An Orphan Receptor Tyrosine Kinase Family Whose Members Serve as Nonintegrin Collagen Receptors

Shrivastava, Ajay; Radziejewski, Czeslaw; Campbell, Ernest B.; Kováč, Ĺubomír; McGlynn, Marion; Ryan, Terence E.; Davis, Sam; Goldfarb, Mitchell; Glass, David J.; Lemke, Greg; Yancopouloš, George D.

doi:10.1016/s1097-2765(00)80004-0

Cited by 487 publications

(493 citation statements)

References 39 publications

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“…3C), and lasted for at least 24 hours, consistent with earlier studies [Shrivastava et al, 1997;Vogel et al, 1997]. Levels of tyrosine phosphorylated DDR1 CTFs, and ectodomain release, both increased in a concentration-dependent fashion following prolonged exposure to collagen type I, although the DDR1 fragments were not detected until hours after phosphorylation of full-length DDR1 was first apparent (Fig.…”

Section: Discussionsupporting

confidence: 89%

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Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

Slack

Siniaia

Blusztajn

2006

J of Cellular Biochemistry

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The discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is highly expressed in breast carcinoma cells. Upon binding to collagen, DDR1 undergoes autophosphorylation followed by limited proteolysis to generate a tyrosine phosphorylated C-terminal fragment (CTF). Although it was postulated that this fragment is formed as a result of shedding of the N-terminal ectodomain, collagen-dependent release of the DDR1 extracellular domain has not been demonstrated. We now report that, in conjunction with CTF formation, collagen type I stimulates concentration-dependent, saturable shedding of the DDR1 ectodomain from two carcinoma cell lines, and from transfected cells. In contrast, collagen did not promote cleavage of other transmembrane proteins including the amyloid precursor protein (APP), ErbB2, and E-cadherin. Collagen-dependent tyrosine phosphorylation and proteolysis of DDR1 in carcinoma cells were reduced by a pharmacologic Src inhibitor. Moreover, expression of a dominant negative Src mutant protein in human embryonic kidney cells inhibited collagen-dependent phosphorylation and shedding of co-transfected DDR1. The hydroxamate-based metalloproteinase inhibitor TAPI-1 (tumor necrosis factor-α protease inhibitor-1), and tissue inhibitor of metalloproteinase (TIMP)-3, also blocked collagen-evoked DDR1 shedding, but did not reduce levels of the phosphorylated CTF. Neither shedding nor CTF formation were affected by the γ-secretase inhibitor, L-685,458. The results demonstrate that collagen-evoked ectodomain cleavage of DDR1 is mediated in part by Src-dependent activation or recruitment of a matrix-or disintegrin metalloproteinase, and that CTF formation can occur independently of ectodomain shedding. Delayed shedding of the DDR1 ectodomain may represent a mechanism that limits DDR1-dependent cell adhesion and migration on collagen matrices. Keywords zinc-dependent metalloproteinase; amyloid precursor protein; tyrosine phosphorylation; TIMP (tissue inhibitor of metalloproteinase)

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Section: Discussionsupporting

confidence: 89%

“…In 1997, two groups reported that DDR1 and DDR2 are collagen receptors [Shrivastava et al, 1997;Vogel et al, 1997]. The addition of collagen to the medium of cells expressing either DDR1 or DDR2 resulted in tyrosine phosphorylation of these receptors with a timecourse that was delayed in onset and lasted for up to 18 hours.…”

Section: Introductionmentioning

confidence: 99%

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

Slack

Siniaia

Blusztajn

2006

J of Cellular Biochemistry

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“…Such a mechanism is illustrated by the type I collageninduced activation of tyrosine kinases of the discoidin domain receptor which ultimately trigger the synthesis of MMP-1. However, the MMP-1 -mediated cleavage of collagen abolishes the receptor activation, creating a specific negative-feedback regulatory loop [67,68]. In the presence of broad-spectrum MMPIs, the impaired collagen degradation might prevent this negative regulation, resulting in an uncontrolled stimulation of MMP-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Maquoi

Munaut

Colige

et al. 2002

Experimental Cell Research

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Enhanced expression and activation of matrix met-alloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with β-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as 11-1β and TNF-α were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-Spectrum MMPIs.

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“…4). MLBR 2 extends from helical position 682-830, and includes sites important for collagen self-assembly [Prockop and Fertala, 1998], for cleavage by matrix metalloproteinases (MMPs) 1, 2, and 13 [Lauer-Fields et al, 2000], as well as for binding by α1β1/α2β1 integrins [Xu et al, 2000], fibronectin [Dzamba et al, 1993;Kleinman and McGoodwin, 1976;Kleinman et al, 1978], cartilage oligomeric matrix protein (COMP) [Rosenberg et al, 1998], phosphophoryn [Dahl et al, 1998], and possibly the discoidin domain (DDR2) receptor [Schlessinger, 1997;Shrivastava et al, 1997;Vogel et al, 1997]. MLBR 3 extends from helical residue 920 to the end of the helical region.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

et al. 2007

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Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proα1(I) and proα2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. Onethird of the mutations that result in glycine substitutions in α1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibrilmatrix interactions. Recurrences at the same site in α2(I) are generally concordant for outcome, unlike α1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In α2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.

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An Orphan Receptor Tyrosine Kinase Family Whose Members Serve as Nonintegrin Collagen Receptors

Cited by 487 publications

References 39 publications

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

Stimulation of Matrix Metalloproteinase-9 Expression in Human Fibrosarcoma Cells by Synthetic Matrix Metalloproteinase Inhibitors

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

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