ライフサイエンスコーパス: DDR1

1 DDR1 (discoidin domain receptor tyrosine kinase 1) kinas

2 DDR1 activation appears to be mediated by its ligand, co

3 DDR1 activation suppressed genotoxic-mediated cell death

4 DDR1 also has a major splice form, which has a 37 amino

5 DDR1 and ADAM10 were found to be in a complex on the cel

6 DDR1 dimerization precedes receptor activation suggestin

7 DDR1 is constitutively expressed in a variety of normal

8 DDR1 is functionally activated as determined by its tyro

9 DDR1 knockdown decreased melanocyte adhesion to collagen

10 DDR1 recognized collagen I only as a dimeric and not as

11 DDR1 shedding is not a result of an activation of its si

12 DDR1 transmembrane signaling thus appears to occur witho

13 DDR1 undergoes autophosphorylation in response to collag

14 DDR1, discoidin domain receptor 1, belongs to a subfamil

15 , including the discoidin domain receptor 1 (DDR1) and E-Cadherin (E-Cad), which interact with COLXV

16 Discoidin domain receptor 1 (DDR1) belongs to a unique family of receptor tyrosine ki

17 llagen receptor discoidin domain receptor 1 (DDR1) by human MKs at both mRNA and protein levels and p

18 tyrosine kinase discoidin domain receptor 1 (DDR1) expressed in granule cells throughout their develo

19 Discoidin domain receptor 1 (DDR1) is a nonintegrin collagen receptor constitutively

20 Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collage

21 Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and trans

22 Discoidin domain receptor 1 (DDR1) is a widely expressed tyrosine kinase receptor whi

23 e, we show that Discoidin Domain Receptor 1 (DDR1), a collagen receptor overexpressed in cancer, colo

24 hich identified discoidin domain receptor 1 (DDR1), a collagen-activated tyrosine kinase, as a potent

25 y, knockdown of discoidin domain receptor 1 (DDR1), a collagen-binding protein that also co-localizes

26 y reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, is expressed dur

27 Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase (RTK), has been shown

28 ls, upregulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen.

29 , we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that acts as a collage

30 in 1 (LMP1) and discoidin domain receptor 1 (DDR1), which is activated by collagen(s) and contributes

31 hoGTPase Cdc42 is activated on collagen in a DDR1-dependent manner.

32 posure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines.

33 nse to exogenous overexpression of activated DDR1, dominant-negative DDR1 inhibited irradiation-induc

34 n, recurrent mutations in ARID1A, ARID1B and DDR1.

35 ortical contractility through E-cadherin and DDR1 proteins.

36 Overall, we show that Galpha13 and DDR1-Par3 differentially regulate cell-cell junctions an

37 phoserine-15 p53, as well as induced p21 and DDR1 levels, suggesting that DDR1 functions in a feedfor

38 ated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC a

39 DR1 tagged with cyan fluorescent protein and DDR1 tagged with yellow fluorescent protein in live cell

40 Moreover, the combination of RG7787 and DDR1 inhibitor caused greater shrinkage of tumor xenogra

41 The AH18.2 was highly conserved between DDR1 and HLA-DQA1 genes; therefore most probably the sec

42 oscopy, we monitored the interaction between DDR1 tagged with cyan fluorescent protein and DDR1 tagge

43 suggest that the 1.65 Mb MHC region between DDR1 and HLA-DRA genes is likely to carry additional sus

44 Nonetheless, both DDR1 JM regions contain potentially usable signaling sit

45 munohistochemistry and demonstrate that both DDR1 and DDR2 are up-regulated in nodules of LAM as comp

46 a novel mechanism of collagen regulation by DDR1.

47 of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 sel

48 Excessive signaling by DDR1 and DDR2 has been linked to the progression of vari

49 sm to explain these findings is signaling by DDR1 clusters.

50 We conclude that non-canonical DDR1 signaling enables breast cancer cells to exploit th

51 These collagenases cleave DDR1 and attenuate collagen I- and IV-induced receptor p

52 Our results therefore indicate that collagen-DDR1 signaling is essential for granule neuron axon form

53 The collagen/DDR1 axis is implicated in tumor-stromal interactions an

54 ctivated EMT, is inhibited and concurrently, DDR1 signaling is suppressed.

