ライフサイエンスコーパス: p38gamma

1 p38gamma and p38delta (p38gamma/p38delta) regulate infla

2 p38gamma and p38delta were necessary to maintain steady-

3 p38gamma contains allosteric sites that are conserved am

4 p38gamma phosphorylation (4-fold) and activity (1.5-fold

5 p38gamma protein was not detected in any cell type, alth

6 p38gamma requires phosphorylation and its C terminus to

7 p38gamma shares high sequence homology, inhibition sensi

8 p38gamma, a Ras effector known to act independent of its

9 p38gamma, on the other hand, increases Ras-dependent gro

10 p38gamma/deltaKIKO mice showed a reduced inflammatory re

11 p38gamma/p38delta interacts with the TPL2/A20 Binding In

12 we have identified a key role for the MKK3/6-p38gamma/delta pathway in the development of cardiac hyp

13 The MKK3/6-p38gamma/delta pathway mediated an inhibitory phosphoryl

14 A p38gamma-antagonistic activity of ER was further shown i

15 Here we report that K-Ras activated p38gamma, a p38 MAPK family member, by inducing its expr

16 The activated p38gamma in turn phosphorylates and stabilizes Topo IIal

17 Inflammation activates p38gamma in mouse colon tissues and intestinal epithelia

18 the MAPK kinase kinase family that activates p38gamma.

19 W1 silencing increases MKK4, which activates p38gamma, p38delta, and JNK2 to phosphorylate p53 on Ser

20 The active p38gamma/c-Jun/MMP9 pathway also exists in human colon c

21 In addition, p38gamma is required for beta-catenin/Wnt activities and

22 Additionally, p38gamma/p38delta regulates TPL2 mRNA translation by mod

23 regulating RhoC expression but also advance p38gamma as a candidate therapeutic target.

24 was not detected in any cell type, although p38gamma mRNA was present in endothelial cells.

25 l rearrangement and activation of ERK1/2 and p38gamma MAP kinases.

26 required for beta-catenin/Wnt activities and p38gamma stimulates Wnt transcription by phosphorylating

27 milar to that observed with JNK activity and p38gamma phosphorylation.

28 cally sensitive but not resistant cells, and p38gamma is co-overexpressed with Topo IIalpha protein i

29 K-ras-mutated human colon cancer cells, and p38gamma transcripts were ubiquitously increased in a se

30 ositively regulates p38gamma expression, and p38gamma in turn mediates Ras nonmitogenic signaling to

31 ed for activation of RhoA, ERK1/2, JNK1, and p38gamma MAP kinases.

32 rminus to bind c-Jun, whereas both c-Jun and p38gamma are required for the trans-activation of MMP9.

33 nd Cds1 and that activation of both MKK6 and p38gamma is essential for the proper regulation of the G

34 Both p38alpha and p38gamma are expressed in primary human fibroblasts and

35 These findings have identified p38alpha and p38gamma as essential components of the signaling pathwa

36 mechanistic connection between p38alpha and p38gamma as well as a rationale for targeting this pathw

37 reas constitutive activation of p38alpha and p38gamma caused premature senescence.

38 clin D1 levels, suggesting that p38alpha and p38gamma converge to regulate cyclin D1 during hypoxia.

39 We show that p38alpha and p38gamma transcripts are expressed in early hematopoieti

40 ream from MEK5 (ERK5) and MKK6 (p38alpha and p38gamma) is necessary to fully activate the c-jun promo

41 ent study, we demonstrated that p38alpha and p38gamma, but not p38beta, play an essential role in onc

42 of JNK and p38, including both p38alpha and p38gamma, was measured with immune complex assays.

43 tutively active p38alpha (MKK6-p38alpha) and p38gamma (MKK6-p38gamma) stimulates and inhibits c-Jun p

44 ver, in addition to JNK, ERK5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by a

45 The functions of p38beta and p38gamma in myoblast differentiation are not clear.

46 cells, leading to activation of p38beta and p38gamma, which are not active in differentiating parent

47 We find that p38alpha, p38beta, and p38gamma are early activated by hyperosmotic shock and s

48 Although ERK1, p38alpha, p38beta2, and p38gamma were involved in induction, ERK2 and p38delta p

49 in wild-type (WT), p38gamma-, p38delta-, and p38gamma/delta-deficient (p38gamma/delta(-/-)) mice.

