ライフサイエンスコーパス: meprin

1 Zn(2+)-dependent metalloproteases (ADAMs and meprins).

2 cretion, sorting, or enzymatic properties of meprin.

3 ize quaternary structures of recombinant rat meprins.

4 ast growth factor 2, tenascin C, collagen 1, meprin 1-alpha, and meprin 1-beta.

5 tenascin C, collagen 1, meprin 1-alpha, and meprin 1-beta.

6 Meprin A and B are highly regulated, secreted, and cell-

7 he results demonstrate that rodent and human meprin A and B cleave IL-6 to a smaller product and, sub

8 Meprin A and B, metalloproteases consisting of evolution

9 found to be the best peptide substrates for meprin A and B, respectively.

10 Meprin A and meprin B cleaved IL-6 with micromolar affin

11 is unique among proteases and distinguishes meprin A as the largest known secreted protease.

12 he recombinant homo-oligomeric form of mouse meprin A by gel filtration, nondenaturing gel electropho

13 The meprin A homo-oligomer is a highly glycosylated, secrete

14 mycin-stimulated shedding of meprin beta and meprin A in the medium of both transfectants.

15 ms of the alpha subunit of recombinant mouse meprin A include an NH2-terminal prosequence, a catalyti

16 of the limited degradation product formed by meprin A indicated that three to five amino acids are re

17 The secreted form of meprin A is a homo-oligomer composed of alpha subunits,

18 Both human and murine IL-6 cleaved by meprin A or B are inactivated, as demonstrated by their

19 Meprin A plays an important role in tubular epithelial c

20 Meprin A secreted from kidney and intestinal epithelial

21 to ADAM9 or ADAM17 inhibited meprin beta and meprin A shedding.

22 ound to be glycosylated in recombinant mouse meprin A using chemical and enzymatic deglycosylation me

23 hat during ischemia-reperfusion-induced AKI, meprin A was shed from proximal tubule membranes, as evi

24 Meprin A, composed of alpha and beta subunits, is a memb

25 oteolytic enzyme responsible for shedding of meprin A, we generated stable HEK cell lines expressing

26 igosaccharides on the secreted form of mouse meprin A.

27 e and stimulated shedding of meprin beta and meprin A.

28 lated ectodomain shedding of meprin beta and meprin A.

29 alpha and meprin beta for the expression of meprin A.

30 demonstrate that the meprin beta subunit of meprins A and B cleaves proIL-18 into a smaller 17-kDa p

31 MAM domain (an extracellular domain found in meprin, A-5 protein, and receptor protein-tyrosine phosp

32 talytic interaction domains; two in the MAM (meprin, A-5 protein, protein-tyrosine phosphatase mu) do

33 ree COOH-terminal domains designated as MAM (meprin, A-5 protein, receptor protein-tyrosine phosphata

34 cture of HMP2 most closely resembles that of meprins, a subgroup of astacin metalloproteinases.

35 action domains: an "MAM" domain (named after meprins, A-5 protein and receptor protein tyrosine phosp

36 uble chimeric proteins demonstrated that the meprin A5 antigen-mu tyrosine phosphatase (MAM) domain a

37 noncovalently by interactions involving the meprin, A5 protein, receptor protein-tyrosine phosphatas

38 nvolving at least partly the neuropilin MAM (meprin, A5, mu) domain.

39 omain and the juxtamembrane portion, or MAM (meprin, A5, mu) domain.

40 MAM (meprin/A5 protein/receptor protein tyrosine phosphatase

41 f a construct comprising its N-terminal MAM (meprin/A5/mu) and Ig domains was determined at 2.7 A res

42 imed to identify critical amino acids in the meprin active sites that determine the substrate specifi

43 showed electrostatic differences within the meprin active sites.

44 85 are substrate specificity determinants in meprin active sites.