55 Making use of enforced covalent DDR1 dimerisation, which does not affect receptor functi

56 The human discoidin domain receptors (DDRs), DDR1 and DDR2, are expressed widely and, uniquely among

57 mammalian discoidin domain receptors (DDRs), DDR1 and DDR2, are unique among receptor tyrosine kinase

58 The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyros

59 DDR1 mutant, we found that ADAM10-dependent DDR1 shedding regulates the half-life of collagen-induce

60 We report here that collagen-dependent DDR1 activation is partly regulated by the proteolytic a

61 and that DNA damage induced a p53-dependent DDR1 response associated with activation of its tyrosine

62 te phosphorylation of receiver DDR1 by donor DDR1 in response to collagen.

63 ion (K562), both of which express endogenous DDR1.

64 how that constitutive shedding of endogenous DDR1 in breast cancer HCC1806 cells is partly mediated b

65 We confirm that endogenous DDR1 is phosphorylated slowly by collagen in adherent T4

66 onuclear neutrophils were induced to express DDR1 after incubation in RPMI 1640.

67 sine kinases of the discoidin domain family, DDR1 and DDR2, are activated by different types of colla

68 Finally, DDR1 depletion blocked cell invasion in a collagen gel.

69 mic domains are individually dispensable for DDR1 dimerization.

70 ther, our data uncover an important role for DDR1, acting through Tuba and Cdc42, in proteolysis-base

71 to be a much better ligand for DDR2 than for DDR1.

72 f combinations of intracellular regions from DDR1 and TrkA (with the extracellular domain of hPDGFRbe

73 nt DDR1 mutants ('receiver') with functional DDR1 ('donor') and demonstrate phosphorylation of receiv

74 However, how DDR1-dependent signaling is regulated has not been under

75 sulted in their partial maturation; however, DDR1 activation markedly amplified TNF-alpha- and LPS-in

76 Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of

77 1 in tumorigenesis, we previously identified DDR1 kinase as a transcriptional target of tumor suppres

78 hey apparently are not activated directly in DDR1 (or DDR1 chimeras) in a ligand-dependent fashion.

79 P-loop residues in DDR1 that confer drug resistance in ABL are therefore ac

80 ed different types of signalling-incompetent DDR1 mutants ('receiver') with functional DDR1 ('donor')

81 , as well as the selective type II inhibitor DDR1-IN-1.

82 as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM.

83 that cannot bind collagen is recruited into DDR1 signalling clusters.

84 1-IN-1 suggesting a structural basis for its DDR1 selectivity.

85 he collagen-binding receptor tyrosine kinase DDR1 (discoidin domain receptor 1) is a drug target for

86 ouples the collagen receptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2 and, hence, to P

87 int-1, the collagen receptor tyrosine kinase DDR1, N-Cadherin, CLCP1/DCBLD2, KIRREL, BCAM and others.

88 Discoidin domain receptor 1 tyrosine kinase (DDR1) and the ErbB1 receptor of amphiregulin are, for ex

89 Upon ligand-mediated DDR1 kinase activation, Notch1 was activated, bound to D

90 Moreover, DDR1 ligand (collagen I) treatment significantly increas

91 Finally, we show that mutant DDR1 that cannot bind collagen is recruited into DDR1 si

92 transmembrane signaling, although the mutant DDR1 proteins were still able to dimerize, whereas mutat

93 ression of activated DDR1, dominant-negative DDR1 inhibited irradiation-induced MAPK activation and p

94 Activation of DDR1 endogenously expressed on macrophages also up-regul

95 Activation of DDR1 on immature DCs resulted in their partial maturatio

96 Collagen stimulation induced aggregation of DDR1, followed by a sharp increase in FRET signal, local

97 PC12 cells, which express modest amounts of DDR1, nor transfected PC12 cells, which express much lar

98 cells, which express much larger amounts of DDR1, respond to this ligand.

99 Further analysis of DDR1 aggregation revealed that DDR1 undergoes cytoplasmi

100 reby collagen induces lateral association of DDR1 dimers and phosphorylation between dimers.

101 nd mutational analyses show that cleavage of DDR1 takes place within the extracellular juxtamembrane

102 Here, we evaluated the contribution of DDR1 in the differentiation of the human monocytic THP-1

103 esidue plays a unique role in the control of DDR1 dimerization and autophosphorylation.

104 study, recombinant extracellular domains of DDR1 and DDR2 were produced to explore DDR-collagen bind

105 otein Par3, which can function downstream of DDR1, also reversed the effects of Galpha13 knockdown on

106 tein tyrosine kinase (Pyk2) is downstream of DDR1, whereas FAK is downstream of alpha2beta1 integrin.