50 diac function and structure of wild-type and p38gamma knockout (KO) mice at baseline and after abdomi

51 sion analyses in LPS-activated wild-type and p38gamma/deltaKIKO macrophages revealed that p38gamma/p3

52 response through disrupting its antagonistic p38gamma family protein.

53 The correlation between p38gamma activation in human muscle during acute exercis

54 n at Ser-118 is required for ER to bind both p38gamma and c-Jun, thereby promoting ER relocation from

55 Moreover, Ras increases both p38gamma and PTPH1 protein expression and there is a cou

56 e transcription factor c-Jun is activated by p38gamma MAPK, and the activated c-Jun then recruits p38

57 Moreover, phosphorylation of calpastatin by p38gamma impaired its ability to inhibit the protease, c

58 n, whereas its inhibition increases cellular p38gamma concentrations, indicating an active role of p3

59 proteins, p38alpha phosphorylation decreases p38gamma protein expression, whereas its inhibition incr

60 a-, p38delta-, and p38gamma/delta-deficient (p38gamma/delta(-/-)) mice.

61 n experiments using Mapk12/Mapk13-deficient (p38gamma/deltaKO) mice, which show low levels of TPL2, t

62 ally reduced in p38gamma/p38delta-deficient (p38gamma/delta(-/-)) cells and tissues without affecting

63 38alpha requires c-Jun activation to deplete p38gamma proteins by ubiquitin-proteasome pathways.

64 technique identified calpastatin as a direct p38gamma substrate.

65 icient for Topo IIalpha expression, the drug-p38gamma-Topo IIalpha axis is only detected in intrinsic

66 E. p38gamma MAPK contributes to left ventricular remodeling

67 Here, we report that the K-Ras effector p38gamma MAPK confers intrinsic resistance to small mole

68 6 KO mice is reverted by knocking out either p38gamma or p38delta or by inhibiting the mTOR pathway w

69 independent of phosphorylation, and elevated p38gamma may serve as a novel diagnostic marker and ther

70 The tumor-promoting activity of epithelial p38gamma was further demonstrated by xenograft studies.

71 that MRK-beta preferentially activates ERK6/p38gamma via MKK3/MKK6 and JNK through MKK4/MKK7.

72 Together, our results establish p38gamma and p38delta as key components in innate immune

73 olving two novel members of the MAPK family, p38gamma (ERK6) and ERK5.

74 ase H1 (PTPH1) as a specific phosphatase for p38gamma mitogen-activated protein kinase (MAPK) and sho

75 e reduced in LPS-stimulated macrophages from p38gamma/delta-null mice, whereas IL-12 and IFNbeta prod

76 stimuli revealed a novel stress pathway from p38gamma to PTPH1/Ser-459 phosphorylation in regulating

77 Significantly, functional p38gamma protein was expressed only in K-ras-mutated hum

78 Furthermore, p38gamma/delta-deficient mice were less sensitive than c

79 Here we demonstrate that p38 MAPK gamma (p38gamma) acts as a CDK-like kinase and thus cooperates

80 In mouse hepatocytes, p38gamma induces proliferation after partial hepatectomy

81 lts offer a detailed characterization of how p38gamma contributes to breast cancer progression.

82 naling event was initiated by hyperexpressed p38gamma that led to increased c-Jun synthesis, MMP9 tra

83 We have identified p38gamma as an important determinant of the progression

84 Evidence implicating p38gamma and p38delta (p38gamma/p38delta) in inflammatio

85 n that invariably couples with a decrease in p38gamma protein expression.

86 ta binds to ACO1, and p38delta expression in p38gamma/delta(-/-) cells fully restores TPL2 protein to

87 tumor number was significantly increased in p38gamma/delta(-/-) chimeric mice with WT bone marrow co

88 Analysis of leukocyte populations in p38gamma/delta(-/-) mouse colon showed less macrophage a

89 2 protein levels are dramatically reduced in p38gamma/p38delta-deficient (p38gamma/delta(-/-)) cells

90 or methionine, the corresponding residue in p38gamma, p38delta, and the JNKs, rendered all five inhi

91 deltaKIKO) mouse, expressing kinase-inactive p38gamma and lacking p38delta.

