ライフサイエンスコーパス: SHIP2

1 cluding SH2-containing inositol phosphatase (Ship2).

2 verexpression of many phosphatases including SHIP2.

3 ces Src-mediated tyrosine phosphorylation of SHIP2.

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

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

6 mediated primarily through the SH2 domain of SHIP2.

7 La cells transiently expressing exogenous WT-SHIP2.

8 kinetics of tyrosine phosphorylation of 51C/SHIP2.

9 restrictive mechanism for PM recruitment of SHIP2.

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

11 activation and inhibition of PTEN but not of SHIP2.

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

13 of the C-terminus region similarly activates SHIP2.

14 higher constitutive activity than wild-type SHIP2.

15 horylations overcome this effect to activate SHIP2.

16 )P(2) by the phosphoinositide 5'-phosphatase SHIP2.

17 t of SH2-containing inositol 5' phosphatase (SHIP2) (a key enzyme for PI(3,4)P(2) biosynthesis).

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

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

20 0(bcr/abl)-expressing hematopoietic cells as SHIP2, a recently reported, unique SH2-domain-containing

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

45 ning inositol polyphosphate 5-phosphatase 2 (SHIP2) as the key enzyme responsible for PI(3,4)P(2) pro

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

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

48 SHIP2 associates with p130Cas and filamin, regulators of

49 pha motif) domain from the lipid phosphatase Ship2 binds the Sam domain from the EphA2 receptor to ne

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

51 We found that B cell-specific deletion of Ship2, but not of its close homolog Ship1, significantly

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

53 Taken together, we provide evidence that SHIP2 contributes to CLL pathogenesis in mouse and human

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

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

56 rin activation of PI3Kbeta is coupled to the SHIP2-dependent production of PI(3,4)P(2,) which regulat

57 SHIP2 dephosphorylates phosphatidylinositol 3,4,5-trisph

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

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

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

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

62 SHIP2 down-regulates insulin signaling and is present at

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

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

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

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

67 Although SHIP2 expression resulted in suppression of interleukin-

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

69 at Pfn1 is unlikely to directly compete with SHIP2 for binding to PM PPIs.

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

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

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

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

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

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

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

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

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

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

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

81 provide evidence for Pfn1's interaction with SHIP2 in cells and modulation of this interaction upon E

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

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

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

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

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

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

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

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

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

91 On the other hand, concomitant Ship1/Ship2 inhibition or specific Ship2 inhibition reduced co

92 ncomitant Ship1/Ship2 inhibition or specific Ship2 inhibition reduced constitutive activation of the

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

94 Overexpression of SHIP2 inhibits EphA2 receptor endocytosis, whereas suppr

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

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

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

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

99 SHIP2 is already implicated as an independent risk facto

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

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

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

103 SHIP2 is mainly localized at the basolateral membrane of

104 SHIP2 is recruited early at the pits and dissociates bef

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

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

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

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

109 containing inositol phosphate phosphatase 2 (SHIP2) is one of the 10 human inositol phosphate 5-phosp

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

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

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

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

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

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

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

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

118 s associated with a concomitant reduction in SHIP2 levels.

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

120 ilitated screening of compound libraries for SHIP2 ligands.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

150 Inhibition of SHIP1/SHIP2 reduced cellular survival and S6 phosphorylation a

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

152 SHIP2 regulates EphA2 endocytosis via phosphatidylinosit

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

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

155 SHIP2 RNAi cells displayed cell-spreading defects involv

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

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

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

159 approach led to the identification of novel Ship2-Sam ligands and shed further light on original app

160 rt on the design and evaluation of EphA2-Sam/Ship2-Sam peptide inhibitors provided with positive char

161 g from the sequence of previously identified Ship2-Sam targeting peptides, an in silico approach was

162 ginal approaches to design inhibitors of the Ship2-Sam/EphA2-Sam interaction.

163 3D models of Ship2-Sam/peptide complexes were predicted by AlphaFold2

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

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

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

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

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

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

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

171 were phenocopied in healthy human ECs after SHIP2 silencing.

172 SHIP2 small interfering RNA or its catalytically dead mu

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

174 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

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

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

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

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

179 itment of the phosphoinositide 5-phosphatase SHIP2 to CCPs.

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

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

182 sed phosphorylation at two tyrosine sites in SHIP2 upon EGF stimulation, which was shown to be depend

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

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

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

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

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

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

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

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

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