ライフサイエンスコーパス: DDR2

1 discoidin domain receptor tyrosine kinase 2 (DDR2).

2 We examined signal transduction pathways of DDR2.

3 uration and mineralization in the absence of Ddr2.

4 se of Flt-1, Flk-1, c-met, PDGFR, and Tyro10/DDR2.

5 e SFK inhibitor dasatinib than those with WT DDR2.

6 ction of type II and III DFG-out binders for DDR2.

7 sion proteins, which contain only the ECD of DDR2.

8 eakened and nearly absent in the presence of DDR2.

9 with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)).

10 Discoidin domain receptor 2 (DDR2), a collagen receptor preferentially activated by t

11 titutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular

12 lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc

13 In this context, we show that DDR2 activation specifically regulates the directional m

14 DDR2 activation was found to be noticeably more effectiv

15 progression to OA, which was associated with DDR2 activation.

16 2 knockdown or pharmacological inhibition of DDR2 also inhibited the MT1-MMP-dependent cellular degra

17 that binding of the GVMGFO motif to VWF and DDR2 also results in structural changes and the formatio

18 The expression of both DDR2 and MMP-13 was increased in chondrocytes cultured o

19 bservations extend the functional roles that DDR2 and possibly other membrane-anchored, collagen-bind

20 2 signaling in skin fibroblasts derived from DDR2(-/-) and DDR2(+/-) mice.

21 d factor (VWF), discoidin domain receptor 2 (DDR2), and the extracellular matrix protein SPARC/osteon

22 chemistry and demonstrate that both DDR1 and DDR2 are up-regulated in nodules of LAM as compared to n

23 Discoidin domain receptors (DDR1 and DDR2) are receptor tyrosine kinases that bind to and are

24 Discoidin domain receptors (DDR1 and DDR2) are widely expressed cell-surface receptors, which

25 ses of the discoidin domain family, DDR1 and DDR2, are activated by different types of collagen and p

26 discoidin domain receptors (DDRs), DDR1 and DDR2, are expressed widely and, uniquely among receptor

27 The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that are activated b

28 discoidin domain receptors (DDRs), DDR1 and DDR2, are unique among receptor tyrosine kinases in that

29 , we identified discoidin domain receptor 2 (DDR2) as a crucial receptor that mediates this process i

30 Collagen II served as a potent stimulator of DDR2 autophosphorylation, the first step in transmembran

31 onstruct, but not the D4 construct, mediated DDR2 binding and receptor autophosphorylation, demonstra

32 e D2 period of collagen II was essential for DDR2 binding and receptor autophosphorylation, whereas t

33 The DDR2 binding site on collagen II was further defined by

34 Here, we localised a specific DDR2 binding site on the triple-helical region of collag

35 To map the DDR2 binding site(s) on collagen II, we used recombinant

36 e collagen molecule and there were preferred DDR2 binding sites on the collagen I triple helix.

37 As expected, DDR2 binding to collagen II was dependent on triple-heli

38 omains, and the isolated discoidin domain of DDR2 bound collagen I with high affinity.

39 en but not on gelatin, and overexpression of DDR2, but not of a truncated form, was found to induce t

40 Furthermore, the discoidin domain of DDR2, but not of DDR1, was sufficient for transmembrane

41 Knocking down DDR2, but not the beta1 integrin subunit, a common subun

42 g the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced prolifera

43 ts was significantly decreased compared with DDR2(+/-) cells.

44 R2 or constitutively active chimeric DDR2 in DDR2(-/-) cells by retroviral infection restored cell pr

45 on of type I collagen was greatly reduced in DDR2(-/-) cells.

46 we characterized the surface topographies of DDR2 complexes and collagen I, and investigated binding

47 e were able to image and identify binding of DDR2 complexes onto individual molecules of triple-helic

48 Binding of DDR2 complexes to collagen I coated on plastic plates wa

49 (multimerized) by use of antibodies to form DDR2 complexes.

50 gnments and homology modeling, we designed a DDR2 construct appropriate for fluorescent labeling.

51 However, since soluble forms of DDR1 and DDR2 containing its ECD are known to naturally exist in

52 the known or suspected STRE-regulated genes DDR2, CTT1, HSP12, and TPS2, transcript induction was im

53 ype XI collagen-deficient [Col11a1(+/-)] and Ddr2-deficient [Ddr2(+/-)]) mutant mice were generated.

54 ements and biochemical assays indicated that DDR2 delays the formation of collagen fibrils.