92 cancer, and there is a coupling of increased p38gamma and MMP9 expression in the primary tissues.

93 ression and there is a coupling of increased p38gamma and PTPH1 protein expression in primary colon c

94 hosphorylation and that depletion of induced p38gamma suppressed Ras transformation in rat intestinal

95 d/or in mice by a mechanism depending on its p38gamma-binding activity.

96 scribed the mitogen-activated protein kinase p38gamma as a cellular partner of PTPN4.

97 ated mitogen-activated protein kinase (MAPK) p38gamma has been implicated in the G(2) phase checkpoin

98 the mitogen activated protein kinase (MAPK) p38gamma.

99 generated a Mapk12(D171A/D171A)/Mapk13(-/-) (p38gamma/deltaKIKO) mouse, expressing kinase-inactive p3

100 hibitors indicated that among the p38 MAPKs, p38gamma is the principal isoform responsible for the ph

101 ic phosphatase and suggest that PDZ-mediated p38gamma/PTPH1 complex may be a novel target for Ras-dep

102 response through depleting its family member p38gamma protein via c-Jun-dependent ubiquitin-proteasom

103 lunts p38alpha activation while causing MKK3-p38gamma/delta hyperphosphorylation and increased mammal

104 irradiation leads to the activation of MKK6, p38gamma, and Cds1 and that activation of both MKK6 and

105 p38alpha (MKK6-p38alpha) and p38gamma (MKK6-p38gamma) stimulates and inhibits c-Jun phosphorylation

106 Activation of the MKK6-p38gamma cascade is sufficient to induce G(2) arrest in

107 Moreover, p38gamma activity was shown to be necessary and sufficie

108 ere, we found that exercise activates muscle p38gamma, increasing locomotor activity through the secr

109 This activation of muscle p38gamma, leading to an increase locomotor activity, pla

110 t p38alpha might be associated with neuronal p38gamma distribution and synaptic dysfunction in these

111 y SB203580, an inhibitor of p38alpha but not p38gamma.

112 This could obscure p38gamma/p38delta roles, since TPL2 is essential for reg

113 3 at Ser(33), suggesting that the ability of p38gamma to mediate senescence is at least partly achiev

114 Here we show that activation of p38gamma (also known as ERK6 or SAPK3), but not the othe

115 K depletion reduced IR-induced activation of p38gamma but had no effect on p38alpha activation, indic

116 stimulated phosphorylation and activation of p38gamma in particular, and also p38alpha, two stress-ac

117 Activation of p38gamma is dependent on ATM and leads to activation of

118 dicating that MRK is a specific activator of p38gamma after IR.

119 Here, we show that deletion of p38gamma and p38delta impaired the innate immune respons

120 rted by evidence that elevated expression of p38gamma is associated with lower overall survival of pa

121 pite the high and preferential expression of p38gamma MAPK in the myocardium, little is known about i

122 tocellular carcinoma show high expression of p38gamma, suggesting that p38gamma could be a therapeuti

123 We found that expression of p38gamma/delta MAPK proteins is required for the elongat

124 Overexpression of a kinase-inactive form of p38gamma was also able to reverse in part the effect of

125 Inhibition of p38gamma by RNA interference, however, did not impair IR

126 Lack of p38gamma or treatment with the p38gamma inhibitor pirfen

127 ently dephosphorylate the activation loop of p38gamma.

128 tase H1 (PTPH1) is a specific phosphatase of p38gamma mitogen-activated protein kinase (MAPK) through

129 hat SKF-86002 promoted the redistribution of p38gamma in neurons differentiated from iPS cells derive

130 ith SKF-86002 promoted the redistribution of p38gamma to synapses and reduced the accumulation of alp

131 We analyzed the role of p38gamma and p38delta in colon cancer associated to coli

132 udies thus demonstrate the essential role of p38gamma in K-Ras transformation independent of phosphor

133 ur previous work showed an essential role of p38gamma mitogen-activated protein kinase in Ras transfo

134 ate the physiologic and biochemical roles of p38gamma in the heart.

