An MMP liberates the Ninjurin A ectodomain to signal a lossof cell adhesion

Zhang, Shuning; Dailey, Gina M; Kwan, Elaine; Glasheen, Bernadette M.; Sroga, Gyna E.; Page-McCaw, Andrea

doi:10.1101/gad.1426906

Cited by 48 publications

(68 citation statements)

References 40 publications

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“…Recently, a new signalling protein that is likely to participate in the normal remodelling of the tracheal tubes was identified 78 . This signalling protein, Ninjurin A, physically associates with DmMMP1 and colocalizes with it at tracheal cell surfaces.…”

Section: Loss Of Dmmmp1 Results In Defects In Tracheal Remodelingmentioning

confidence: 99%

“…In cell culture, the Ninjurin A ectodomain is shed by DmMMP1 protein, and the liberated ectodomain signals cells to release adhesion. It is likely that in larvae, DmMMP1 releases the Ninjurin A ectodomain, which signals a release of cell adhesion from the tracheal cuticle 78 . The Ninjurin-family proteins were first identified because of their upregulation in injured rat neurons.…”

Section: Loss Of Dmmmp1 Results In Defects In Tracheal Remodelingmentioning

confidence: 99%

“…• Shedding of Ninjurin A to signal release of cell adhesion 78 Change in the range of action of a signalling molecule…”

Section: Proliferationmentioning

confidence: 99%

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Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

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2,558

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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Section: Loss Of Dmmmp1 Results In Defects In Tracheal Remodelingmentioning

confidence: 99%

Section: Loss Of Dmmmp1 Results In Defects In Tracheal Remodelingmentioning

confidence: 99%

See 1 more Smart Citation

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

Self Cite

2,558

2,180

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“…Primary antibody stains were done at 4°overnight, and secondary antibody stains were done at room temperature for 4 hr. Primary antibodies used were rat anti-Elav 1:50 Developmental Studies Hybridoma Bank (DSHB), rabbit anti-aPKC (Santa Cruz) 1:1000, mouse anti-Dlg (DSHB) 1:100, and mouse anti-Mmp1 1:100 (DSHB) (Zhang et al 2006). Secondary antibodies from Molecular Probes (Eugene, OR) were anti-rat Alexa488, anti-rabbit Alexa488, and anti-mouse Alexa647, all used at 1:200.…”

Section: Methodsmentioning

confidence: 99%

A Mosaic Genetic Screen for Drosophila Neoplastic Tumor Suppressor Genes Based on Defective Pupation

et al. 2007

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The Drosophila neoplastic tumor suppressor genes (TSGs) coordinately control cell polarity and proliferation in epithelial and neuronal tissues. While a small group of neoplastic TSG mutations have been isolated and their corresponding genes cloned, the regulatory pathways that normally prevent inappropriate growth remain unclear. Identification of additional neoplastic TSGs may provide insight into this question. We report here the design of an efficient screen for isolating neoplastic TSG mutations utilizing genetically mosaic larvae. This screen is based on a defective pupation phenotype seen when a single pair of imaginal discs is homozygous for a neoplastic TSG mutation, which suggests that continuously proliferating cells can interfere with metamorphosis. Execution of this screen on two chromosome arms led to the identification of mutations in at least seven new neoplastic TSGs. The isolation of additional loci that affect hyperplastic as well as neoplastic growth indicates the utility of this screening strategy for studying epithelial growth control.

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“…18,[21][22][23] Recently, it has been reported that Drosophila NijA (a fly homolog of vertebrate Ninj1) regulates the remodeling of the tracheal system through interaction with matrix metalloproteinase 1 (MMP1), suggesting that it may be involved in the process of vascular remodeling in higher vertebrates. 24 In this study, we…”

mentioning

confidence: 95%

Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development

et al. 2009

Cell Death Differ

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Developmental tissues go through regression, remodeling, and apoptosis. In these processes, macrophages phagocytize dead cells and induce apoptosis directly. In hyaloid vascular system (HVS), macrophages induce apoptosis of vascular endothelial cells (VECs) by cooperation between the Wnt and angiopoietin (Ang) pathways through cell-cell interaction. However, it remains unclear how macrophages are activated and interact with VECs. Here we show that Ninjurin1 (nerve injury-induced protein; Ninj1) was temporally increased in macrophages during regression of HVS and these Ninj1-expressing macrophages closely interacted with hyaloid VECs. Systemic neutralization using an anti-Ninj1 antibody resulted in the delay of HVS regression in vivo. We also found that Ninj1 increased cell-cell and cell-matrix adhesion of macrophages. Furthermore, Ninj1 stimulated the expression of Wnt7b in macrophages and the conditioned media from Ninj1-overexpressing macrophages (Ninj1-CM) decreased Ang1 and increased Ang2 in pericytes, which consequently switched hyaloid VEC fate from survival to death. Collectively, these findings suggest that macrophages express Ninj1 to increase the death signal through cell-cell interaction and raise the possibility that Ninj1 may act similarly in other developmental regression mediated by macrophages.

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An MMP liberates the Ninjurin A ectodomain to signal a lossof cell adhesion

Cited by 48 publications

References 40 publications

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteinases and the regulation of tissue remodelling

A Mosaic Genetic Screen for Drosophila Neoplastic Tumor Suppressor Genes Based on Defective Pupation

Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development

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