ライフサイエンスコーパス: LTBP

1 LTBP and the LAP propeptides of TGF-beta (isoforms 1 and

2 LTBP-1 expression increased during the first 12 d in cul

3 LTBP-1 mRNA expression was reduced in slow-track (0.99 +

4 LTBP-1 was not detected in extracted beaded-string micro

5 LTBP-2 colocalized with tropoelastin within the perichon

6 LTBP-2 expression was not detected by in situ hybridizat

7 LTBPs and fibrillins are highly homologous molecules, an

8 orming growth factor beta-binding protein 1 (LTBP-1) targets latent complexes of transforming growth

9 identify latent TGF-beta binding protein 1 (LTBP-1), an extracellular matrix protein and key regulat

10 Cys33 to latent TGF-beta binding protein 1 (LTBP-1).

11 orming growth factor-beta-binding protein-1 (LTBP-1) belongs to a family of extracellular glycoprotei

12 in-1, and latent TGF-beta binding protein-1 (LTBP-1) were measured by real-time RT-PCR.

13 s such as latent TGF-beta binding protein-1 (LTBP-1), decorin, biglycan, and fibromodulin can bind an

14 ibulin-4 (Fbln4) null cultures, fibrillin-1, LTBP-1, and LTBP-4 are incorporated into microfibrils.

15 ression reduced left atrial dimension (19%), LTBP-1 hydrolysis (40%), and collagen content (32%) when

16 th factor beta (TGF-beta) binding protein 2 (LTBP-2) is an integral component of elastin-containing m

17 Latent TGF-beta-binding protein-2 (LTBP-2) is an extracellular matrix protein associated wi

18 orming growth factor-beta-binding protein-3 (LTBP-3) sequesters pro-myostatin in the extracellular ma

19 ent and human tissues, little is known about LTBP-1 in embryonic development.

20 aVbeta6-mediated latent TGF-beta activation; LTBP-3 is unable to substitute for LTBP-1 in this assay.

21 Our results demonstrate an LTBP-1 isoform-specific function in alphaVbeta6-mediated

22 We analyzed LTBP-1 gene expression and LTBP-1 fiber appearance with

23 trates that the binding sites for LTBP-1 and LTBP-4 are different and suggests that EGF3 may also con

24 (Fbn1) null fibroblast cultures, LTBP-1 and LTBP-4 are not incorporated into microfibrils.

25 1 contribute to interactions with LTBP-1 and LTBP-4.

26 d two TGF-beta1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secret

27 ln4) null cultures, fibrillin-1, LTBP-1, and LTBP-4 are incorporated into microfibrils.

28 or by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the oute

29 he addition of medium containing activin and LTBP-1 to animal caps enhanced the activin effect.

30 We analyzed LTBP-1 gene expression and LTBP-1 fiber appearance with respect to the emergence an

31 d the TGF-beta1 modulators, fibromodulin and LTBP-1.

32 Complex formation between LAP and LTBP is mediated by an intramolecular disulfide exchange

33 3; type I, II, and III receptors; as well as LTBP-1, decorin, and biglycan were up-regulated during a

34 rillins and their associated ligands such as LTBPs, fibulins, and EMILINs are of particular interest

35 e show that the covalent association between LTBP-1 and the extracellular matrix is transglutaminase

36 pite these differences, interactions between LTBP-1 and fibrillin-1 compete for interactions between

37 ng studies demonstrated interactions between LTBP-1 and fibrillins.

38 A model depicting the relationship between LTBP-1 and fibrillin microfibrils is proposed.

39 molecular basis of complex formation between LTBPs and LAPs.

40 Both LTBP-2 and tropoelastin expression were seen throughout

41 ll as by CARASIL mutations and disrupts both LTBP-1 binding to fibronectin and its incorporation into

42 1 knockout mice had increased levels of both LTBP-4 expression and TGF-beta activation, as well as en

43 ted the activation of TGF-beta1 presented by LTBPs but did not bind to TGF-beta1 presented by GARP or

44 gest that during differentiation of ES cells LTBP-1 facilitates endothelial cell organization via a T

45 those that use the latent complex containing LTBP.

46 ction of latent TGFbeta complexes containing LTBP-3 with mutant fibrillin-1 microfibrils.

47 fibrillin-1 (Fbn1) null fibroblast cultures, LTBP-1 and LTBP-4 are not incorporated into microfibrils

48 Although 8-Cys3(LTBP-1) binds proTGF-betas effectively, the domain from

49 erved that a two-residue insertion in 8-Cys3(LTBP-1) increased the potential for disulfide exchange o

50 From comparison of the 8-Cys3(LTBP-1) structure with that of the non-TGF-beta-binding

51 ion of LTBP-4 is changed to the FP in 8-Cys3(LTBP-1).