135 of recognition of the C-terminal sequence of p38gamma that displays the highest affinity among all en

136 e, the binding of the C-terminal sequence of p38gamma to PTPN4 abolishes the catalytic autoinhibition

137 reinforced, and broken in various states of p38gamma, reflecting the functional state of the protein

138 PTPH1 was identified as a substrate of p38gamma by unbiased proteomic analysis, and its resulta

139 To identify potential substrates of p38gamma, we generated an analog-sensitive mutant to aff

140 ther substrates, as a novel direct target of p38gamma that may contribute to the protection observed

141 Selective targeting of p38gamma-dependent invasion pathways may be a novel stra

142 tight interaction between the C terminus of p38gamma and the PDZ domain of PTPN4.

143 investigated the effects of this compound on p38gamma and neurodegenerative pathology.

144 sion of dominant negative alleles of MKK6 or p38gamma allows cells to escape the DNA damage-induce G(

145 airpin RNA-mediated silencing of p38alpha or p38gamma expression abrogated ras-induced senescence, wh

146 ng exercise did not affect JNK, p38alpha, or p38gamma protein expression in the days following the ra

147 inhibition of p38alpha with selectivity over p38gamma and p38delta isoforms.

148 f the MAPK family, including ERK5, p38alpha, p38gamma, and p38delta, and that the activation of certa

149 cribe here for the first time that p38alpha, p38gamma, and p38delta down-regulate fibulin 3 expressio

150 Thus, p38alpha is an inhibitor of p38beta+p38gamma, which perhaps replace it in promoting differen

151 p38alpha, p38beta, p38gamma, and p38delta are four isoforms of p38 mitogen-

152 four p38 family members (p38alpha, p38beta, p38gamma, and p38delta) that are activated by MKK3 and M

153 (JNK1, JNK2, JNK3); p38s (p38alpha, p38beta, p38gamma, p38delta) and ERK5.

154 our isoforms in mammals (p38alpha, p38beta2, p38gamma and p38delta).

155 Evidence implicating p38gamma and p38delta (p38gamma/p38delta) in inflammation are mainly based on e

156 p38gamma and p38delta (p38gamma/p38delta) regulate inflammation, in part by con

157 alpha and X-ray structures of phosphorylated p38gamma.

158 ositively regulates myelination by promoting p38gamma mitogen-activated protein kinase (MAPK)-mediate

159 The related p38alphaMAPK (MAPK14) proteins p38gamma (MAPK12) and p38delta (MAPK13) were recently sh

160 d by Ras signaling and is important for Ras, p38gamma, and PTPH1 oncogenic activity.

161 rthermore, upon activation by oncogenic ras, p38gamma stimulated the transcriptional activity of p53

162 Expression of the Ras/p38gamma axis, however, is trans-suppressed by ER that i

163 MAPK, and the activated c-Jun then recruits p38gamma as a cofactor into the matrix metalloproteinase

164 Ras positively regulates p38gamma expression, and p38gamma in turn mediates Ras n

165 pha phosphorylation in negatively regulating p38gamma protein expression.

166 However, the role of the related p38gamma and p38delta kinases has remained unclear.

167 substrate for the p38gamma MAP kinase (SAPK3/p38gamma) isoform.

168 o identify physiological substrates of SAPK3/p38gamma as well as those of p38alpha and p38beta.

169 t this is a physiological substrate of SAPK3/p38gamma.

170 its the activity and the activation of SAPK3/p38gamma.

171 PK4/p38delta, but poorly by SAPK2/p38, SAPK3/p38gamma, SAPK1/JNK or extracellular signal-regulated ki

172 The SAPK3/p38gamma-catalysed phosphorylation of SAP97/hDlg trigger

173 Significantly, p38gamma KO inhibits tumorigenesis in a colitis-associat

174 Silencing p38gamma, p38delta, or JNK2 partially rescued G(1) arres

175 lyses further identified PTPH1 as a specific p38gamma phosphatase through PDZ-mediated binding.

176 sues and intestinal epithelial cell-specific p38gamma knockout (KO) attenuates colitis and inhibits p

177 g it an excellent tool to elucidate specific p38gamma/p38delta functions.

178 The specific p38gamma pharmacological inhibitor pirfenidone also supp

179 itogen-activated protein kinase superfamily, p38gamma.

