ライフサイエンスコーパス: PP4

1 ement of protein phosphatase 2A (PP2A) or 4 (PP4).

2 t the levels of other phosphatases (PP2A and PP4).

3 ucture, function and potential regulation of PP4.

4 ased serine and threonine phosphorylation of PP4.

5 egulated kinase activation in the absence of PP4.

6 using okadaic acid, may in fact be those of PP4.

7 RNA interference-mediated gene silencing of PP4-19c, PP4R2, and Falafel, which encode the catalytic

8 por pressures (PP1, 294 mbar; PP2, 141 mbar; PP4, 9.6 mbar; and PP9, 2.9 mbar) were examined.

9 Okadaic acid inhibits protein phosphatase 4 (PP4), a novel PP2A-related serine/threonine phosphatase,

10 uld bind and regulate protein phosphatase 4 (PP4), a tumor-promoting protein, but not the related pro

11 atase (PPP) family, including PP1, PP2A, and PP4-abundant enzymes with pleiotropic roles in cellular

12 thern blots demonstrated the conservation of PP4 across species.

13 PP4 action is likely direct, as a portion of PP4 co-prec

14 Consequently, elimination of PP4 activity affects resection and repair by single-stra

15 nding of Flfl to CENP-C is required to bring PP4 activity to centromeres to maintain CENP-C and attac

16 checkpoint kinase activity, suggesting that PP4 acts directly on gamma-H2AX in cells.

17 ombinant adenovirus carrying a gene encoding PP4 (Ad-PP4) showed significant reduction in IL-6 and TN

18 egulating FRQ phosphorylation and stability, PP4 also dephosphorylates and activates WCC.

19 the serine/threonine protein phosphatase 4 (PP4), also called PPX.

20 sitively regulated by protein phosphatase 4 (PP4; also called PPX and PPP4), a serine/threonine phosp

21 Protein phosphatase 4 (PP4; also named PPX or PPP4) is a PP2A-related protein s

22 Taken together, our results suggest that PP4 and PP2A are two phosphatases that act at different

23 Using an in vivo RNAi screen, we identified PP4 and PP2A as phosphatases that influence Hh signaling

24 ), alpha4, but instead associates with PP2A, PP4 and PP6 catalytic subunits independently of mammalia

25 Ac is conserved in the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, bu

26 ry protein of PP2A and the PP2A-like enzymes PP4 and PP6.

27 g subunit of the PP2Ac-related phosphatases, PP4 and PP6.

28 receptor substrate 4 (IRS-4) interacted with PP4 and that this interaction was enhanced following TNF

29 Taken together, our results show that PP4 and Wip1 are differentially required to counteract t

30 ET found in adrenals inhibited PP2A, but not PP4, and fostered 17,20 lyase activity.

31 We find that the catalytic subunits of PP2A, PP4, and PP6 are frequently methylated in cancer cells a

32 the role of C-terminal methylation on PP2A, PP4, and PP6 holoenzyme assembly.

33 T-1 is the major methyltransferase for PP2A, PP4, and PP6 in mouse embryonic fibroblasts (MEFs).

34 etion leads to progressive loss of all PP2A, PP4, and PP6 phosphatase complexes.

35 e family contains three enzymes called PP2A, PP4, and PP6 with separate biological functions inferred

36 e 2A (PP2A) subfamily of phosphatases, PP2A, PP4, and PP6, are multifunctional serine/threonine prote

37 pose a PPP family that includes type-2 PP2A, PP4, and PP6, each with essential functions.

38 For PP2A, PP4, and PP6, holoenzyme formation is in part regulated

39 28 coprecipitated with PP6, not with PP2A or PP4, and with SAPS domain subunits PP6R1 and PP6R3.

40 the nucleotide sequences of murine and human PP4 are distinct, their amino acid sequences are identic

41 entities of the methyltransferase enzyme for PP4 are not known.

42 induced JNK activation, our studies identify PP4 as a positive regulator for HPK1 and the HPK1-JNK si

43 PP4 associates with the inner kinetochore protein CENP-C

44 Such a CDK/PP4-based regulation of cohesin loader activity could pr

45 Serine/threonine protein phosphatase type 4 (PP4) belongs to a family of okadaic acid and microcystin

46 Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, i

47 RNAi knockdown of PP4, but not of PP2A, elevates Smo phosphorylation and a

48 We also found that PP4, but not PP2A, down-regulated IRS-4 in a phosphatase

49 ly proportional to the cellular abundance of PP4(c).