52 Additional experiments with 8-Cys3(LTBP-4) indicated that enhanced binding of LAP to 8-Cys3

53 cated that enhanced binding of LAP to 8-Cys3(LTBP-4) is achieved if the residues A, S, and R are chan

54 sfected CHO cultures revealed that deltaN293 LTBP-1S was matrix associated via a transglutaminase-dep

55 minase-dependent reaction, whereas deltaN441 LTBP-1S was not.

56 Here, we describe LTBP-49247, an antibody that selectively bound to and in

57 ace properties of TB3 domains from different LTBP isoforms correlate with binding activities.

58 of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating t

59 In animal cap experiments, LTBP-1 potentiates the activity of activin and nodal.

60 To explore LTBP function in vivo, we created an Ltbp-3(-/-) mouse t

61 In tissues where LTBP-1 is not expressed, LTBP-4 may substitute for LTBP-1, because the C-terminal

62 By immunostaining, fibrillar LTBP-1 was observed in those regions of the culture cont

63 The results reveal a functional role for LTBP-1 in latent TGF-beta activation and suggest that ac

64 her, these data identify a critical role for LTBP-4 in the regulation of latent TGF-beta1 activation

65 1, explaining the antibody's selectivity for LTBP-complexed TGF-beta1.

66 contribute residues to the binding site for LTBP-4.

67 ated demonstrates that the binding sites for LTBP-1 and LTBP-4 are different and suggests that EGF3 m

68 tivation; LTBP-3 is unable to substitute for LTBP-1 in this assay.

69 is not expressed, LTBP-4 may substitute for LTBP-1, because the C-terminal end of LTBP-4 binds equal

70 Modelling of a homologous TB domain from LTBP-1 (residues 1018-1080) suggests that hydrophobic co

71 ds proTGF-betas effectively, the domain from LTBP-4 does so poorly.

72 ng growth factor-beta binding protein (human LTBP).

73 Previously, we identified LTBP-1 and transglutaminase, a cross-linking enzyme, as

74 LTBP-4, since lung fibroblasts deficient in LTBP-4 did not activate TGF-beta1.

75 activation that include unique sequences in LTBP-1 and an appropriate matrix molecule.

76 Bleomycin treatment of mice increased LTBP-4 expression in the lung.

77 PO in MT1-MMP overexpression increased LTBP-1 hydrolysis (18%), collagen content (60%), and lef

78 f TGF-beta by PSCs in vitro by investigating LTBP-1 organisation with fibrillar fibronectin and show

79 ins that includes three additional isoforms (LTBP-2, -3, and -4) and the matrix proteins fibrillin-1

80 e, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms,

81 though alphavbeta6 recognizes an RGD on LAP, LTBP-1 is required for alphaVbeta6-mediated latent TGF-b

82 rix is transglutaminase dependent, as little LTBP-1 is recovered from matrix digests prepared from cu

83 A encodes a protein similar to the mammalian LTBP-1 in both size and domain structure.

84 signaling caused by a lack of HtrA1-mediated LTBP-1 processing as mechanism underlying CARASIL pathog

85 odeling), a 60% increase in MT1-MMP-mediated LTBP-1 hydrolysis and a 190% increase in collagen conten

86 differences in LV function, MT1-MMP-mediated LTBP-1 hydrolysis, and collagen content occurred.

87 In mice, LTBP-49247 did not have the toxic effects associated wit

88 Although several reported human mutant LTBP-2 proteins retain normal domain structure and keep

89 activate latent TGF-beta1 in the absence of LTBP, these mechanisms are not as efficient as those tha

90 We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that

91 The activity of LTBP-1 did not appear to require covalent association wi

92 These data suggest that the association of LTBP with the latent TGF-beta complex is important for p

93 Covalent association of LTBP-1 (latent TGF-beta binding protein-1) to latent TGF

94 tion of latent TGFbeta complexes composed of LTBP-3 and TGFbeta contributes to aortic disease progres

95 To examine the contribution of LTBP to TGF-beta function, we generated mice in which th

96 ween the third 8-cysteine (8-Cys3) domain of LTBP with a pair of cysteine residues in LAP.

97 ression system, we have mapped the domain of LTBP-1 mediating covalent association with small latent

98 of LTBP-1S were used to identify domains of LTBP-1 involved in cross-linking and formation of TGF-be

99 The domains of LTBP-1 necessary for activation include the TGF-beta pro

100 Only the third 8-Cys domains of LTBP-1, -3, and -4 bind LAP.

101 ponse to bleomycin, but expression either of LTBP-4 lacking the TGF-beta-binding site or only the TGF

102 te for LTBP-1, because the C-terminal end of LTBP-4 binds equally well to fibrillin.

