ライフサイエンスコーパス: BMP-1

1 BMP-1 affects morphogenesis, at least partly, via biosyn

2 BMP-1 and mTLL-1 are shown to cleave Chordin, at sites s

3 BMP-1 is also related to the product of the Drosophila p

4 BMP-1 lacking CUB glycosylation was translocated to the

5 BMP-1 molecules lacking any one of the CUB-specific glyc

6 BMP-1 molecules lacking individual glycosylation sites w

7 BMP-1 stimulates the conversion of newly secreted proapo

8 BMP-1, however, differed from other BMPs in that it its

9 BMP-1-related proteases mammalian Tolloid and mammalian

10 BMP-1/tolloid-like proteinases (BTPs) are major enzymes

11 BI-1 (BMP-1 isoenzyme inhibitor-1), a selective inhibitor of a

12 Vertebrate bone morphogenetic protein 1 (BMP-1) and Drosophila Tolloid (TLD) are prototypes of a

13 Bone morphogenetic protein 1 (BMP-1) and mammalian Tolloid (mTLD), two proteinases enc

14 C-proteinases: bone morphogenetic protein 1 (BMP-1) and mammalian Tolloid (mTLD).

15 which includes bone morphogenetic protein 1 (BMP-1), mammalian Tolloid (mTLD), mammalian Tolloid-like

16 Bone morphogenetic protein 1 (BMP-1), which is a tolloid member of the astacin-like fa

17 gene encoding bone morphogenetic protein 1 (BMP-1).

18 Bone morphogenetic protein-1 (BMP-1) also plays key roles in regulating vertebrate mat

19 tant proteases bone morphogenetic protein-1 (BMP-1) and Drosophila Tolloid.

20 Bone morphogenetic protein-1 (BMP-1) is a metalloprotease that plays important roles i

21 Bone morphogenetic protein-1 (BMP-1) is a metalloprotease that plays key roles in regu

22 Bone morphogenetic protein-1 (BMP-1) plays key roles in regulating the deposition of v

23 Bone morphogenic protein-1 (BMP-1) was originally identified as one of several BMPs

24 Bone morphogenetic protein-1 (BMP-1), a metalloprotease isolated from osteogenic extra

25 rocollagens by bone morphogenetic protein-1 (BMP-1), also known as type I procollagen C-proteinase ()

26 alloproteinase bone morphogenetic protein-1 (BMP-1), and for a gene encoding the closely related meta

27 of the family: bone morphogenetic protein-1 (BMP-1), mammalian tolloid (mTLD), tolloid-like (TLL)-1 a

28 loid and human bone morphogenetic protein-1 (BMP-1).

29 endoproteinase/bone morphogenetic protein-1 (BMP-1).

30 nases, such as bone morphogenetic protein-1 (BMP-1).

31 -propeptide by bone morphogenetic protein-1 (BMP-1).

32 enzymes of the bone morphogenetic protein-1 (BMP-1)/Tolloid family of metalloproteases that cleave LG

33 Bone morphogenetic protein-1 (BMP-1)/Tolloid-like metalloproteinases play key roles in

34 The mammalian bone morphogenetic protein-1 (BMP-1)/Tolloid-related metalloproteinases play key roles

35 Studies with recombinant BMP-1, BMP-1 antibody, and BMP-1 siRNA establish this proteinas

36 In a proteinase survey, all BMP-1 isoenzymes processed human laminin-5 gamma2 and al

37 with recombinant BMP-1, BMP-1 antibody, and BMP-1 siRNA establish this proteinase as the major or on

38 Both tolloid and BMP-1 encode metalloproteases that might activate TGF-be

39 n) was enhanced by PCPE-1 but not as well as BMP-1 retaining the CUB3 domain.