50 Ouzounis-Woese (KOW) motifs 4 and 5, whereas PP4 can target both sites.

51 al product contained two major proteins: the PP4 catalytic subunit plus a protein that migrated as a

52 hore protein CENP-C; however, disrupting the PP4-CENP-C interaction does not perturb chromosome segre

53 In the absence of PP4, chromosomes exhibit extended monopolar orientation

54 PP4 action is likely direct, as a portion of PP4 co-precipitates with Maf1, and purified PP4 dephosph

55 PP2A but not PP4 coimmunoprecipitated with P450c17, and suppression o

56 PP4 regulatory subunit 1 (PP4R1)-containing PP4 complex being the most dramatically affected by the

57 When the PP4 complex is silenced, repair of DNA replication-media

58 The smaller PP4 complex was purified by sequential phenyl-Sepharose,

59 the highly conserved protein phosphatase 4 (PP4) complex as a bona fide negative regulator of the IM

60 ere, we establish the protein phosphatase 4 (PP4) complex as the main Maf1 phosphatase, and define th

61 Depletion of PP4-complex subunits increases phosphorylation of both S

62 Analysis of PP2A and PP4 complexes by blue native polyacrylamide gel electrop

63 alyzes inhibitory phosphorylation of PP1 and PP4 complexes that localize to 3' and 5' ends of genes,

64 e generated conventional and T-cell-specific PP4 conditional knockout mice.

65 entify and thoroughly characterize a general PP4 consensus-binding motif, the FxxP motif.

66 Pef1 and PP4 control the phosphorylation state of the cohesin kle

67 ever, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence

68 Pulse-chase analysis revealed that PP4 decreased the half-life of IRS-4 from 4 to 1 h.

69 ding domain of Mis4 alleviated the effect of PP4 deficiency.

70 aling is associated with reduced lifespan of PP4-deficient flies in the absence of any infection.

71 Anti-CD3 injection in PP4-deficient mice led to enhanced thymocyte apoptosis,

72 tion and T-cell-mediated immune responses in PP4-deficient mice were dramatically compromised.

73 PP4-deficient thymocytes showed decreased proliferation

74 reover, we found that TNF-alpha stimulated a PP4-dependent degradation of IRS-4, as indicated by the

75 Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates betw

76 These results establish that PP4-dependent outer kinetochore assembly prior to NEBD i

77 PP4-dependent Rad53 dephosphorylation stimulates DNA end

78 PP4 dephosphorylates Kruppel-associated box domain-assoc

79 PP4 co-precipitates with Maf1, and purified PP4 dephosphorylates Maf1 in vitro.

80 Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its

81 ion, we showed that Thr-355 of HPK1 is a key PP4 dephosphorylation site, through which CUL7/Fbxw8 ubi

82 Despite this high homology, PP4 does not appear to associate with known PP2A regulat

83 eric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1

84 that Rad53 phosphorylation is controlled by PP4 during the repair of a DNA lesion and demonstrate th

85 PP4 efficiently dephosphorylates gamma-H2AX within monon

86 Combined with the observation that PP4 enhanced HPK1-induced JNK activation, our studies id

87 the PP4-HPK1 interaction and that wild-type PP4 enhanced, whereas a phosphatase-dead PP4 mutant inhi

88 that nuclear-enriched protein phosphatase 4 (PP4) ensures robust assembly of the microtubule-coupling

89 Ptc3, as well as the protein phosphatase 4 (PP4) enzyme, Pph3.

90 NK interaction was detected, suggesting that PP4 exerts its positive regulatory effect on JNK in an i

91 PP4 existed in two complexes of approximately 270-300 an

92 in of the regulatory subunit 3 of Drosophila PP4, Falafel (Flfl), directly interacts with the centrom

93 lucidating a novel function of the conserved PP4 family phosphatase Pph3-Psy2, the yeast counterpart

94 dicate that the serine/threonine phosphatase PP4 functions as a negative regulator of innate immunity

95 PP4 gene deletion in the T-cell lineage resulted in aber

96 PP4 to chromosome 16, and comparison of the PP4 gene structure with that of PP2A and PP1 suggests th

97 he cloning and characterization of the human PP4 gene.