180 Targeting p38gamma may be a novel strategy for colon cancer preven

181 breast cancer growth and invasion, and that p38gamma specifically integrates their antagonistic acti

182 Together, our results establish that p38gamma and p38delta are central to colitis-associated

183 We found that p38gamma increases EGFR transcription by c-Jun-mediated

184 We found that p38gamma/delta deficiency significantly decreased tumor

185 Here, we report that p38gamma MAPK is selectively activated by treatment with

186 Here, we report that p38gamma mitogen-activated protein kinase mediates infla

187 Here, we report that p38gamma motogen-activated protein kinase regulates brea

188 Here, we report that p38gamma, but not p38alpha, MAPK is specifically activat

189 p38gamma/deltaKIKO macrophages revealed that p38gamma/p38delta-regulated numerous genes implicated in

190 These results show that p38gamma activation links inflammation and colon tumorig

191 nal epithelial cells, and here, we show that p38gamma integrates invasive antagonism between Ras and

192 through PDZ binding, and here, we show that p38gamma is also a PTPH1 kinase through which it execute

193 We show that p38gamma/p38delta posttranscriptionally regulates the TP

194 on the finite element method, we showed that p38gamma-mediated cytoskeletal changes are sufficient to

195 Our data suggest that p38gamma could be targeted to improve myelin repair in m

196 These results suggest that p38gamma/p38delta govern innate immune responses by regu

197 high expression of p38gamma, suggesting that p38gamma could be a therapeutic target in the treatment

198 pathway leading to cell cycle arrest and the p38gamma MAPK pathway.

199 activated by the p38beta or inhibited by the p38gamma and/or -delta isoforms.

200 t cancers, EGFR activity is regulated by the p38gamma/c-Jun/PTPH1 signaling network, whose disruption

201 or Dlg, as a physiological substrate for the p38gamma MAP kinase (SAPK3/p38gamma) isoform.

202 lpha MAPK isoform and mislocalization of the p38gamma MAPK isoform are associated with neuroinflammat

203 Silencing the p38gamma/c-Jun/PTPH1 signaling network increased sensiti

204 We showed that the p38gamma C terminus is also an efficient inducer of cell

205 We presume that the p38gamma.PTPN4 interaction promotes cellular signaling,

206 ture of the PDZ domain of PTPN4 bound to the p38gamma C terminus.

207 The main contribution to the p38gamma.PTPN4 complex formation is the tight interactio

208 levels of phosphorylated c-Jun, whereas the p38gamma and -delta isoforms may act by regulating the c

209 Lack of p38gamma or treatment with the p38gamma inhibitor pirfenidone protects against the chem

210 Similar results were obtained with the p38gamma-specific pharmacological inhibitor pirfenidone.

211 This p38gamma activity contrasts with that of its family memb

212 This p38gamma-RhoC regulatory connection was mediated by a no

213 ription, and MMP9-dependent invasion through p38gamma interacting with c-Jun.

214 mutant reveals that ER additionally binds to p38gamma protein, leading to its specific down-regulatio

215 thermore, WT chimeric mice with transplanted p38gamma/delta(-/-) bone marrow had less tumors than WT

216 nistic analyses showed that unphosphorylated p38gamma may promote Ras transformation through an incre

217 oietic cell response to injury, and validate p38gamma and p38delta as potential targets for cancer th

218 -2D (MEF2D) was phosphorylated at Ser444 via p38gamma/p38delta.

219 activities by MKK6 and/or arsenite, whereas p38gamma/p38delta inhibits or has no effect on the stimu

220 ted to cytokine dependent induction, whereas p38gamma played no role.

221 ation serves as a central mechanism by which p38gamma regulates signaling transduction of ER with its

222 These results reveal a new paradigm in which p38gamma actively regulates the drug-Topo IIalpha signal

223 meric mice with WT bone marrow compared with p38gamma/delta(-/-) mice transplanted with p38gamma/delt

224 h p38gamma/delta(-/-) mice transplanted with p38gamma/delta(-/-) bone marrow.

225 ciated colon cancer model in wild-type (WT), p38gamma-, p38delta-, and p38gamma/delta-deficient (p38g