40 e used these differences in activity between BMP-1 and mTLL-2 to narrow in on the domains in BMP-1 th

41 s null for the Bmp1 gene, which encodes both BMP-1 and mammalian Tolloid, produce predominantly unpro

42 m of the propeptide resistant to cleavage by BMP-1/TLD proteinases can cause significant increases in

43 alpha3 is also cleaved by BMP-1 in vitro, but the cleavage site is yet to be deter

44 -terminal sequences of products generated by BMP-1 cleavage of DMP1 match those predicted from proces

45 pro-alpha2(V) C-propeptides are processed by BMP-1-like enzymes, and pro-alpha1(V) C-propeptides are

46 sis, and that processing of the prodomain by BMP-1 potentiates the ability of OGN to modulate the for

47 otrimers, the processing of pro-alpha3(V) by BMP-1 occurs at an unexpected site within NH2-terminal g

48 (mTLL)-1 and -2 are two genetically distinct BMP-1-related proteinases, and mTLL-1 has been shown to

49 In the shorter form, pCP-1 (i.e., BMP-1), the sequence ends after the CUB3-domain.

50 many bone morphogenetic proteins-especially BMP-1, -3, and -4-to confer osteoinductivity upon these

51 oinductive because (1) they uniquely express BMP-1, (2) they express an appropriate combination of in

52 s redefining the specificity of cleavage for BMP-1-like enzymes.

53 As previously demonstrated for BMP-1 and mTLD, mTLL-1 is shown to specifically process

54 Saos-2 cells expressed mRNA for BMP-1, -2, -3, -4,-6, and TGF-beta 1.

55 Thus, a further role for BMP-1-Tolloid-like proteinases in formation of mineraliz

56 However, in vivo evidence of roles for BMP-1 and mTLL-1 in BMP signaling in mammals is lacking.

57 lpha3 and gamma2 chains to be substrates for BMP-1 in vitro.

58 es alternatively spliced RNA transcripts for BMP-1 and for a second longer protein, designated mammal

59 ises a metalloproteinase domain (either from BMP-1 or from mTLL-2) and the CUB1 domain of BMP-1 (the

60 ort the use of a cDNA library, prepared from BMP-1/mTld-null mouse embryos, to isolate cDNA clones fo

61 alian sFRP-1, -2, and -4 do not modify human BMP-1 activity on several of its known substrates includ

62 ppears as a tight binding inhibitor of human BMP-1, with a K(i) of 1.5 +/- 0.5 nM, and is shown to st

63 t the same site as the previously identified BMP-1 cleavage site.

64 ontrast to its action on procollagens I-III, BMP-1 does not cleave the C-propeptide of pro-alpha1(V)

65 with either of the corresponding domains in BMP-1 and mTLL-2 did not result in procollagen cleavage

66 -1 and mTLL-2 to narrow in on the domains in BMP-1 that specify PCP and chordinase activity.

67 part of the innate immune response, inhibits BMP-1 activity and blocks the maturation of proapo A1.

68 Tll1 double null mouse embryos, thus lacking BMP-1/mTLD, mTLL-1, or all three enzymes, respectively,

69 r genes encoding three of the four mammalian BMP-1/Tolloid-like proteinases appear to be deficient in

70 sed to varying extents by all four mammalian BMP-1/Tolloid-like proteinases, to generate a 27-kDa spe

71 d, to varying extents, by all four mammalian BMP-1/Tolloid-like proteinases, to generate fragments si

72 r genes encoding three of the four mammalian BMP-1/Tolloid-related proteinases produce only unprocess

73 pression domains of all four known mammalian BMP-1/TLD-like proteases [BMP-1, mammalian Tolloid (mTLD

74 oids, but truncated forms of TLL-2 mimicking BMP-1 are unable to cleave chordin.

75 n differences in the activities of monomeric BMP-1 and dimers of mTLD and TLL-1.

76 In addition, mTLD/BMP-1 null mice were shown to have deficient laminin-5 p

77 mp1 gene, which encodes variants of the mTLD/BMP-1 metalloproteases, as a critical regulator of alpha

78 h reduced laminin-gamma2 processing via mTLD/BMP-1.

79 that PCPE-1 had no effect on the ability of BMP-1 to cleave chordin.

80 Thus, the combination of BMP-1/mTLD and mTLL-1 is shown to be responsible for the

81 BMP-1 or from mTLL-2) and the CUB1 domain of BMP-1 (the CUB1 domain of mTLL-2 cannot substitute for t

82 ollagen, but in addition, the CUB3 domain of BMP-1 appears to augment the interaction.

83 L-2 cannot substitute for the CUB1 domain of BMP-1).

84 ave chordin if coupled to the CUB1 domain of BMP-1.

85 it acts directly on the catalytic domain of BMP-1.

