested, only MEKK3 and MEKK4 are involved in arsen

64 but not ERKs or p38, distinguishing it from MEKKs 1, 2 and 3, which are capable of activating the ER

65 These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT an

66 Immunoprecipitated MEKK 2 phosphorylated the MAP kinase kinases, MEK 1, and

67 on of JNK activity by catalytically inactive MEKK (in which methionine was substituted for the lysine

68 mera also was inhibited by a kinase-inactive MEKK.

69 ockdown of PKC downstream targets, including MEKK-1, MEK-6, MEK-3, or p38-delta, indicates that these

70 results also demonstrate that c-Abl induces MEKK-1-mediated phosphorylation and activation of SEK1-S

71 egulated kinase 1 (MEK-1), and MEK-1 kinase (MEKK-1).

72 llular signal-regulated kinase (ERK) kinase (MEKK) > stress-activated protein kinase (SAPK)-ERK kinas

73 We found that MAP kinase kinase kinase (MEKK) 1, a JNK1 activator, induced transcription from th

74 ctivated protein (MAP) kinase kinase kinase (MEKK) 1, MAP kinase kinase (MEK) 3/6, and p38 MAP kinase

75 -activated protein kinase/ERK kinase kinase (MEKK) 1, MEKK2, apoptosis-signal regulating kinase-1, TG

76 xtracellular signal-regulated kinase kinase (MEKK) and Saccharomyces cerevisiae STE11, is required fo

77 However, coexpression of JNK kinase kinase (MEKK) effectively increased JNK activity, but resulted i

78 signal-regulated kinase (ERK) kinase kinase (MEKK) level of stress-responsive MAPK pathways.

79 lular-signal regulated kinase kinase kinase (MEKK), an activator of MAP kinases.

80 ed by a dominant negative JNK kinase kinase (MEKK)-1.

81 y, we cloned a full-length human MEK kinase (MEKK) 2 cDNA from Jurkat T-cells and demonstrated that i

82 negative forms of Ras, RacI, and MEK kinase (MEKK) inhibited EGF induction.

83 5PAK protein kinases), Ste11 [an MEK kinase (MEKK) or MAPK kinase (MEK) kinase], Ste7 (MEK or MAPK ki

84 e first kinase in the cascade, a MEK kinase (MEKK), is characterized by its ability to activate one o

85 ough a pathway requiring Ras and MEK kinase (MEKK).

86 f MAP kinase/ERK kinase (MEK) by MEK kinase (MEKK).

87 kinase (ERK) kinase (MEK), and a MEK kinase (MEKK).

88 se (MEK), in turn activated by a MEK kinase (MEKK).

89 f activated by Wik1/Wak1/Wis4, a MEK kinase (MEKK).

90 we investigated the role of the MEK kinase (MEKK)1/ERK/p90 ribosomal S6 kinase (RSK)1-dependent C/EB

91 ellular response kinase kinase (MEK) kinase (MEKK) is a serine-threonine kinase that regulates sequen

92 nant-negative MAP kinase kinase (MEK kinase, MEKK-1), confirming that HBx stimulates the prolonged sy

93 MAPKK kinase/MEKK phosphorylates and activates its downstream protein

94 antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular sig

95 inase cascades, the MAPK/ERK kinase kinases (MEKK), have been described in several systems.

96 itogen-activated protein/ERK kinase kinases (MEKKs) phosphorylate and activate protein kinases which

97 ular signal-regulated kinase kinase kinases (MEKKs), we have identified specific proteins that are in

98 lar signal-regulated kinase kinase) kinases (MEKKs) regulate c-Jun N-terminal kinase and extracellula

99 MEK kinases (MEKKs) 1, 2, 3 and 4 are members of sequential kinase pa

100 MEK kinases (MEKKs) are serine-threonine kinases that regulate sequen

101 ulates apoptosis; the wild-type, full-length MEKK-1 sensitizes cells to anoikis; and a cleavage-resis

102 e isolated the cDNAs for two novel mammalian MEKKs (MEKK 2 and 3).

