Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands

Şahin, Umut; Weskamp, Gisela; Kelly, Kristine; Zhou, Hongming; Higashiyama, Shigeki; Peschon, Jacques J.; Hartmann, Dieter; Säftig, Paul; Blobel, Carl P.

doi:10.1083/jcb.200307137

Cited by 901 publications

(1,034 citation statements)

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“…Our analyses of an uncleavable human FasL mutant (Supplementary Figure 1) showed that the release of sFasL was completely abrogated in human and murine cells, indicating that despite the loose cleavage specificity the protease susceptible region is located within this region. ADAM10 has been implicated before in the shedding of different substrates including CD44, 37 amphiregulin, 38 N-cadherin, 21 E-cadherin 24 and the neuronal adhesion molecule L1. 39 For some of these substrates, ADAM10 is responsible for both the constitutive and the inducible shedding.…”

Section: Discussionmentioning

confidence: 99%

“…293T cells, MEFs from ADAM9 À/À , ADAM10 À/À , ADAM15 À/À , ADAM17 À/À mice and respective wild-type animals were generated and characterized as described elsewhere. 20,38 All cells were grown in Dulbecco's modified Eagle's medium with high glucose (PAA Laboratories, Pasching, Austria), supplemented with antibiotics and 10% fetal calf serum (FCS). Cells were transfected with FuGENE 6 (Roche Applied Science, Mannheim, Germany) according to manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

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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“…• Epidermal-growth-factor receptor (EGFR) ligands need to be processed to function 28,[142][143][144] Cell survival…”

Section: Proliferationmentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,585

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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“…Expression of these two proteins in precursor cell cultures, and their persistence in differentiating conditions, suggested that one of these enzymes, or both, participate in determining the cell fate of neural precursors. A systematic characterization of EGFR ligand processing by ADAM-10 and ADAM-17 [40,47] demonstrated that ADAM-10 is the major convertase of EGF and betacellulin, whereas ADAM-17 is the main sheddase of TGF-a, HB-EGF, epiregulin, amphiregulin, and epigen. Interestingly, among the four EGFR ligands studied in this work, specifically those that were substrates for ADAM-17 (TGF-a, HB-EGF, and amphiregulin) were expressed in the cultured cells, whereas EGF mRNA was undetectable.…”

Section: Adam-17 and Tgf-a Are Directly Involved In Npc Differentiationmentioning

confidence: 99%

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

et al. 2011

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Neural precursor cells (NPCs) are activated in central nervous system injury. However, despite being multipotential, their progeny differentiates into astrocytes rather than neurons in situ. We have investigated the role of epidermal growth factor receptor (EGFR) in the generation of non-neurogenic conditions. Cultured mouse subventricular zone NPCs exposed to differentiating conditions for 4 days generated approximately 50% astrocytes and 30% neuroblasts. Inhibition of EGFR with 4-(3-chloroanilino)-6,7-dimethoxyquinazoline significantly increased the number of neuroblasts and decreased that of astrocytes. The same effects were observed upon treatment with the metalloprotease inhibitor galardin, N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM 6001), which prevented endogenous transforming growth factor-a (TGF-a) release. These results suggested that metalloprotease-dependent EGFRligand shedding maintained EGFR activation and favored gliogenesis over neurogenesis. Using a disintegrin and metalloprotease 17 (ADAM-17) small interference RNAs transfection of NPCs, ADAM-17 was identified as the metalloprotease involved in cell differentiation in these cultures. In vivo experiments revealed a significant upregulation of ADAM-17 mRNA and de novo expression of ADAM-17 protein in areas of cortical injury in adult mice. Local NPCs, identified by nestin staining, expressed high levels of ADAM-17, as well as TGF-a and EGFR, the three molecules necessary to prevent neurogenesis and promote glial differentiation in vitro. Chronic local infusions of GM6001 resulted in a notable increase in the number of neuroblasts around the lesion. These results indicate that, in vivo, the activation of a metalloprotease, most probably ADAM-17, initiates EGFR-ligand shedding and EGFR activation in an autocrine manner, preventing the generation of new neurons from NPCs. Inhibition of ADAM-17, the limiting step in this sequence, may contribute to the generation of neurogenic niches in areas of brain damage.

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Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands

Cited by 901 publications

References 62 publications

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

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

Matrix metalloproteinases and the regulation of tissue remodelling

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

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