ライフサイエンスコーパス: SHIP2

1 ces Src-mediated tyrosine phosphorylation of SHIP2.

2 ain, but not on the Src homology 2 domain of SHIP2.

3 SH2 domain-containing inositol-5-phosphatase SHIP2.

4 mediated primarily through the SH2 domain of SHIP2.

5 La cells transiently expressing exogenous WT-SHIP2.

6 kinetics of tyrosine phosphorylation of 51C/SHIP2.

7 ects of A34 on virus release are mediated by SHIP2.

8 activation and inhibition of PTEN but not of SHIP2.

9 was suppressed, enabling miR-205 to inhibit SHIP2.

10 of the C-terminus region similarly activates SHIP2.

11 higher constitutive activity than wild-type SHIP2.

12 horylations overcome this effect to activate SHIP2.

13 SHIP2, a 5'-inositol phosphatase, localizes at the invad

14 udy, we show that the inositol 5-phosphatase SHIP2, a negative regulator of PI(3,4,5)P(3)-dependent s

15 0(bcr/abl)-expressing hematopoietic cells as SHIP2, a recently reported, unique SH2-domain-containing

16 ltilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possib

17 are critical for EGF-induced stimulation of SHIP2 activity.

18 ated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2(Delta/+)).

19 reased the formation of a complex containing SHIP2 and a faster-migrating tyrosine-phosphorylated for

20 Together, these data suggest that SHIP2 and A34 may act as gatekeepers to regulate dissemi

21 cells stimulated tyrosine phosphorylation of SHIP2 and increased the formation of a complex containin

22 nd a stable pool that is dephosphorylated by Ship2 and is unable to activate Akt.

23 strate the rapid tyrosine phosphorylation of SHIP2 and its resulting association with SHC.

24 s, we identify specific interactions between SHIP2 and Mena, an Ena/VASP-family actin regulatory prot

25 SHIP2 and p130(Cas) association was detected in anti-SHI

26 bl)-expressing cells indicate that both Ptyr SHIP2 and Ptyr SHIP1 bind to the PTB domain of SHC but n

27 anism for regulating the interaction between SHIP2 and pY proteins.

28 We describe here a novel interaction between SHIP2 and the p130(Cas) adapter protein, a mediator of a

29 domain-containing inositol 5'-phosphatase 2 (SHIP2) and phosphatase and tensin homolog deleted on chr

30 )P3, through the phosphoinositol phosphatase SHIP2, and not through PTEN.

31 ate the role of the 5'-inositol phosphatase, SHIP2, and reveal an unexpected scaffold function of SHI

32 The 51C/SHIP2 antiserum precipitated a protein of approximately

33 H2-domain-containing inositol 5-phosphatase (SHIP2; approved gene symbol Inppl1) is believed to have

34 d signaling, our finding that both SHIP1 and SHIP2 are constitutively tyrosine phosphorylated in CML

35 First, SHIP1 and SHIP2 are potent inhibitors of Tec activity.

36 ing inositol 5-phosphatases 1 (SHIP1) and 2 (SHIP2) are structurally similar proteins that catalyze t

37 The timing of SHIP2 arrival at the invadopodium precursor coincides wi

38 Together, these findings identify SHIP2 as a key modulator of carcinoma invasiveness and a

39 nd reveal an unexpected scaffold function of SHIP2 as a prerequisite for invadopodia-mediated ECM deg

40 CSF receptor after M-CSF stimulation; and 3) SHIP2 associated with the actin-binding protein filamin

41 d the murine macrophage cell line RAW264; 2) SHIP2 associated with the M-CSF receptor after M-CSF sti

42 SHIP2 associates with p130Cas and filamin, regulators of

43 of an arginine at the pY + 1 position by the SHIP2 but not SHIP1 SH2 domain.

44 Therefore the activation of SHIP2 by APOE4-VLDL, with the subsequent inhibition of t

45 It is suggested that SHIP2 could be a promising target for anti-HCV treatment

46 ion of a catalytic domain deletion mutant of SHIP2 (DeltaRV) inhibited cell spreading.

47 SHIP2 dephosphorylates phosphatidylinositol 3,4,5-trisph

48 However, SHIP2 depletion had no discernible effect on insulin-reg

49 terference and analyzed the global effect of SHIP2 depletion on gene expression using Affymetrix micr

50 Furthermore, in contrast to SHIP1, SHIP2 did not bind to either the N-terminal or C-termina

51 association and dissociation rates while the SHIP2 domain showing apparent slow-binding behavior.

52 SHIP2 down-regulates insulin signaling and is present at

53 utant of SHIP2 or the proline-rich domain of SHIP2 enhanced Akt activation.

54 Both knockdown of SHIP2 expression and acute production of PI(3,4,5)P(3) s

55 receptor endocytosis, whereas suppression of SHIP2 expression by small interfering RNA-mediated gene

56 Of interest, SHIP2 expression rescues polarity, RhoA activation, and

57 Although SHIP2 expression resulted in suppression of interleukin-

58 coordinately regulate the lipid phosphatase SHIP2 for Akt survival signaling in keratinocytes.