103 MAPKK or MEK) and a MAPKK/MEK kinase (MAPKKK/MEKK).

104 homology to the kinase domains of the MAPKKK/MEKK level protein kinases from mouse MEKK2 and -3, Dros

105 ted the cDNAs for two novel mammalian MEKKs (MEKK 2 and 3).

106 d activated by MKK/MEK kinases (Raf and MKKK/MEKKs).

107 h as intracellular signaling (e.g. Raf, MLK, MEKK, PI-3 kinase, IRS-1), cell cycling (e.g. Cdc25, Wee

108 owever, the pro-apoptotic signaling molecule MEKK-1 was up-regulated in both apoptotic and non-apopto

109 r gene expression, while a dominant negative MEKK mutant inhibits ANF expression induced by PE.

110 n that the expression of a dominant negative MEKK-1 mutant abrogated this response.

111 the siRNA induced knockdown of NIK, but not MEKK-1, prevented the TNF-alpha activation of both NF-ka

112 by the serine/threonine kinases NIK but not MEKK.

113 a indicate that in neutrophils activation of MEKK in addition to Raf may underlie stimulation of MAP

114 Activation of MEKK was determined on immunoprecipitates from FMLP-stim

115 d that IL-1beta caused a rapid activation of MEKK-1 and NIK.

116 his association as well as the activation of MEKK-1 are disrupted by dexamethasone treatment.

117 Notably, activation of MEKK-1 or MEK-1 signaling in transfected cells also lead

118 Activation of MEKK-1, which acts as a mitogen-activated protein kinase

119 nstrate c-Abl kinase-dependent activation of MEKK-1.

120 in vivo and that MLK3 mediates activation of MEKK-SEK-JNK kinase cascade by Rac1 and Cdc42.

121 g that JNK is a major downstream effector of MEKK-1 on NF phosphorylation.

122 Expression of MEKK 2 or 3 in HEK293 cells results in activation of p42

123 These findings define a family of MEKK proteins capable of regulating sequential protein k

124 A constitutively active form of MEKK-1 but not mitogen-activated protein kinase kinase-1

125 pression of a dominant-negative (dn) form of MEKK-1 decreases it.

126 hoA-dependent pathway that is independent of MEKK, and microinjection of mutationally active Galpha 1

127 acellular stress stimuli or via induction of MEKK, an upstream kinase of SAPK, results in MKP-1 gene

128 Inhibition of MEKK-1 activation of the canonical pathway prevented the

129 The knockdown of MEKK-1, but not NIK, inhibited the IL-1beta increase in

130 A constitutively activated mutant of MEKK that preferentially activates JNK, stimulates ANF r

131 anoikis; and a cleavage-resistant mutant of MEKK-1 partially protects cells against anoikis.

132 to NF-kappaB and suggest that processing of MEKK-1 is required for its function in the Toll/IL-1 pat

133 of wild-type ECSIT accelerates processing of MEKK-1, whereas a dominant-negative fragment of ECSIT bl

134 uction and partial N-terminal proteolysis of MEKK-1 observed in apoptotic cells.

135 -dependent MEK cleavage and up-regulation of MEKK-1.

136 the Toll/IL-1 pathways and is a regulator of MEKK-1 processing.

137 The functional role of MEKK-1 in TPA-induced SAPK activity was further supporte

138 Titration of MEKK 2 and 3 expression in transfection assays indicated

139 gs indicate that c-Abl functions upstream of MEKK-1-dependent activation of SAPK in the response to g

140 y 55% homologous to the catalytic domains of MEKKs 1, 2, and 3.

141 PAK-regulated JNK pathway is independent of MEKKs.

142 , protected cells from either anisomycin- or MEKK-1COOH-induced apoptosis.