103 Whereas the expression of LTBP-1 has been analyzed in normal and malignant cells a

104 We studied the expression of LTBP-2 in the developing mouse and rat by in situ hybrid

105 rylation of Smad2, and ectopic expression of LTBP-3 in mature mouse skeletal muscle increases fiber a

106 Co-expression of LTBP-3 with myostatin reduces phosphorylation of Smad2,

107 Expression of LTBP-4 restored TGF-beta1 activation in response to bleo

108 ion site, which is conserved in all forms of LTBP known to date.

109 is study, we explore the in vivo function of LTBP-2 by generating Ltbp2(-/-) mice.

110 in eye development, although the function of LTBP-2 in vivo has not been well understood.

111 D, and E) and the QQ dipeptide insertion of LTBP-4 is changed to the FP in 8-Cys3(LTBP-1).

112 -cysteine (also referred to as TB) module of LTBP-1, a domain designated as CR3.

113 ll latent TGF-beta1 with deletion mutants of LTBP-1 showed that the third eight-cysteine repeat of LT

114 amino-terminal region of LTBP-1S, mutants of LTBP-1S with deletions of either the amino-terminal 293

115 Activation required the presence of LTBP, as TGF-beta1 contained in complex with only LAP co

116 itical to the transglutaminase reactivity of LTBP-1S.

117 y antibodies to the amino-terminal region of LTBP-1 block transglutaminase-dependent cross-linking of

118 domains within the amino-terminal region of LTBP-1S, mutants of LTBP-1S with deletions of either the

119 ibodies to the amino and carboxyl regions of LTBP-1S abrogate TGF-beta generation by vascular cell co

120 aining amino, middle, or carboxyl regions of LTBP-1S were used to identify domains of LTBP-1 involved

121 owed that the third eight-cysteine repeat of LTBP-1 is necessary and sufficient for covalent interact

122 e the first in vivo indication for a role of LTBP in modulating TGF-beta bioavailability.

123 We have investigated the role of LTBP in modulating TGF-beta generation by the integrin a

124 cells to analyze the appearance and role of LTBP-1 during ES cell differentiation.

125 progression, indicating the central role of LTBP-presented TGF-beta1 in renal fibrosis.

126 To gain insight into the potential roles of LTBP in early development, we isolated the Xenopus LTBP-

127 We reported that a specific sequence of LTBP-1 is required for latent TGF-beta activation by the

128 accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix

129 required for appropriate matrix assembly of LTBPs.

130 fibulins may affect matrix sequestration of LTBPs, because in vitro interactions between these prote

131 ted that LTBP-49247 recognized an epitope on LTBP-presented TGF-beta1 that is not accessible on GARP-

132 complex, and large latent complex but not on LTBP-coated plastic.

133 antibody, a TGF-beta receptor antagonist, or LTBP gene silencing results in the reversal of TGF-beta-

134 ent cross-linking of large latent complex or LTBP-1.

135 owth factors interact with fibrillins and/or LTBPs and are also targeted to the extracellular matrix.

136 s lost while other fibulin family members or LTBPs remained unaffected.

137 the ability of PSCs to mechanically organise LTBP-1 and activate TGF-beta through a mechanism involvi

138 mber of the latent TGF-beta binding protein (LTBP) family.

139 een LAP and latent TGF-beta-binding protein (LTBP) produces the most common form of latent TGF-beta,

140 sociate with latent TGFbeta-binding protein (LTBP) to produce a large latent form.

141 sforming growth factor-beta binding protein (LTBP), which plays roles in targeting and activation, a

142 molecule of latent TGFbeta binding protein (LTBP).

143 P), and the latent TGF-beta binding protein (LTBP).

144 AP) and the latent TGF-beta binding protein (LTBP).

145 de, and the latent TGF-beta binding protein (LTBP).

146 AP)], and a latent TGF-beta binding protein (LTBP).

147 ing by the latent TGF-beta1-binding protein (LTBP).

148 omplex with latent TGF-beta binding protein (LTBP).

149 molecule of latent TGF-beta binding protein (LTBP).

150 er, and the latent TGF-beta binding protein (LTBP).