55 Discoipyrroles A-D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show sel

56 No DDR2-dependent degenerative changes were seen in knees.

57 Furthermore, DDR2-dependent MT1-MMP activation by cartilage was found

58 However, the increased DDR2 did not induce MMP-13 expression.

59 site to the polypeptide chain termini of the DDR2 discoidin domain constitutes the collagen recogniti

60 spatially adjacent surface loops within the DDR2 discoidin domain were found to be critically involv

61 ple-helical collagen and was mediated by the DDR2 discoidin domain.

62 teoblast cell lines stably secreting DDR1 or DDR2 ECD as soluble proteins.

63 a novel and important functional role of the DDR2 ECD that may contribute to collagen regulation via

64 esults led to a novel functional role of the DDR2 ECD.

65 tion, the current study investigates how the DDR2-ECD, when expressed as a membrane-anchored, cell-su

66 1 at both mRNA and protein levels, but only DDR2 enhances MMP2 activation.

67 e phosphorylated tyrosine kinases, including DDR2, EphB4, TYR2, AXL, SRC, LYN, and FAK.

68 r, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in

69 DDR2 expression increased in the knee joints of transgen

70 involved in collagen binding of the isolated DDR2 extracellular domain.

71 we confirmed that further oligomerization of DDR2-Fc (by means of anti-Fc antibody) greatly enhances

72 Our in vitro binding assay utilizes DDR2-Fc fusion proteins, which can be clustered (multime

73 Our in vitro assays utilized DDR2-Fc fusion proteins, which contain only the ECD of D

74 Clustering of the DDR2-Fc with antibody was found to be requisite for bind

75 M in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and MET Our results indicate

76 ane (Matrigel), and MMP-2 levels to those of DDR2(+/-) fibroblasts.

77 DDR2(-/-) fibroblasts exhibited markedly impaired capaci

78 Proliferation of DDR2(-/-) fibroblasts was significantly decreased compar

79 discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinas

80 e development and homeostasis and that these DDR2 functions are restricted to TMJ fibrocartilage and

81 rapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amp

82 nds for discoidin domain receptors (DDR1 and DDR2), generating an interest in studying the properties

83 Activation of the CUP1, CYC1, GAL1, and DDR2 genes was decreased or abolished completely in the

84 In contrast, a lack of DDR2 had no effect on cell motility or alpha-smooth musc

85 Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human

86 llagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migratio

87 mouse model with inducible overexpression of DDR2 in cartilage.

88 o/+) permits activation and up-regulation of DDR2 in chondrocytes.

89 These data establish a role for DDR2 in critical events during wound repair.

90 -type DDR2 or constitutively active chimeric DDR2 in DDR2(-/-) cells by retroviral infection restored

91 vitro, retroviral overexpression of DDR1 or DDR2 in human SMCs cultured on polymerized collagen gels

92 Conditional overexpression of DDR2 in mature mouse articular cartilage was controlled

93 The specific induction of MMP-13 by DDR2 in response to its cartilage-specific ligand, type

94 Therefore, conditionally overexpressing DDR2 in the mature articular cartilage of mouse knee joi

95 evidence for the potential roles of DDR1 and DDR2 in the regulation of collagen turnover mediated by

96 To assess the requirement for Ddr2 in TMJ development, studies were undertaken to comp

97 The DDR2-induced expression of MMP-13 appears to be specific

98 collagen, the extracellular domain (ECD) of DDR2 inhibits collagen fibrillogenesis and alters the mo

99 monstrate that overexpression of full length DDR2 inhibits fibrillogenesis of collagen type 1.

100 llagen receptor discoidin domain receptor 2 (DDR2) inhibits fibrillogenesis of collagen endogenously

101 These data suggest that DDR2 is a microenvironment sensor that regulates fibrobl

102 Here we show that DDR2 is also unusual in that it requires Src activity to

103 These data show that DDR2 is induced during stellate cell activation and impl

104 These studies demonstrate that DDR2 is necessary for normal TMJ condyle development and

105 mice and immunohistochemistry, we found that DDR2 is preferentially expressed and activated in the ar

106 Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variet

107 Discoidin domain receptor 2 (DDR2) is a tyrosine kinase receptor expressed in mesench

108 Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its

109 lagen receptor, discoidin domain receptor 2 (DDR2), is increased in chondrocytes of the articular car

110 e assays demonstrated that the expression of DDR2/-KD reduced the rate and abundance of collagen depo

111 sses a kinase-deficient form of DDR2, termed DDR2/-KD, on its cell surface.