59 To better understand SHIP2 function, we employed RNA interference (RNAi) appr

60 together, these experiments demonstrate that SHIP2 functions in the maintenance and dynamic remodelin

61 The goal of this study was to determine how SHIP2 functions to regulate M-CSF signaling.

62 inally, fetal liver-derived macrophages from SHIP2 gene knockout mice enhanced activation of Akt in r

63 Cells lacking SHIP2 have normal actin tails but release more virus.

64 in; however, no Shc could be detected in 51C/SHIP2-immune precipitates from cells treated with IGF-1

65 d p130(Cas) association was detected in anti-SHIP2 immunoprecipitates from several cell types.

66 in kinase activation, expression of SHIP and SHIP2 in a PTEN-null myeloma line did not suppress Akt a

67 r, our studies suggest an important role for SHIP2 in adhesion and spreading.

68 skeletal functions, but a large reduction of SHIP2 in C2C12 muscle cells is not sufficient to affect

69 To understand the function of SHIP2 in C2C12 muscle cells, we depleted SHIP2 through t

70 to silence the expression of the endogenous SHIP2 in HeLa cells.

71 Analyzing the function of SHIP2 in M-CSF-stimulated cells by expressing either wil

72 ese data suggest a novel regulatory role for SHIP2 in M-CSF-stimulated myeloid cells.

73 y, but call into question a dominant role of SHIP2 in modulating glucose homeostasis.

74 Thus, the SH2 domain of SHIP2, in conjunction with the C-terminus, confers an in

75 tablished the role of PTEN, but not SHIP and SHIP2, in negatively regulating the PI3K/Akt cascade and

76 ted damping of the Akt signaling pathway via SHIP2 induction.

77 Similarly, the expression of wild-type SHIP2 inhibited NF-kappaB-mediated gene transcription.

78 sistent with its late arrival, we found that SHIP2 inhibition does not affect precursor formation but

79 n of potent and selective SPsynaptojanin and SHIP2 inhibitors for pharmacological investigation.

80 Overexpression of SHIP2 inhibits EphA2 receptor endocytosis, whereas suppr

81 Antibodies raised against the 51C/SHIP2 inositol polyphosphate 5'-phosphatase were used to

82 that the inositol 5' phosphatases SHIP1 and SHIP2 interact preferentially with Tec, compared with ot

83 Because SHIP2 is a negative regulator of insulin signaling, our

84 onstrate not only that the lipid phosphatase SHIP2 is a target of miRNA-205 (miR-205) in epithelial c

85 SHIP2 is already implicated as an independent risk facto

86 We conclude that SHIP2 is an important regulator of polarity, which is su

87 The rank order for SHIP2 is Ins(1,2,3,4,5)P5 > Ins(1,3,4,5)P4 > PtdIns(3,4,

88 Taken together, our results suggest that SHIP2 is involved in the regulation of cytoskeletal func

89 SHIP2 is mainly localized at the basolateral membrane of

90 SHIP2 is recruited early at the pits and dissociates bef

91 Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose ho

92 Tyrosine phosphorylation of SHIP2 is shown to enhance its phosphatase activity.

93 logy 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin sign

94 H2 domain-containing 5-inositol phosphatase (SHIP2) is implicated in the development of type 2 diabet

95 lar expression of SHIP1, the related isoform SHIP2, is widely expressed in both parenchymal and hemop

96 osphate levels are significantly elevated in SHIP2 knockdown cells, phosphatidylinositol 3-kinase inh

97 the Rac1-GTP levels are further increased in SHIP2 knockdown cells.

98 We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation

99 Furthermore, decreased SHIP2 levels altered distribution of early endocytic ant

100 of HEKs and HCEKs with antago-205 increased SHIP2 levels and impaired the ability of these cells to

101 Suppression of SHIP2 levels caused severe F-actin deformities character

102 We were able to increase SHIP2 levels in SCC cells after inhibition of miR-205.

103 s associated with a concomitant reduction in SHIP2 levels.

104 fere with the ability of miR-205 to suppress SHIP2 levels.

105 l SH2 domain and a central catalytic region, SHIP2 (like SHIP1) possesses both potential PTB(NPXY) an

106 This finding suggests that SHIP2, like that reported for SHIP1 previously, is linke

107 Immunofluorescence studies indicated that SHIP2 localized to focal contacts and to lamellipodia.

108 ound that the phosphoinositide 5-phosphatase SHIP2 localizes to actin tails.

109 hese observations suggest (1) that SHIP1 and SHIP2 may have a different hierarchy of binding SH3 cont

110 The data suggest that 51C/SHIP2 may play a significant role in regulation of phosp

111 erence raises the possibility that SHIP1 and SHIP2 may serve different functions.