45 l glycosylation sites on a truncated form of meprin alpha (alpha-(1-445)) were mutated, the protein w

46 By contrast, a mutant of meprin alpha (C320AalphaDeltaI) that did not form disulf

47 pha(1-528) mutant was as active as wild-type meprin alpha against a bradykinin substrate, but had no

48 Because IL-6 levels are elevated markedly in meprin alpha and alpha/beta knockout mice in an experime

49 These studies show that meprin alpha and beta are expressed in leukocytes of the

50 Homology models of the mouse meprin alpha and beta protease domains, based on the ast

51 Thus, although the meprin alpha and beta subunits share 55% amino acid iden

52 Thus, meprin alpha and meprin beta are unique in their ability

53 lines expressing meprin beta alone and both meprin alpha and meprin beta for the expression of mepri

54 able to inhibit the astacin-like proteinases meprin alpha and meprin beta, we herein demonstrate alph

55 Recombinant meprin alpha and mutants in which one of the 10 potentia

56 anism for post-transcriptional regulation of meprin alpha and will help clarify the role of meprins i

57 Homooligomers of meprin alpha are secreted; oligomers containing meprin b

58 Mutation of mouse meprin alpha Cys-320 to Ala in the MAM domain (an extrac

59 horbol 12-myristate 13-acetate downregulates meprin alpha expression by inducing tristetraprolin.

60 The size of the meprin alpha homo-oligomers was dependent on protein con

61 By contrast, meprin alpha homodimers formed heterogeneous multimers (

62 By contrast, the propensity of secreted meprin alpha homodimers to self-associate concentrates p

63 beta knockout mice lack membrane-associated meprin alpha in kidney and intestine, and (iv) null mice

64 expression profiles, and the distribution of meprin alpha in kidney and intestine.

65 This work indicates that 1) Cys-320 of mouse meprin alpha is most likely responsible for the covalent

66 ne kidney cells transiently transfected with meprin alpha or meprin beta constructs also cleave exoge

67 human procollagen I heterotrimers by either meprin alpha or meprin beta led to the generation of mat

68 amino acid inserted domain (the I domain) of meprin alpha prevents COOH-terminal proteolytic processi

69 ic residue by a basic amino acid enabled the meprin alpha protease to cleave gastrin.

70 NH2-terminal extension mutants of meprin alpha retained partial activity, with greater dec

71 vary the NH2-terminal residue of the mature meprin alpha subunit (Asn78) and its putative salt bridg

72 In this study, we have used the mouse meprin alpha subunit as a model to test this hypothesis

73 The meprin alpha subunit is secreted as a disulfide-linked d

74 However, all changes in meprin alpha subunit NH2-terminal structure were found t

75 The meprin alpha subunit selected for small (e.g. serine, al

76 The meprin alpha subunit, a multidomain metalloproteinase, i

77 ain for one member of this family, the mouse meprin alpha subunit.

78 he studies herein demonstrate that the human meprin alpha transcript is bound and stabilized by Hu an

79 Replacement of the meprin alpha transmembrane (alphaT) and cytoplasmic (alp

80 disease show decreased colonic expression of meprin alpha, although regulation of expression, particu

81 ytes of the mouse mesenteric lymph node, and meprin alpha, but not beta, decreased during intestinal

82 r meprin beta, while it is not hydrolyzed by meprin alpha.

83 imal enzymatic activity and for secretion of meprin alpha.

84 cts as a determinant for apical targeting of meprin alpha.

85 Meprin alphabeta heterodimers tended to form tetramers b

86 and mutagenesis of basic residues within the meprin alphaC domain did not enhance the movement of the

87 Furthermore, in meprin alphaKO mice, which express meprin beta but not a

88 The meprin alphaT and alphaC domains substituted into meprin

89 Taken together, the data indicate that the meprin alphaT and alphaC domains together contain a weak

90 Replacement of glycines in the meprin alphaT domain GXXXG motif with leucine residues,

91 leucine residues, alanine insertions in the meprin alphaT domain, and mutagenesis of basic residues

92 a variety of peptides extended evidence that meprin alphaTyr-199/betaLys-185 are substrate specificit