98 Despite the importance of PP4, general principles of substrate selection are unkno

99 risk loci from 22 IMDs with high confidence (PP4 >= 0.75).

100 We also found that PP4 had phosphatase activity toward HPK1 in vivo and tha

101 accharide (LPS) treatment, whereas silencing PP4 had the opposite effect.

102 P2A, another phosphatase that activates WCC, PP4 has a major function in promoting nuclear entry of W

103 Phosphoprotein phosphatase 4 (PP4) has been recently shown to participate in the regul

104 The phosphatases PP2A and PP4 have previously been shown to dephosphorylate gamma-

105 gel electrophoresis (BN-PAGE) indicates that PP4 holoenzyme complexes, like those of PP2A, are differ

106 As a first step toward characterization of PP4 holoenzymes and identification of putative PP4 regul

107 , we found that TCR stimulation enhanced the PP4-HPK1 interaction and that wild-type PP4 enhanced, wh

108 The involvement of PP4 in JNK signaling was further demonstrated by the spe

109 ltiple approaches support a central role for PP4 in Maf1 dephosphorylation, Maf1 nuclear localization

110 dization, we have examined the expression of PP4 in murine embryos and adult tissues.

111 To investigate the in vivo roles of PP4 in T cells, we generated conventional and T-cell-spe

112 activation of JNK, but not p38 and ERK2, by PP4 in transient transfection assays.

113 Pulse-chase analysis showed that PP4 increased the half-life of HPK1.

114 Moreover, we found that the PP4-induced HPK1 kinase activation was accompanied by an

115 Survival of Ad-PP4-infected mice was markedly increased due to a better

116 PP2A but not PP4 inhibited 17,20 lyase activity in microsomes from cu

117 and ubiquitin-targeted degradation and that PP4 inhibited HPK1 ubiquitination.

118 ctive protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC(50) = 40-3 nM and 1.5 nM), resulting

119 the blockage of the degradation by a potent PP4 inhibitor (okadaic acid) and a phosphatase-dead PP4

120 We found that PP4 interacted with HPK1 and that the proline-rich regio

121 arches integrated with proteomic analysis of PP4 interacting proteins allow us to identify numerous F

122 functions of PP4, we isolated and identified PP4-interacting proteins using a proteomic approach.

123 istically, we show that Hh downregulates Smo-PP4 interaction that is mediated by Cos2.

124 Deletion of a PP4-interaction domain (amino acids 626-678) in Smo prom

125 other PPP family phosphatases (e.g. PP2A and PP4), intercrosses with mouse lines that ubiquitously ex

126 ferent developmental stages, suggesting that PP4 is a developmentally regulated protein phosphatase.

127 Taken together, these data indicate that PP4 is a signaling component of the JNK cascade and invo

128 n the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, but the identities

129 Mechanistically, PP4 is directly recruited by phosphorylated sNASP to dep

130 Thus, our results indicate that PP4 is essential for thymocyte development and pre-TCR s

131 We also found that PP4 is involved in relaying the TNF-alpha signal to c-Ju

132 We provide evidence that PP4 is involved in tumor necrosis factor (TNF)-alpha sig

133 ture with that of PP2A and PP1 suggests that PP4 is more closely related to PP2A than PP1.

134 These data indicate that one form of PP4 is similar to the core complex of PP2A in that it co

135 Phosphoprotein phosphatase 4 (PP4) is a conserved and essential nuclear serine and thr

136 mined that the specific phenotype criterion (PP4) is inseparably coupled to the co-segregation criter

137 Here, we showed that protein phosphatase 4 (PP4) is the specific sNASP phosphatase that negatively r

138 However, no direct PP4-JNK interaction was detected, suggesting that PP4 ex

139 We found that the ablation of PP4 led to the embryonic lethality of mice.

140 NEBD, a cytoplasmic activity compensates for PP4 loss, leading to outer kinetochore assembly and reco

141 Our results define a new role for PP4-mediated dephosphorylation in the DDR, including the

142 subject to regulation by TNF-alpha and that PP4 mediates TNF-alpha-induced degradation of IRS-4.