107 sion proteins, which contain only the ECD of DDR1.

108 Therefore, we investigated the effects of DDR1 on RIT.

109 A and protein levels and provide evidence of DDR1 involvement in the regulation of MK motility on typ

110 previously reported inducible expression of DDR1 in human leukocytes and suggested a role for the DD

111 The ectopic expression of DDR1 significantly increased the survival of collagen-tr

112 verexpression of a dominant-negative form of DDR1 in immature granule cells results in severe reducti

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

114 have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung

115 Conversely, induction of DDR1 expression or collagen-stimulated DDR1 activity pro

116 ifically, we demonstrated that inhibition of DDR1 binding to type I collagen, preserving the engageme

117 Nonetheless, inhibition of DDR1 function resulted in strikingly increased apoptosis

118 Interaction of DDR1 oligomers with collagen was found to modulate colla

119 ittle is understood about the interaction of DDR1 with collagen and its possible functional implicati

120 duces the aggregation and internalization of DDR1 dimers at timescales much before receptor activatio

121 occurs naturally in kinase-dead isoforms of DDR1 and as a shedded soluble protein.

122 We found the kinetics of DDR1 internalization to be fast, with a significant perc

123 Knockdown of DDR1 by siRNA or treatment with inhibitor, 7rh, greatly

124 Conversely, knockdown of DDR1 significantly decreased the survival of collagen-tr

125 The expression level of DDR1 in PBMC was increased further by stimulation with t

126 man diseases, but the molecular mechanism of DDR1 activation is poorly defined.

127 re, the discoidin domain of DDR2, but not of DDR1, was sufficient for transmembrane receptor signalin

128 we confirmed that further oligomerization of DDR1-Fc (by means of anti-Fc antibody) greatly enhances

129 In vitro, retroviral overexpression of DDR1 or DDR2 in human SMCs cultured on polymerized colla

130 Notch1 protein as an interacting partner of DDR1 receptor, as determined by tandem affinity protein

131 downstream signals after phosphorylation of DDR1 by collagen were not transmitted through the classi

132 s, collagen induced rapid phosphorylation of DDR1.

133 may inhibit or delay the phosphorylation of DDR1.

134 The presence of DDR1 ECD resulted in "locking" of collagen molecules in

135 Collagen fibers formed in the presence of DDR1 had a larger average diameter, were more cross-link

136 insights into the cellular redistribution of DDR1 following its interaction with collagen type I.

137 contacts within the extracellular region of DDR1 by using cysteine-scanning mutagenesis.

138 at the extracellular juxtamembrane region of DDR1 is exceptionally flexible and does not constrain th

139 e, the extracellular juxtamembrane region of DDR1 tolerated large deletions as well as insertions of

140 e transmembrane and intracellular regions of DDR1, also fails to mediate neuronal-like differentiatio

141 enase of membrane-type MMPs in regulation of DDR1 cleavage and activation at the cell-matrix interfac

142 if evolved to act as a negative repressor of DDR1 phosphorylation in the absence of ligand.

143 olecular mechanism(s) underlying the role of DDR1 in cancer.

144 In this study, we evaluated the role of DDR1 in DC maturation using human monocyte-derived DCs.

145 Besides the role of DDR1 in tumorigenesis, we previously identified DDR1 kin

146 provide evidence for the potential roles of DDR1 and DDR2 in the regulation of collagen turnover med

147 uces ADAM10-dependent ectodomain shedding of DDR1.

148 While the oligomeric state of DDR1 is reported to play a significant role in collagen

149 nown about the effect of collagen binding on DDR1 oligomerization and cellular distribution.

150 pe MMPs (MT4- and MT6-MMP) have no effect on DDR1 cleavage or activation.

151 entiated DDR1b-overexpressing THP-1 cells or DDR1 on mature DCs induced the formation of TNFR associa

152 ently are not activated directly in DDR1 (or DDR1 chimeras) in a ligand-dependent fashion.

153 ociated with collagen frequently overexpress DDR1 and that short-term exposure to collagen is suffici

154 itro and on surfaces of cells overexpressing DDR1.

155 and demonstrate phosphorylation of receiver DDR1 by donor DDR1 in response to collagen.

156 r beta (PDGFRbeta) and the collagen receptor DDR1.