93 The meprin alphaY199K mutant was most effective; the corresp

94 ate that the zymogen activation mechanism of meprin and other astacins differs from that of the tryps

95 plants, the role of TRAF-like proteins with meprin and the TRAF homology (MATH) domain is far from c

96 ption factors, mediated by Math-BTB/POZ (for Meprin and TRAF [tumor necrosis factor receptor associat

97 ation of a subset of BTB proteins containing Meprin and TRAF homology (MATH) substrate recognition si

98 r SPOP binds linear motifs through its MATH (meprin and TRAF homology) domain and forms higher-order

99 ptor protein-tyrosine phosphatase mu), MATH (meprin and TRAF homology), and AM (after MATH).

100 atory bowel disease, the interaction between meprins and IL-6 was studied.

101 that are susceptible to hydrolysis by mouse meprins and kinetically characterize the hydrolysis.

102 resent in transmembrane proteins such as the meprins and receptor protein-tyrosine phosphatases, wher

103 de, 2) determine whether macrophages express meprins, and 3) determine whether deletion of the meprin

104 Meprins are mammalian zinc metalloendopeptidases with pr

105 Meprins are metalloendopeptidases expressed by leukocyte

106 Meprins are multidomain zinc metalloproteases that are h

107 Meprins are multimeric proteases that are implicated in

108 Meprins are oligomeric, glycosylated cell surface or sec

109 Mature meprins are oligomers of evolutionarily related, separat

110 esulted in expression of a monomeric form of meprin, as determined by SDS-polyacrylamide gel electrop

111 Meprin B (MB) is a multidomain type-I membrane metallope

112 nregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p.

113 how the tertiary and quaternary structure of meprin B affects function, the disulfide-bonding pattern

114 The product of meprin B cleavage of proIL-18 activated NF-kappaB in EL-

115 Meprin A and meprin B cleaved IL-6 with micromolar affinities (Km of

116 From these observations, a model of the meprin B dimer structure is proposed that provides insig

117 Cross-linking studies of the meprin B dimer with the amine-reactive cross-linker disu

118 The meprin B isoform exists primarily as a cell-surface homo

119 steine residues resulted in the inability of meprin B to form disulfide-linked dimers.

120 Meprin B, consisting of meprin beta subunits only, was d

121 proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPE

122 or and BACE knock-out cells, indicating that meprin beta acts independently of beta-secretase.

123 Thus, disruption of the meprin beta allele in mice affects embryonic viability,

124 e generated stable HEK cell lines expressing meprin beta alone and both meprin alpha and meprin beta

125 Direct interaction of meprin beta and ADAM proteases could be shown by immunof

126 As demonstrated by a bacterial activator of meprin beta and additional measurement of TNF-alpha shed

127 e studies indicate that the messages for the meprin beta and beta' subunit result from differential p

128 -terminal processing of ADAM9, 10, and 17 by meprin beta and identify cleavage sites within their pro

129 18 as a biologically important substrate for meprin beta and implicates meprins in the modulation of

130 etate-, and ionomycin-stimulated shedding of meprin beta and meprin A in the medium of both transfect

131 ADAM10 but not to ADAM9 or ADAM17 inhibited meprin beta and meprin A shedding.

132 the constitutive and stimulated shedding of meprin beta and meprin A.

133 ionomycin stimulated ectodomain shedding of meprin beta and meprin A.

134 rin alpha are secreted; oligomers containing meprin beta are plasma membrane associated.

135 Thus, meprin alpha and meprin beta are unique in their ability to process and r

136 rmore, in meprin alphaKO mice, which express meprin beta but not alpha, active IL-18 was elevated in

137 In this work, we present evidence that meprin beta can also process APP in a manner reminiscent

138 Indeed, prodomain cleavage by meprin beta caused increased ADAM protease activities, a

139 As meprin beta cleavage of APP has been shown to result in

140 , suggesting that MUC2 unfolding exposed the meprin beta cleavage sites.

141 ly, we demonstrated that the metalloprotease meprin beta cleaves APP and liberates soluble N-terminal

142 transiently transfected with meprin alpha or meprin beta constructs also cleave exogenous IL-6.