143 ibitor (okadaic acid) and a phosphatase-dead PP4 mutant (PP4-RL).

144 ype PP4 enhanced, whereas a phosphatase-dead PP4 mutant inhibited, TCR-induced activation of HPK1 in

145 hatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 wi

146 y the ability of PP4-RL, a dominant-negative PP4 mutant, to block TNF-alpha-induced JNK activation.

147 In pp4 mutants, early stages of crossover repair and homolo

148 est that switches comprising Cdk9 and either PP4 or PP1 govern pause release and the elongation-termi

149 ein, which also associates with phosphatases PP4 or PP6.

150 When the PP2A, PP4, or PP6 catalytic subunits were overexpressed, inhib

151 d in time-dependent activation of endogenous PP4, peaking at 10 min, as well as increased serine and

152 Here we describe a three-protein PP4 phosphatase complex in mammalian cells, containing P

153 Here, we describe that PP4 phosphatase is required to avoid Rad53 hyper-phospho

154 synthetic growth effects, identified loss of PP4 phosphatase, pph3Delta and psy2Delta, as the stronge

155 y turned over during S phase by the PP2A and PP4 phosphatases.

156 in response to diverse stresses, suggesting PP4 plays a key role in the integration of cell nutritio

157 the invariant motifs of the PP1, PP2A, PP2B, PP4, PP5, and PP6 gene family.

158 unique to PP2Ac, compared with phosphatases PP4, PP6, and PP1.

159 Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Sacchar

160 Protein phosphatase 4 (PP4, previously named protein phosphatase X (PPX)), a PP

161 AD51) or control of RPA phosphorylation (the PP4 protein phosphatase complex) are not recruited to th

162 f the mec1-100-compromised targets on HU are PP4 regulated, including a phosphoacceptor site within M

163 hrough which CUL7/Fbxw8 ubiquitin ligase and PP4 regulates HPK1 stability.

164 We further find that PP4 regulates the Hh-induced Smo cell-surface accumulati

165 differentially regulated by LCMT-1, with the PP4 regulatory subunit 1 (PP4R1)-containing PP4 complex

166 xxP motifs bind to a conserved pocket in the PP4 regulatory subunit PPP4R3.

167 s and directly phosphorylates PP4R3beta, the PP4 regulatory subunit that recognizes 53BP1.

168 4 holoenzymes and identification of putative PP4 regulatory subunits, PP4 was purified from bovine te

169 The disruption of pp4 results in short period rhythms with low amplitude.

170 inhibited in HEK293 cells stably expressing PP4-RL in comparison to parental HEK293 cells.

171 aic acid) and a phosphatase-dead PP4 mutant (PP4-RL).

172 kinase (JNK) as indicated by the ability of PP4-RL, a dominant-negative PP4 mutant, to block TNF-alp

173 4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and

174 have analyzed the protein, cDNA and genomic PP4 sequences to provide insight into the structure, fun

175 adenovirus carrying a gene encoding PP4 (Ad-PP4) showed significant reduction in IL-6 and TNF-a prod

176 precipitated endogenous PP6, but not PP2A or PP4, showing specificity for recognition of phosphatases

177 Ectopic expression of PP4 specifically inhibited sNASP-dependent proinflammato

178 Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Cu

179 tively our work uncovers basic principles of PP4 specificity with broad implications for understandin

180 e X (PPX; also called protein phosphatase 4 (PP4)) that specifically associated with c-Rel, NF-kappaB

181 human/rodent somatic cell hybrid panel maps PP4 to chromosome 16, and comparison of the PP4 gene str

182 sphoprotein phosphatase 4 catalytic subunit (PP4) to be specifically required for cell cycle restart

183 s establishes a physical and functional Mec1-PP4 unit for regulating the checkpoint response.

184 PP4 was differentially expressed in murine embryos at di

185 In adult tissues, PP4 was expressed at high levels in the testis, kidney,

186 ication of putative PP4 regulatory subunits, PP4 was purified from bovine testis soluble extracts.

187 For PP4, we find that PP4R1 and PP4R3B bind in a methylation

188 urther investigate the cellular functions of PP4, we isolated and identified PP4-interacting proteins

189 ard HPK1 in vivo and that co-transfection of PP4 with HPK1 resulted in specific kinase activation of