157 The discoidin domain receptor (DDR1) is characterized by a discoidin I motif in the ext

158 Discoidin domain receptors (DDR1 and DDR2) are receptor tyrosine kinases that bind t

159 Discoidin domain receptors (DDR1 and DDR2) are widely expressed cell-surface recepto

160 d as ligands for discoidin domain receptors (DDR1 and DDR2), generating an interest in studying the p

161 The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that are ac

162 ADAM10 plays an important role in regulating DDR1-mediated cell adhesion to achieve efficient cell mi

163 Using a shedding-resistant DDR1 mutant, we found that ADAM10-dependent DDR1 sheddin

164 mouse osteoblast cell lines stably secreting DDR1 or DDR2 ECD as soluble proteins.

165 tigation into the mechanism of action showed DDR1 silencing was associated with decreased expression

166 n activation of its signaling pathway, since DDR1 mutants defective in signaling were shed in an effi

167 sm (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell

168 on of DDR1 expression or collagen-stimulated DDR1 activity protected cancer cells from RG7787 killing

169 bsence of collagen was able to induce strong DDR1 phosphorylation, indicating that a phosphatase may

170 somatic mutations, JAK1(V623A), JAK1(T478S), DDR1(A803V), and NTRK1(S677N), once each in 4 respective

171 These data demonstrate that DDR1 is a key modulator of RIT activity and represents a

172 We further demonstrated that DDR1 activated the MAPK cascade in a Ras-dependent manne

173 ans of atomic force microscopy revealed that DDR1 oligomers bound at overlapping or adjacent collagen

174 r analysis of DDR1 aggregation revealed that DDR1 undergoes cytoplasmic internalization and incorpora

175 We showed that DDR1 is a direct p53 transcriptional target, and that DN

176 The results suggest that DDR1 exerts prosurvival effect, at least in part, throug

177 specific apoptotic stimulus, suggesting that DDR1 also influences baseline survival.

178 induced p21 and DDR1 levels, suggesting that DDR1 functions in a feedforward loop to increase p53 lev

179 The DDR1 transmembrane domain contains two putative dimeriza

180 Those with the TrkA kinase domain and the DDR1 JM regions were able to produce differentiation to

181 odulation of collagen fibrillogenesis by the DDR1 ECD elucidates a novel mechanism of collagen regula

182 to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a beta-hairpin replaces the cage-like

183 er cryptic binding sites for PLCgamma in the DDR1 sequences) and markedly reduced the differentiative

184 requirement for receptor dimerization in the DDR1-collagen interaction.

185 leading to MAPK activation) is weaker in the DDR1/TrkA chimeras than in TrkA alone, and the PLCgamma

186 Moreover, the DDR1 knockdown cancer cells showed the reduced transform

187 at maintains the autoinhibitory state of the DDR1 dimers is unknown.

188 signify an important functional role of the DDR1 ECD, which occurs naturally in kinase-dead isoforms

189 ere, we elucidate the binding pattern of the DDR1 extracellular domain (ECD) to collagen type 1 and i

190 These findings suggest that the DDR1 receptors do have signaling capacity but may requir

191 eporter assay (named TOXCAT) showed that the DDR1 transmembrane domain has a strong potential for sel

192 ow clear that aberrant signaling through the DDR1 receptor is closely associated with various steps o

193 Among three DDR1 isoforms, DDR1alpha was the major transcript in leu

194 ivation of wild-type Notch signaling through DDR1.

195 e activation, Notch1 was activated, bound to DDR1, and activated canonical Notch1 targets, including

196 dding did not occur unless collagen bound to DDR1.

197 nds was further investigated with respect to DDR1 inhibition.

198 centromeric to HLA-DRA gene and telomeric to DDR1 gene.

199 In addition, a chimeric TrkA-DDR1 receptor failed to become phosphorylated on stimula

200 Two DDR1 isoforms, DDR1a and DDR1b, were expressed in both i

201 an affinity similar to that of the wild-type DDR1 ectodomain.

202 Unexpectedly, DDR1 kinase activity is not required for invadosome form

203 Our in vitro assays utilized DDR1-Fc fusion proteins, which contain only the ECD of D

204 In vivo, DDR1 mRNA was detectable in mononuclear leukocytes infil

205 h1 receptor in the nuclear fraction, whereas DDR1 knockdown cells show little or no increase of the a

206 signaling responses of the two chimeras with DDR1 JM sequences (with and without the insert) indicate