143 n alphaT and alphaC domains substituted into meprin beta delayed movement of this chimera through the

144 The meprin beta dimer displays a compact shape, whose cataly

145 the cytoplasmic moiety homologous to that of meprin beta during their ER-to-Golgi transition.

146 crystal structure of a major fragment of the meprin beta ectoprotein, the first of a multidomain olig

147 meprin beta alone and both meprin alpha and meprin beta for the expression of meprin A.

148 racellular region of the membrane proteinase meprin beta found in brush border membranes of kidney an

149 n of ADAM10 resulted in enhanced shedding of meprin beta from both transfectants.

150 ns, and 3) determine whether deletion of the meprin beta gene (Mep-1beta) mitigated the ability of le

151 The mouse meprin beta gene encodes an integral membrane protease t

152 were generated by targeted disruption of the meprin beta gene on mouse chromosome 18q12.

153 We identified cleavage sites of meprin beta in the amyloid beta sequence of the wild typ

154 specific inhibitors, we postulate a role for meprin beta in the regulation of ADAM activities.

155 to the goblet cells and requires an enzyme, meprin beta in the small intestine, to be detached and r

156 Meprin beta induces activities of A disintegrin and meta

157 s as they did not shed the membrane-anchored meprin beta into the luminal mucus.

158 Human meprin beta is a 145-kDa disulfide-linked homodimeric mu

159 Additionally, meprin beta is a candidate gene for diabetic nephropathy

160 Meprin beta is a membrane-bound metalloprotease involved

161 Meprin beta is an endogenous zinc-dependent metalloprote

162 Thus overall, meprin beta is expressed by leukocytes in the draining l

163 extran sulfate sodium (DSS) to wild-type and meprin beta knock-out (betaKO) mice, and the serum level

164 Analyses of meprin beta knockout mice indicated that (i) 50% fewer n

165 p normally and are viable and fertile, (iii) meprin beta knockout mice lack membrane-associated mepri

166 en I heterotrimers by either meprin alpha or meprin beta led to the generation of mature collagen mol

167 The meprin beta mRNA in the embryo, kidney and intestinal ce

168 in vivo functions of these metalloproteases, meprin beta null mice were generated by targeted disrupt

169 This enzymatic activity of meprin beta on APP and Abeta generation was also observe

170 uration of meprin beta, OS-9 associates with meprin beta only transiently, coinciding with ER-to-Golg

171 -9-binding site in the cytoplasmic domain of meprin beta overlaps the region essential for this trans

172 ysis also revealed several ADAMs as putative meprin beta substrates.

173 The meprin beta subunit favors acidic residues proximal to t

174 turally occurring peptides revealed that the meprin beta subunit has a clear preference for acidic am

175 The results demonstrate that the meprin beta subunit of meprins A and B cleaves proIL-18

176 By contrast, the evolutionarily related meprin beta subunit retains the COOH-terminal domains du

177 Meprin B, consisting of meprin beta subunits only, was dimeric under a wide rang

178 We observed even higher kinetic values for meprin beta than BACE1 for both the wild type and the Sw

179 Addition of recombinant meprin beta to CF mucus did not release the mucus, but f

180 When recombinant meprin beta was added to the attached mucus of meprin be

181 n-Darby canine kidney cells transfected with meprin beta when proIL-18 was added to the culture mediu

182 we identified a novel proteolytic pathway of meprin beta with ADAM proteases to control protease acti

183 Meprin beta, but not alpha, was detected in cortical and

184 t only the non-spliced form of OS-9 binds to meprin beta, implicating the spliced out segment in the

185 onsistent with the kinetics of maturation of meprin beta, OS-9 associates with meprin beta only trans

186 ted knockdown of the astacin metalloprotease meprin beta, the levels of the alternative CTF decreased

187 he astacin-like proteinases meprin alpha and meprin beta, we herein demonstrate alpha(2)-macroglobuli