112 Interestingly, DDR2 knockdown or pharmacological inhibition of DDR2 als

113 Using Ddr2 LacZ-tagged mice and immunohistochemistry, we found

114 ve compound library identified high-affinity DDR2 ligands validated by orthogonal activity-based assa

115 ace collagen degradation by MT1-MMP involves DDR2-mediated collagen signaling.

116 This DDR2-mediated mechanism is only present in non-transform

117 Furthermore, Src is required for DDR2-mediated transactivation of the matrix metalloprote

118 on toward OA was dramatically delayed in the Ddr2(+/-) mice compared with that in their wild-type lit

119 Knee joints of Ddr2(+/-) mice were subjected to microsurgical destabili

120 skin fibroblasts derived from DDR2(-/-) and DDR2(+/-) mice.

121 DDR2 mRNA and protein are induced in stellate cells acti

122 broblasts and show selective cytotoxicity to DDR2 mutant lung cancer cell lines (IC50 120-400 nM).

123 deficient [Col11a1(+/-)] and Ddr2-deficient [Ddr2(+/-)]) mutant mice were generated.

124 binding site within the discoidin domain of DDR2, mutant constructs were created, in which potential

125 d ligand stimulation of EGFR and MET rescued DDR2-mutant lung SCC cells from dasatinib-induced loss o

126 ylation was weakly inhibited by dasatinib in DDR2-mutant lung SCC cells, suggesting that dasatinib in

127 st new, rationale cotargeting strategies for DDR2-mutant lung SCC.

128 Select DDR2 mutations have been shown to confer enhanced sensit

129 DDR2 mutations occur in approximately 4% of lung squamou

130 ll lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor

131 ons, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangeme

132 a panel of human lung SCC tissues harboring DDR2 mutations.

133 3K pathway changes, FGFR1 amplification, and DDR2 mutations.

134 The PDGFRA(pos):Lin(neg):THY1(neg):DDR2(neg) cells were bipotential as the majority express

135 tified by the PDGFRA(pos):Lin(neg):THY1(neg):DDR2(neg) signature, expresses desmosome proteins and di

136 Stable reconstitution of either wild-type DDR2 or constitutively active chimeric DDR2 in DDR2(-/-)

137 Moreover, DDR2 overexpression increases SMC-mediated collagen and

138 ications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.

139 llagen receptor Discoidin domain receptor 2 (DDR2) promotes neutrophil chemotaxis in 3D by triggering

140 -type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing

141 he data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct

142 D2 period of collagen II harbours a specific DDR2 recognition site.

143 We further demonstrate that DDR2 regulates directionality through its ability to inc

144 pression of the discoidin domain receptor 2 (DDR2) results from its interaction with collagen type II

145 , or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through

146 rotein Shc as key signaling intermediates in DDR2 signal transduction.

147 We have compared DDR2 signaling in skin fibroblasts derived from DDR2(-/-

148 ), from Bacillus hunanensis that inhibit the DDR2 signaling pathway.

149 Analysis of older Ddr2(slie/slie) mice (3 and 10 mo) revealed that the ear

150 tive changes in the TMJs of 3- and 10-mo-old Ddr2(slie/slie) mice as compared with wild-type controls

151 Analysis of TMJs from newborn Ddr2(slie/slie) mice revealed a developmental delay in c

152 MJ articular chondrocytes from wild-type and Ddr2(slie/slie) mice showed defects in chondrocyte matur

153 In marked contrast, knee joints of Ddr2(slie/slie) mice were normal.

154 TK-driven adaptive-resistant mechanisms upon DDR2 targeting, and they suggest new, rationale cotarget

155 stably expresses a kinase-deficient form of DDR2, termed DDR2/-KD, on its cell surface.

156 II was found to be a much better ligand for DDR2 than for DDR1.

157 n 3-month-old transgenic mice overexpressing DDR2 to destabilize the medial meniscus, and serial para

158 ice, which contain a spontaneous deletion in Ddr2 to produce an effective null allele.

159 f the pericellular matrix of chondrocytes on DDR2, we generated a mouse model with inducible overexpr

160 in which potential surface-exposed loops in DDR2 were exchanged for the corresponding loops of funct

161 ecombinant extracellular domains of DDR1 and DDR2 were produced to explore DDR-collagen binding in de

162 ; that is, the extracellular domain (ECD) of DDR2, when used as a purified, soluble protein, inhibits

163 discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in

164 monomeric state of collagen was present with DDR2, while control solutions had an abundance of polyme

165 ore potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM.

166 We are interested in the interaction of DDR2 with collagen I because of its potential role in li

167 discovery of a site-specific interaction of DDR2 with collagen II gives novel insight into the natur

168 at Src activity also promotes association of DDR2 with Shc.