ライフサイエンスコーパス: p38gamma

1 p38gamma and p38delta were necessary to maintain steady-

2 p38gamma contains allosteric sites that are conserved am

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

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

5 p38gamma requires phosphorylation and its C terminus to

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

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

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

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

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

11 The activated p38gamma in turn phosphorylates and stabilizes Topo IIal

12 Inflammation activates p38gamma in mouse colon tissues and intestinal epithelia

13 the MAPK kinase kinase family that activates p38gamma.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

40 response through disrupting its antagonistic p38gamma family protein.

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

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

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

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

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

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

47 38alpha requires c-Jun activation to deplete p38gamma proteins by ubiquitin-proteasome pathways.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

72 the mitogen activated protein kinase (MAPK) p38gamma.

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

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

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

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

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

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

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

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

81 3 at Ser(33), suggesting that the ability of p38gamma to mediate senescence is at least partly achiev

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

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

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

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

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

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

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

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

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

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

92 ently dephosphorylate the activation loop of p38gamma.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

111 alpha and X-ray structures of phosphorylated p38gamma.

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

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

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

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

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

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

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

119 pha phosphorylation in negatively regulating p38gamma protein expression.

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

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

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

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

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

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

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

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

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

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

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

131 The specific p38gamma pharmacological inhibitor pirfenidone also supp

132 itogen-activated protein kinase superfamily, p38gamma.

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

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

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

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

137 We found that p38gamma/delta deficiency significantly decreased tumor

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

157 This p38gamma activity contrasts with that of its family memb

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

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

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

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

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

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

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

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

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

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

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

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

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