188 Thus, the presence of meprin beta, which has a transmembrane domain in vivo, r

189 egion is indispensable for the maturation of meprin beta, which included an endoplasmic reticulum (ER

190 Glu residues, is an excellent substrate for meprin beta, while it is not hydrolyzed by meprin alpha.

191 However, the mucus of the small intestine of meprin beta-deficient mice was now found to be attached.

192 Similar to meprin beta-deficient mice, germ-free mice have attached

193 prin beta was added to the attached mucus of meprin beta-deficient mice, the mucus was detached from

194 rs the balance of APP processing, increasing meprin beta-mediated and decreasing alpha-secretase-medi

195 ies how APP-Ser-675 phosphorylation promotes meprin beta-mediated APP cleavage.

196 secretory pathway, although more slowly than meprin beta.

197 ly, coinciding with ER-to-Golgi transport of meprin beta.

198 be involved in the ER-to-Golgi transport of meprin beta.

199 shedding on bone marrow-derived macrophages, meprin beta/ADAM protease interactions likely influence

200 ost effective; the corresponding mutation of meprin betaK185Y resulted in decreased activity toward g

201 DSS-treated meprin betaKO mice had lower levels of the active cytoki

202 Thus, the expression of meprins by leukocytes of the intestinal immune system ma

203 the base of the tentacles, suggest that this meprin-class metalloproteinase may be multifunctional in

204 The work herein clearly demonstrates that meprin dimers differ markedly in their ability to oligom

205 Meprins have been implicated in cancer and intestinal in

206 Meprins have been implicated in the pathogenesis of seve

207 milar to that of disulfide-linked oligomeric meprin; however, activity against azocasein was markedly

208 prin alpha and will help clarify the role of meprins in the inflammatory response and disease.

209 ant substrate for meprin beta and implicates meprins in the modulation of inflammation.

210 studies were to 1) examine the expression of meprins in the mouse mesenteric lymph node, 2) determine

211 This isoform of meprin is composed of disulfide-bonded dimers of alpha s

212 red with wild-type mice, indicating that the meprin isoforms have opposing effects on the IL-18 level

213 sine phosphatase mu) that is only present in meprin-like astacin proteinases; and a unique C-terminal

214 The alpha and beta subunits of meprins, mammalian zinc metalloendopeptidases, are exten

215 Meprins, metalloendopeptidases of the astacin family, ar

216 tionarily related alpha and beta subunits of meprin metalloproteases are approximately 55% identical

217 nt with the proposition that one function of meprin metalloproteases is to modulate inflammation by i

218 ducator and researcher, especially regarding meprin metalloproteases; and 3) my participation in comm

219 Because meprin metalloproteinases have been implicated in IBD, t

220 ytic activity of membrane-bound and secreted meprin metalloproteinases.

221 , restricts the oligomerization potential of meprin molecules and localizes meprins to the plasma mem

222 Meprins, multimeric metalloproteases expressed in kidney

223 n addition, metalloproteinases, particularly meprins of the astacin family, will be discussed with re

224 Meprin oligomers consist of evolutionarily related alpha

225 A1, JNK kinase, MAP kinase 1), phosphatases (meprin, PTPK, protein phosphatase 2 subunit), and heat s

226 Meprin substrates include bioactive peptides and extrace

227 cy constants are among the highest for known meprin substrates.

228 Transcripts of the meprin subunit truncated after the protease (alpha(1-275

229 evious work established that the multidomain meprin subunits (each approximately 80 kDa) form disulfi

230 t gene structure that has been completed for meprin subunits from all species.

231 the first such description for the mammalian meprin subunits.

232 de bonds but less efficiently than wild-type meprin subunits.

233 potential of meprin molecules and localizes meprins to the plasma membrane.

234 Proteolytic activity of the monomeric meprin using a bradykinin analog or aminobenzoyl-Ala-Ala

235 tunicamycin markedly decreased secretion of meprin, whereas castanospermine and swainsonine had litt

236 ological significance of the interactions of meprins with proIL-18, an experimental model of IBD was