143 K or MEK), and MAPK kinase kinase (MAPKKK or MEKK).

144 e inhibitors of p38 MAP kinase (SB203580) or MEKK (PD98059), p38 but not ERK activation was shown to

145 Potential upstream MAPKK kinases (MAPKKKs or MEKKs) in this cascade include the orthologs of Arabidop

146 nonical and noncanonical NF-kappaB pathways; MEKK-1 regulated the activation of the canonical pathway

147 inds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo.

148 mids expressing dominant-negative Ras, Rac1, MEKK-1, or JNK along with the [PGS2][luciferase] reporte

149 3T3 cells requires activation of a Ras/Rac1/MEKK-1/JNK kinase/JNK signal transduction leading to pho

150 se activities of protein kinase C, Abl, Raf, MEKK, ERK, JNK, MKK-3, MKK-4/SEK, MKK-6, Cdk2, or Cdk4.

151 R mediates ANF gene expression through a Ras-MEKK-JNK pathway and that activation of this pathway is

152 y fluid shearing activates primarily the Ras-MEKK-JNK pathway in inducing endothelial gene expression

153 s of MEK expression, and did not up-regulate MEKK-1.

154 I by a novel mechanism that does not require MEKK activation or Pyp1 inhibition.

155 s, in different cellular locations, specific MEKKs are required for the regulation of MAPK family mem

156 ivated protein kinase (MAPK) cascade: Ste11 (MEKK), Ste7 (MEK), and Fus3 (MAPK).

157 RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic

158 ession in transfection assays indicated that MEKK 2 preferentially activated JNK while MEKK 3 prefere

159 to ultraviolet irradiation, indicating that MEKK-regulated pathways sensitize cells to apoptotic sti

160 usion, our data show for the first time that MEKK-1 plays an integral role in IL-1beta modulation of

161 protein (MAP) kinase cascade comprising the MEKK Ste11, the MEK Ste7 and two MAP kinases, Fus3 and K

162 either of two MAPK cascade constituents, the MEKK (Ste11) and the MEK (Ste7).

163 lls, which express Wis1 protein that has the MEKK consensus phosphorylation sites replaced with aspar

164 Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional act

165 We were unable to show inhibition of the MEKK response by GF 109203X, a protein kinase C-specific

166 of ROS is associated with activation of the MEKK-1-->SAPK cascade.

167 ctivation is necessary for activation of the MEKK-1-->SEK1-->SAPK cascade in the TPA response of myel

168 When overexpressed, the MEKK-1 cleavage product stimulates apoptosis; the wild-t

169 Mutational analysis revealed that the MEKK-1 response element (MRE) contained 2 cis-acting Sp1

170 for TPA-induced ROS production and that the MEKK-1-->SAPK pathway is activated by a ROS-mediated mec

171 owever, additional studies indicate that the MEKK-1/JNK pathway mediates critical aspects of neuronal

172 These findings indicate that the MEKK-1/JNK pathway regulates critical aspects of initial

173 and responded to MAPK activation through the MEKK pathway but not in hippocampal cells.

174 ng a protein with sequence similarity to the MEKK family of Ser/Thr kinases, was isolated from an eye

175 se domain has the greatest similarity to the MEKK protein kinase family.

176 serine/threonine kinase that belongs to the MEKK/STE11 family of MAP kinase kinase kinases (MAP(3)Ks

177 e the NF-kappaB-inducing activities of these MEKKs.

178 Thus, MEKK selectively regulates signal transduction pathways

179 72, and 54 kDa with a monoclonal antibody to MEKK.

180 demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and

181 a kinase domain that is 40-48% identical to MEKK family members.

182 ese signaling pathways that bridges TRAF6 to MEKK-1.

183 ivates the c-jun promoter by a Ras-to-Rac-to-MEKK pathway.

184 /StyI in cells that express Wis1AA, in which MEKK consensus phosphorylation sites were replaced with

185 at MEKK 2 preferentially activated JNK while MEKK 3 preferentially activated p42/44MAPK.

186 any of the cellular changes associated with MEKK-mediated cell death.

187 Similarly, interfering with MEKK, which lies upstream of JNK1, using a dominant nega