112 VASP, to invadopodia and that disruption of SHIP2-Mena interaction in cancer cells leads to attenuat

113 d C2C12 muscle cells led to >80% decrease in SHIP2 mRNA and 60-80% decrease in SHIP2 protein, which r

114 Knockdown of the lipid phosphatase Ship2, on the other hand, dramatically increased the ste

115 mulated cells by expressing either wild-type SHIP2 or an Src homology 2 domain mutant of SHIP2 reduce

116 by selectively inhibiting the expression of SHIP2 or PTEN in intact cultured 3T3-L1 adipocytes throu

117 ssion of a catalytically deficient mutant of SHIP2 or the proline-rich domain of SHIP2 enhanced Akt a

118 invadopodia and matrix degradation, whereas SHIP2 overexpression increases matrix degradation.

119 Accordingly, we suggest that, in HeLa cells, SHIP2 plays a distinct role in signaling pathways mediat

120 ontaining inositol 5-phosphatase (INPPL1, or SHIP2) plays an important role in the control of insulin

121 phosphates reveals that SP-synaptojanin and SHIP2 possess much broader substrate specificity than pr

122 These effects were not seen with SHIP2 possessing a mutation in the SH2 domain (R47G).

123 In a previous study, we found that the SHIP2 protein became tyrosine phosphorylated and associa

124 In contrast, depletion of SHIP2 protein by about 90% surprisingly failed to modula

125 Tyrosine phosphorylation of the 51C/SHIP2 protein occurred in response to treatment of cells

126 Immunoblot analysis revealed that the 51C/SHIP2 protein was widely expressed in fibroblast and non

127 , and PDGF stimulated the association of 51C/SHIP2 protein with the Shc adapter protein; however, no

128 Interaction of the SHIP2 protein with the various forms of p130(Cas) was me

129 ecrease in SHIP2 mRNA and 60-80% decrease in SHIP2 protein, which resulted in significant gene expres

130 in prolonged tyrosine phosphorylation of 51C/SHIP2 protein, with 40-80% maximal phosphorylation susta

131 We demonstrate that SHIP2 recruits Mena, but not VASP, to invadopodia and th

132 idylinositol-3,4,5-triphosphate by SHIP1 and SHIP2-recruits lamellipodin, which in turn engages endop

133 SHIP2 or an Src homology 2 domain mutant of SHIP2 reduced Akt activation in response to M-CSF stimul

134 recently reported that the lipid phosphatase Ship2 regulates endocytosis of the EphA2 receptor, a pro

135 SHIP2 regulates EphA2 endocytosis via phosphatidylinosit

136 y, expression of only PTEN, but not SHIP and SHIP2, resulted in growth inhibition and increased apopt

137 on calorimetry) studies on the Sam domain of Ship2 revealing its three-dimensional structure and its

138 SHIP2 RNAi cells displayed cell-spreading defects involv

139 EGF treatment of SHIP2 RNAi cells led to the following: enhanced EGF rece

140 igated the dissociation process of the EphA2-SHIP2 SAM-SAM domain heterodimer complex using unrestrai

141 sly characterized one such system: the EphA2:SHIP2 SAM-SAM heterodimer by solution NMR.

142 eins, we demonstrate that, whereas SHIP1 and SHIP2 selectively hydrolyze PtdIns(3,4,5)P3 in vitro, on

143 nesis and kinetic studies indicated that the SHIP2 SH2 domain exists as a mixture of two conformation

144 n this work, the sequence specificity of the SHIP2 SH2 domain was systematically defined through the

145 Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2),

146 heir high sequence identity (51%), SHIP1 and SHIP2 share little overlap in their in vivo functions.

147 in migration were observed following direct SHIP2 silencing in HEKs.

148 lial keratinocytes (HCEKs) as well as direct SHIP2 silencing using siRNA oligos.

149 were phenocopied in healthy human ECs after SHIP2 silencing.

150 SHIP2 small interfering RNA or its catalytically dead mu

151 Here we show that SHIP2 (Src homology 2 domain-containing phosphoinositide

152 h is consistent with a positive role of both SHIP2 substrates, PI(4,5)P(2) and PI(3,4,5)P(3), on coat

153 substrate specificity for SPsynaptojanin and SHIP2 suggest that these enzymes likely have multiple ro

154 Expression of SHIP2-targeting small-hairpin RNA in differentiated C2C1

155 dentification of a minimal peptide region of Ship2 that retains binding affinity for the Sam domain o

156 of SHIP2 in C2C12 muscle cells, we depleted SHIP2 through the use of RNA interference and analyzed t

157 indings provide evidence that recruitment of SHIP2 to EphA2 attenuates a positive signal to receptor

158 itor A34 release more virus but recruit less SHIP2 to tails.

159 Interestingly, SHIP2 was found to selectively bind to the SH3 domain of

160 We report that 1) SHIP2 was tyrosine-phosphorylated in M-CSF-stimulated hu

161 uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5

162 k1 and Erk2 was observed when either PTEN or SHIP2 were depleted.

163 polarity protein Dlg1 and the PI phosphatase SHIP2, which converts phosphatidylinositol 3,4,5-trispho

164 o interacts with the 5' inositol phosphatase SHIP2, which is important for the recruitment of the Men

165 SHIP2 with a disrupted SH2 domain (R47G mutation) displa

166 ed transient tyrosine phosphorylation of 51C/SHIP2, with maximal tyrosine phosphorylation occurring a

167 These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-i