The ADAMs family of metalloproteases: multidomain proteins with multiple functions

Seals, Darren F.; Courtneidge, Sara A.

doi:10.1101/gad.1039703

Cited by 961 publications

(916 citation statements)

References 200 publications

(274 reference statements)

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“…More importantly, ADAM8 truncated isoforms also showed distinct functions compared with the native protein, as previously reported for other members of the ADAMs family (Reiss et al, 2006, Seals andCourtneidge, 2003). In agreement with these earlier studies, the novel D14 0 isoform identified in this report showed a marked increase in the induction of TRAP þ cells.…”

Section: Discussionsupporting

confidence: 91%

“…The majority of ADAMs require removal of their prodomain by proprotein convertases to become catalytically active. Other typical domains include the cysteine-rich, epidermal growth factor -like, transmembrane and short cytoplasmic domains (Seals and Courtneidge, 2003). Over 40 different ADAMs have been identified that have important roles in extracellular matrix remodeling, cell migration and signaling.…”

Section: Introductionmentioning

confidence: 99%

“…Over 40 different ADAMs have been identified that have important roles in extracellular matrix remodeling, cell migration and signaling. ADAMs modulate extracellular signals through their sheddase activity by processing several membrane-bound proteins including cytokines, growth factors and their receptors (Seals and Courtneidge, 2003). In the context of lung cancer, the metalloprotease (MMP) domains of ADAM10 and ADAM17 are key components in the epithelial-derived growth factor receptor signaling cascade that mediate proteolytic shedding of its membrane-tethered ligands (Blobel, 2005, Sahin et al, 2004.…”

Section: Introductionmentioning

confidence: 99%

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Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

et al. 2010

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ADAMs (a disintegrin and metalloprotease) are transmembrane proteins involved in a variety of physiological processes and tumorigenesis. Recently, ADAM8 has been associated with poor prognosis of lung cancer. However, its contribution to tumorigenesis in the context of lung cancer metastasis remains unknown. Native ADAM8 expression levels were lower in lung cancer cell lines. In contrast, we identified and characterized two novel spliced isoforms encoding truncated proteins, D18a and D14 0 , which were present in several tumor cell lines and not in normal cells. Overexpression of D18a protein resulted in enhanced invasive activity in vitro. ADAM8 and its D14 0 isoform expression levels were markedly increased in lung cancer cells, in conditions mimicking tumor microenvironment. Moreover, addition of supernatants from D14 0 -overexpressing cells resulted in a significant increase in tartrate-resistant acid phosphatase þ cells in osteoclast cultures in vitro. These findings were associated with increased pro-osteoclastogenic cytokines interleukin (IL)-8 and IL-6 protein levels. Furthermore, lung cancer cells overexpressing D14 0 increased prometastatic activity with a high tumor burden and increased osteolysis in a murine model of bone metastasis. Thus, the expression of truncated forms of ADAM8 by the lung cancer cells may result in the specific upregulation of their invasive and osteoclastogenic activities in the bone microenvironment. These findings suggest a novel mechanism of tumor-induced osteolysis in metastatic bone colonization.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

et al. 2010

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“…One protease in particular, ADAM28, was found to be highly upregulated in senescent CD8 + T cells and offers a novel functional biomarker of T‐cell senescence. ADAMs (a disintegrin and metalloprotease) are a family of transmembrane proteins which control interactions with the extracellular matrix through proteolytic modification of cell surface proteins, as well as acting as adhesion molecules (Seals & Courtneidge, 2003). ADAM28 has been shown to be involved in membrane‐bound TNF‐α cleavage (Jowett et al ., 2012), as well as serving as a ligand for the integrin α4β1, where it is thought to target the active protease to substrates at the site of cell–cell contact (Bridges et al ., 2002).…”

Section: Discussionmentioning

confidence: 99%

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

et al. 2017

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SummaryCellular senescence is accompanied by a senescence‐associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age‐associated inflammation. We found the CD8+ CD45RA + CD27− EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8+ T cells once generated, they both adopt a unique secretory profile with no commonality to any other subset, aligning more closely with senescence than quiescence. Furthermore, we also show that the SASP observed in senescent CD8+ T cells is governed by p38 MAPK signalling.

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“…6 This family of zinc-dependent transmembrane proteases has been implicated in the ectodomain shedding of various membrane-bound proteins. 17 ADAMs are generated as inactive zymogenes. During the maturation process in the late golgi compartment the prodomain is removed from the ADAM precursor protein, leading to the generation of the mature active protease.…”

Section: For Review)mentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

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The ADAMs family of metalloproteases: multidomain proteins with multiple functions

Cited by 961 publications

References 200 publications

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

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The ADAMs family of metalloproteases: multidomain proteins with multiple functions

Cited by 961 publications

References 200 publications

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

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Human CD8⁺EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK