ライフサイエンスコーパス: MEKK4

1 ted JNK activation requires MEKK2, MEKK3 and MEKK4.

2 lso interacted with MEKK1 and MEKK2, but not MEKK4.

3 oding splice variants of a novel MEK kinase, MEKK4.

4 serines and threonines in the N terminus of MEKK4.

5 TRAF4 interacts with the kinase domain of MEKK4.

6 n-interacting MAP kinase kinase kinase Ssk2p/MEKK4, a member of the high-osmolarity glycerol (HOG) MA

7 muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase

8 ficient mice generated thus far, the loss of MEKK4, a regulator of Flna, produces striking PH in mice

9 ocks MEKK4 dimerization that is required for MEKK4 activation, effectively inhibiting MEKK4 stimulati

10 e TRAF4, Axin, and GADD45, GSK3beta inhibits MEKK4 activity and prevents its activation of JNK and p3

11 Lack of MEKK4 activity in vivo also leads to a significant reduc

12 cochlear and vestibular HCs, suggesting that MEKK4 activity is essential for overall development of H

13 expression, suggesting that Fgf20 modulates MEKK4 activity to regulate cellular differentiation.

14 hat loss of FGF20 signaling in vivo inhibits MEKK4 activity, whereas gain of Fgf20 function stimulate

15 ly, we demonstrate, for the first time, that MEKK4 acts as a critical node to integrate FGF20-FGFR1 s

16 RNA interference (RNAi) targeting MEKK4 also impaired neuronal migration.

17 en-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to p

18 vely, our results demonstrate a link between MEKK4 and Fln-A that impacts neuronal migration initiati

19 K4 protein precipitated a complex containing MEKK4 and Fln-A, and MKK4 mediated signaling between MEK

20 d Fln-A, and MKK4 mediated signaling between MEKK4 and Fln-A, suggesting that MKK4 may bridge these m

21 Kinase-inactive MEKK4 and inhibition of the p38 MAPK pathway both select

22 ity of the mitogen-activated protein kinases MEKK4 and p38 but is independent of NFkappaB signaling.

23 ADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cyto

24 that GSK3beta binds to the kinase domain of MEKK4 and regulates MEKK4 dimerization.

25 The interaction of MEKK4 and TRAF4 are further demonstrated by the colocali

26 xpression while only trace amounts of MEKK3, MEKK4, and MLK3 mRNA were detected.

27 Of the four MEKKs tested, only MEKK3 and MEKK4 are involved in arsenate-mediated activation of JN

28 We also identify MEKK4 as a critical hub kinase for FGF20-FGFR1 signaling

29 Our results define MEKK4 as a signaling hub for FGF4 activation of JNK that

30 The findings identify MEKK4 as the MAPK kinase kinase for TRAF4 regulation of

31 These data identify MEKK4 as upstream of c-Jun N-terminal kinase in the path

32 In contrast, other MAP3Ks, including MEKK4, ASK1, and MLK3, fail to show evidence of activati

33 Here, we show that endogenous TRAF4 and MEKK4 associate in both human K562 cells and mouse E10.5

34 MEKK4 binds the TRAF domain of TRAF4 and MEKK4/TRAF4 act

35 MEKK4 binds to Cdc42 and Rac; kinase-inactive mutants of

36 We find that a MAP3K, MEKK4, binds to RIP2 to sequester RIP2 from the NOD2 sig

37 to Cdc42 and Rac; kinase-inactive mutants of MEKK4 block Cdc42/Rac stimulation of the JNK pathway.

38 GSK3beta binding to MEKK4 blocks MEKK4 dimerization that is required for MEK

39 The MEKK4 carboxyl-terminal catalytic domain is approximatel

40 a production in MEKK4+/+ T cells, but not in MEKK4-/- cells or in cells treated with a p38 inhibitor.

41 ition of the NOD2-driven NFkappaB pathway by MEKK4 could be important in the pathogenesis of Crohn's

42 Analyses of the neuroepithelium in MEKK4-deficient embryos showed massively elevated apopto

43 Here we generated MEKK4-deficient mice to define the function and regulati

44 In contrast, proliferation of MEKK4-deficient neuroepithelial cells appeared to be lar

45 a significant reduction in MKK4 activity in MEKK4-deficient neuroepithelium at sites of neural tube

46 Mice deficient in MEKK4 develop highly penetrant NTDs that cannot be rescu

47 Thus, control of MEKK4 dimerization is regulated both positively and nega

48 GSK3beta binding to MEKK4 blocks MEKK4 dimerization that is required for MEKK4 activation

49 ta is required for binding and inhibition of MEKK4 dimerization.

50 to the kinase domain of MEKK4 and regulates MEKK4 dimerization.

51 n can be stimulated by chemical induction of MEKK4 dimerization.

52 t with this model, silencing of TNFalpha and MEKK4 dramatically reduces cystine-deprived death.

53 losure, suggesting an antiapoptotic role for MEKK4 during development.

54 To identify downstream targets of MEKK4 during neural tube development, we examined the ac

55 ominant negative versions of either MEKK1 or MEKK4 effectively blocks both the activation of Jun N-te

56 togen-activated protein kinase kinase kinase MEKK4 exhibit dysregulated placental development with in

57 phogenesis and identifies the requirement of MEKK4 expression in regulating the specific response of

58 y, whereas gain of Fgf20 function stimulates MEKK4 expression, suggesting that Fgf20 modulates MEKK4

59 w that mitogen-activated protein 3 kinase 4 (MEKK4) expression is highly regulated during inner ear d

60 elopment and FGF20/FGFR1 signaling activated MEKK4 for normal sensory cell differentiation.

61 iated NOD2 polymorphisms cannot compete with MEKK4 for RIP2 binding.

62 Expression of Fln was elevated in MEKK4(-/-) forebrain, most notably near sites of failed

63 MEKK4 has a putative pleckstrin homology domain and a pr

64 The amino-terminal region of MEKK4 has little sequence homology to the previously clo

65 Lastly, we find that MEKK4 helps dictate signal specificity downstream of NOD

66 onstrated by the colocalization of TRAF4 and MEKK4 in cells.

67 compelling evidence of an essential role for MEKK4 in inner ear morphogenesis and identifies the requ

68 ownstream of NOD2 activation as knockdown of MEKK4 in macrophages exposed to MDP causes increased NFk

69 re, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4

70 d protein kinase kinases (MKKs) regulated by MEKK4 in the p38 pathway.

71 Expression of the dominant negative form of MEKK4, in contrast, effectively blocks both morphogen-in

72 activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses.

73 on with TRAF4 and Axin, the kinase domain of MEKK4 interacts with the multifunctional serine/threonin

74 MEKK4 is a MAP kinase kinase kinase that interacts with

75 MEKK4 is believed to be auto-inhibited, and its interact

76 MEKK4 is localized in a perinuclear, vesicular compartme

77 d that FGFR1 signaling through activation of MEKK4 is necessary for outer hair cell differentiation.

78 The MAPK kinase kinase MEKK4 is required for neurulation and skeletal patternin

79 re, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepit

80 a pathway that sequentially involved H-Ras, MEKK4, JNK, Fas ligand/Fas interactions, and caspase-9 a

81 Hindbrains of exencephalic MEKK4(K1361R) embryos show a striking increase in neuroe

82 ted, demonstrating a loss of p38 activity in MEKK4(K1361R) embryos.

83 Compared to the wild type, MEKK4(K1361R) fibroblasts showed significantly reduced p

84 4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R)).

85 e activity with SB216763 results in enhanced MEKK4 kinase activity and increased JNK and p38 activati

86 Furthermore, TRAF4 stimulates MEKK4 kinase activity by promoting MEKK4 oligomerization

87 ls induced a similar EMT response as loss of MEKK4 kinase activity, including inhibition of E-cadheri

88 However, this association does not require MEKK4 kinase activity.

89 Isolated MEKK4 kinase-inactive trophoblast stem (TS) cells cultur

90 MEKK4 kinase-inactive TS cells show a preferential diffe

91 JNK) and p38 activity is markedly reduced in MEKK4 kinase-inactive TS cells.

92 regulatory regions of Gcm1 and MMP2 genes in MEKK4 kinase-inactive TS cells.

93 Here, we show that the MEKK4 (MAP3K4) pathway is involved in Fln-A regulation a

94 Thus, MEKK4 mediates the action of GADD45beta and GADD45gamma

95 A human MAPKKK, MTK1 (= MEKK4), mediates activation of both p38 and JNK in respo

96 is inhibited by a kinase-inactive mutant of MEKK4, MEKK4K1361R.

97 MEKK4(-/-) mice developed PVH associated with breaches i

98 CD4 T cells from MEKK4-/- mice have reduced p38 activity and defective IF

99 onstitutively active form of either MEKK1 or MEKK4 mimicked the action of retinoic acid, inducing the

100 The MEKK4 mRNA is widely expressed in mouse tissues and enco

101 Unlike most mouse models of NTDs, MEKK4 mutant embryos display genetically co-segregated e

102 Mice homozygous for a kinase-inactive MEKK4 mutation exhibit significant hearing loss.

103 timulates MEKK4 kinase activity by promoting MEKK4 oligomerization and JNK activation can be stimulat

104 umors have strong activation of TNFalpha and MEKK4-p38-Noxa pathways that render them susceptible to

105 differentiation, the GADD45beta/GADD45gamma/MEKK4 pathway appears to integrate upstream signals tran

106 MEKK4 phosphorylates and activates MKK4/MKK7 and MKK3/MK

107 n of the active site lysine of MEK kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K

108 kinase 4 (MEKK4) produces a kinase-inactive MEKK4 protein (MEKK4(K1361R)).

109 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient

110 he findings are the first demonstration that MEKK4-regulated p38 activity is critical for neurulation

111 Together, these data demonstrate MEKK4 regulation of p38 and that substrates downstream o

112 JNK independently, coexpression of TRAF4 and MEKK4 results in synergistic activation of JNK that is i

113 This MEKK4:RIP2 complex dissociates upon exposure to the NOD2

114 his study, we show, for the first time, that MEKK4 signaling is essential for the development of norm

115 mal cytoarchitecture and hearing function as MEKK4 signaling-deficient mice exhibit a significant red

116 MEKK4 specifically activates the JNK pathway but not ERK

117 for MEKK4 activation, effectively inhibiting MEKK4 stimulation of the JNK and p38 MAPK pathways.

118 GADD45gamma promotes IFNgamma production in MEKK4+/+ T cells, but not in MEKK4-/- cells or in cells

119 MEKK4 therefore plays a critical role in regulating MKK4

120 MEKK4 thus sequesters RIP2 to inhibit the NOD2:RIP2 comp

121 The signal linkage map from MEKK1/MEKK4 to MEK1/MKK4 to JNK is obligate in this G alpha(13

122 MEKK4 binds the TRAF domain of TRAF4 and MEKK4/TRAF4 activation of JNK is inhibited by expression

123 The role of MEKK1 and MEKK4 upstream of the c-Jun N-terminal kinase was invest

124 racellular signal-regulated kinase kinase 4 (MEKK4), was induced by IL-18 and augmented by IL-12.

125 e and dominant negative mutants of MEKK1 and MEKK4 were created and characterized.

126 Dominant negative forms of MEKK1 and MEKK4 were expressed stably in the clones harboring Q226

127 AP kinase kinase kinase, MTK1 (also known as MEKK4), which mediates activation of both p38 and JNK.

128 AF4, GADD45, and Axin each bind and activate MEKK4, with TRAF4 and Axin binding to the kinase domain