86 1) the metalloproteinase and CUB2 domains of BMP-1 are absolutely required for PCP activity; swaps wi

87 he glycosylation sites in the CUB domains of BMP-1 are important for secretion and stability of the m

88 atal, and adult brain in which expression of BMP-1 and mTld has not been observed.

89 cyte cultures but little or no expression of BMP-1, mTLL-1, or mTLL-2.

90 edundancy obscuring the in vivo functions of BMP-1-related proteases in mammals, we here characterize

91 as well as TGF-beta 1 mRNA, while levels of BMP-1 and BMP-3 mRNA were either not detectable or detec

92 sacrcoma cells, TGF-beta1 elevated levels of BMP-1 mRNA approximately 7-fold and elevated levels of m

93 The unexpectedly large number of BMP-1/TLD-like protease genes (23) results primarily fro

94 The presence of BMP-1 and -4 protein was confirmed in Saos-2 cells by im

95 To more directly assess the roles of BMP-1 and mTLL-1 in lysyl oxidase activation by connecti

96 of PCPE mRNA is shown to differ from that of BMP-1 and type I procollagen during mouse development, c

97 ur known mammalian BMP-1/TLD-like proteases [BMP-1, mammalian Tolloid (mTLD), mammalian Tolloid-like

98 d that the minimal procollagen C-proteinase (BMP-1 lacking the EGF and CUB3 domain) was enhanced by P

99 e NC2 domain by the procollagen C-proteinase/BMP-1 in dimer assembly.

100 Recombinant BMP-1 cleaves gamma2 in vitro, both within intact lamini

101 Recombinant BMP-1 molecules lacking all glycosylation sites or the t

102 Studies with recombinant BMP-1, BMP-1 antibody, and BMP-1 siRNA establish this pr

103 ons and were induced by TGF-beta1 to secrete BMP-1 and mTld predominantly as unprocessed proenzymes.

104 Secreted BMP-1 and mTld, induced by TGF-beta1 in MG-63 and other

105 up-regulated by TGF-beta1 and that secreted BMP-1, induced by TGF-beta1, is either processed to an a

106 In vitro studies have shown BMP-1 and mTLL-1 capable of cleaving Chordin, an extrace

107 Instead, the single BMP-1-specific cleavage site within pro-alpha1(V) chains

108 ession domains of the four proteases suggest BMP-1 as the major Chordin antagonist in early mammalian

109 strated developmental roles in other systems-BMP-1/TLD (tolloid) (astacins), MMPs (matrix metalloprot

110 e at the correct physiological site but that BMP-1 is 3-, 15-, and 20-fold more efficient than mTLL-1

111 Here, we show that BMP-1 cleaves probiglycan at a single site, removing the

112 Here we show that BMP-1 is itself up-regulated by TGF-beta1 and that secre

113 This further suggests that BMP-1 activity facilitates basement membrane assembly, b

114 Sequence analysis suggests that BMP-1 has six potential N-linked glycosylation sites (i.

115 The BMP-1/Tolloid family of metalloproteases is thereby impl

116 ap extensively that previously shown for the BMP-1 and mTld RNA forms.

117 Consistent with possible roles for the BMP-1/Tolloid-like proteinases in the physiological proc

118 rventricular septum, where expression of the BMP-1 gene, Bmp1, was not observed.

119 mmunoblot and quantitative PCR survey of the BMP-1 isoenzymes revealed expression of mTLD in primary

120 ferent chromosomal location than that of the BMP-1/mTld gene.

121 gs raise the possibility that members of the BMP-1/TLD family may be involved in activating latent my

122 Therefore, BMP-1 was a member of the "astacin families" of zinc-req

123 hat procollagen C-proteinase is identical to BMP-1.

124 lloid, a putative metalloprotease related to BMP-1, enhances DPP function, while SOG, an ortholog of

125 ditional proteinases structurally similar to BMP-1 and mTLD: the genetically distinct mammalian Tollo

126 of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metalloproteinases can cleave the m

127 Aplysia tolloid/BMP-1-like protein (apTBL-1) might regulate the morpholo

128 he interactions of Complement C1r/C1s, Uegf, BMP-1 (CUB) domain-containing proteins in diverse biolog

129 related to Drosophila tolloid and vertebrate BMP-1 (Reynolds et al., Development 114, 769-786).

130 ction may be mediated, at least in part, via BMP-1 by this novel mechanism.