151 transforming growth factor-binding protein (LTBP-1) and activation of transforming growth factor-dep

152 ransforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activit

153 lly described as a TGF-beta-masking protein, LTBP-1 is involved both in the sequestration of latent T

154 The latent TGF-beta binding proteins (LTBP) are believed to control the availability of TGF-be

155 forming growth factor-beta-binding proteins (LTBPs) are extracellular matrix (ECM) glycoproteins that

156 forming growth factor-beta-binding proteins (LTBPs) are extracellular matrix (ECM) glycoproteins that

157 ing growth factor B (TGFB)-binding proteins (LTBPs) are microfibril-associated proteins essential for

158 g growth factor (TGF) beta-binding proteins (LTBPs) interact with fibrillin-1.

159 g growth factor (TGF)-beta binding proteins (LTBPs) modulate the secretion and activation of latent T

160 The latent TGF-beta-binding proteins (LTBPs) present TGF-beta1 in the extracellular matrix, an

161 illins and latent TGF-beta-binding proteins (LTBPs) which are localized to fibrillar structures in th

162 he role of latent TGF-beta-binding proteins (LTBPs), key regulators of TGF-beta bioavailability and a

163 mulation of latent TGFbeta-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (a

164 n with the latent TGF-beta binding proteins (LTBPs).

165 linkage to latent TGFbeta binding proteins (LTBPs).

166 via LAP, to latent TGFbeta-binding proteins (LTBPs).

167 GF-beta1 and two TGF-beta1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary

168 Supplementation of recombinant LTBP-2 in culture medium not only rescued the microfibri

169 Reduced LTBP-1 mRNA expression in SFs from slow-track patients m

170 t of fibroblasts with bleomycin up-regulated LTBP-4 mRNA, protein, and soluble LTBP-4-bound large lat

171 omycin-induced TGF-beta1 activation required LTBP-4, since lung fibroblasts deficient in LTBP-4 did n

172 -regulated LTBP-4 mRNA, protein, and soluble LTBP-4-bound large latent TGF-beta1 complexes in Thy-1 (

173 nding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in t

174 ish the feasibility of selectively targeting LTBP-bound TGF-beta1 as an approach for treating fibrosi

175 In the testes, LTBP-2 expression was seen within lumenal cells of the e

176 In this study, we demonstrate that LTBP-1 and large latent complex are substrates for trans

177 Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-b

178 ata were consistent with the hypothesis that LTBP-1 is a fibrillin-associated protein present in cert

179 Collectively, these results imply that LTBP-2 plays a structural role within elastic fibers in

180 other elastic fiber proteins, implying that LTBP-2 performs a yet undiscovered function in early dev

181 These results indicate that LTBP-1 may be part of the regulatory system that establi

182 observations give support to the notion that LTBP-3 is important for the control of TGF-beta action.

183 The findings of this study suggest that LTBP-2 is an essential component for the formation of mi

184 beaded-string microfibrils, suggesting that LTBP-1 is not an integral structural component of microf

185 enotype related to glaucoma, suggesting that LTBP-2 deficiency primarily causes lens dislocation but

186 y determined DN protection and suggests that LTBP-1 may be involved in the pathogenesis of DN through

187 The LTBP-1 polypeptide rL1N, which includes the hinge, assoc

188 nct mechanisms that may be determined by the LTBP isoform and its potential interaction with the matr

189 dues by alanine, serine, and arginine in the LTBP-4 sequence.

190 binding site was within three domains of the LTBP-1 C terminus, and in fibrillin-1 the site was defin

191 Analysis of the LTBP-1S content in matrices of transfected CHO cultures

192 binding protein 1 (LTBP1) is a member of the LTBP/fibrillin family of extracellular proteins.

193 Previous studies have revealed that the LTBP-LAP interaction is mediated by intracellular exchan

194 xons and shows a similar organization to the LTBP-2 gene, suggesting that these genes originated from

195 suggesting secretion arrest occurred to the LTBP-2 mutants owing to conformational alteration.

196 We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-beta1 were mut

197 These data demonstrate that the third LTBP-1 eight-cysteine repeat recognizes and associates c

198 d that inclusion of a polyclonal antibody to LTBP-1 during EB differentiation suppressed the expressi

199 was tested for binding to fibrillin-1 or to LTBP-1.

200 ch the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent

201 In tissues where LTBP-1 is not expressed, LTBP-4 may substitute for LTBP-

202 to adult-type repair in fetal skin, whereas LTBP-1 and fibromodulin expression decreased.

203 To address whether LTBP-1 functions architecturally like fibrillins, microf

204 studies were conducted to determine whether LTBP-1 interacts with fibrillins.

205 fibrillin-1 contribute to interactions with LTBP-1 and LTBP-4.

206 serine precluding covalent interactions with LTBP.

207 n early development, we isolated the Xenopus LTBP-1 (xLTBP-1) cDNA.