Identification of ADAM10 as a major TNF sheddase in ADAM17-deficient fibroblasts

Mężyk-Kopeć, Renata; Bzowska, Monika; Stalińska, Krystyna; Chełmicki, Tomasz; Podkalicki, Michał; Jucha, Jarosław; Kowalczyk, Katarzyna A.; Mak, Paweł; Bereta, Joanna

doi:10.1016/j.cyto.2009.03.002

Cited by 48 publications

(39 citation statements)

References 28 publications

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“…29 The activation of NFB in MCL can be partly attributed to TNF␣, 30,31 the bioavailability of which has been shown to be regulated by ADAM10. [11][12][13] In the present study, we show for the first time that ADAM10 is constitutively activated in MCL cell lines and tumors. In view of the importance of TNF␣ in the biology of MCL and of a previous report that ADAM10 can increase the bioavailability of TNF␣, [11][12][13] we hypothesize that ADAM10 may be important in the pathogenesis of MCL.…”

mentioning

confidence: 86%

“…In view of previous studies showing that ADAM10 regulates the production of TNF␣ in murine cell lines and immortalized human cell lines, 11,13 as well as the importance of the TNF␣ in the biology of MCL, [29][30][31] we hypothesized that ADAM10 may promote the growth of MCL via up-regulation of TNF␣. In keeping with this concept, we found that down-regulation of ADAM10 using siRNA in Jeko-1 cells resulted in a significant decrease in the levels of TNF␣ present in the culture medium (P ϭ .001; Figure 5A).…”

Section: Adam10 Activates the Tnf␣/nfb Axismentioning

confidence: 99%

“…10 Directly relevant to our study, ADAM10 was recently found to be one of the enzymes responsible for cleaving TNF␣ and releasing its active form. [11][12][13] Furthermore, it has been reported that ADAM10 is important for the development of the marginal zone B cells. 14 By regulating the bioavailability of ligands to various cellular-signaling receptors, ADAM10 modulates the activation status of various cellularsignaling pathways that have an impact on cellular responses such as proliferation and migration.…”

Section: Introductionmentioning

confidence: 99%

“…11,13 In this study, inhibition of ADAM10 expression with the use of siRNA led to down-regulation of TNF␣ secretion. To our knowledge, this is the first study directly linking ADAM10 and TNF␣ in a human cancer model.…”

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Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway

Armanious¹,

Gélébart²,

Anand³

et al. 2011

Blood

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One of the main functions of A Disintegrin and Metalloproteinase 10 (ADAM10) is to regulate the bioavailability of adhesion molecules and ligands to various cellularsignaling receptors. Constitutive activation of ADAM10 has been implicated in the pathogenesis of several types of solid tumors. In this study, we found that mantle cell lymphoma (MCL) cell lines and all 12 patient samples examined expressed the active/mature form of ADAM10. In contrast, PBMCs from healthy donors (n ‫؍‬ 5) were negative. Using immunohistochemistry, ADAM10 was readily detectable in 20 of 23 (87%) MCL tumors, but absent in 5 reactive tonsils. Knockdown of ADAM10 using short interfering RNA (siRNA) in MCL cells significantly induced growth inhibition and cell-cycle arrest, and these changes were correlated with down-regulation of cyclin D1, up-regulation of p21 waf1 , and significant reductions in the TNF␣ production/transcriptional activity of NFBp65. The addition of recombinant ADAM10 to MCL cells led to the opposite biologic effects. Lastly, down-regulation of ADAM10 using siRNA enhanced the growth-suppressing effects mediated by the proteasome inhibitors MG132 and bortezomib. We conclude that constitutive activation of ADAM10 contributes to the growth of MCL and therefore inhibition of ADAM10 may be a useful strategy to enhance the response of MCL to other therapeutic agents. IntroductionA Disintegrin and Metalloproteinase 10 (ADAM10), a member of the ADAM family of metalloproteinases, was discovered in the protein extract of brain myelin membranes and subsequently found to be a homolog of the Drosophila kuzbanian gene. [1][2][3] ADAM10 is secreted as a precursor protein and consists of multiple functional domains, including a prodomain, catalytic domain, cysteine-rich domain, transmembranous domain, and cytoplasmic domain. 4 To become the active/mature form, the precursor ADAM10 protein needs to be cleaved by proprotein convertase 7 and furin, both of which remove the ADAM10 prodomain. 5 ADAM10 is biologically important, because ADAM10 knockout mice die on day 9 of embryogenesis due to multiple abnormalities in the nervous and cardiovascular systems. 6 The key biologic function of ADAM10 appears to be attributed to its enzymatic activity as a metalloproteinase. Specifically, ADAM10 is involved in the intramembrane proteolysis process, whereby it mediates ectodomain shedding of various membrane-bound receptors, adhesion molecules, growth factors, and cytokines. [7][8][9] For example, ADAM10 is involved in the regulation of the shedding of Notch, HER-2, CD44, IL-6 receptor, amyloid precursor protein, and cadherins. 10 Directly relevant to our study, ADAM10 was recently found to be one of the enzymes responsible for cleaving TNF␣ and releasing its active form. [11][12][13] Furthermore, it has been reported that ADAM10 is important for the development of the marginal zone B cells. 14 By regulating the bioavailability of ligands to various cellular-signaling receptors, ADAM10 modulates the activation status of various cellularsignaling...

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mentioning

confidence: 86%

Section: Adam10 Activates the Tnf␣/nfb Axismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway

Armanious¹,

Gélébart²,

Anand³

et al. 2011

Blood

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“…It therefore seems possible that ADAM10 inhibition increases the half-life of FASL at the Sertoli cell surface, resulting in a juxtacrine signal that elicits apoptosis in germ cells. On the other hand, ADAM10 has been shown to be the sheddase of several growth factors involved in germ cells survival, such as TNF, EGF, or NOTCH, all of them present in the testis (Hayashi et al 2001, von Schonfeldt et al 2004, Mezyk-Kopec et al 2009, Yao et al 2009). Alternatively, the inhibition of ADAM10 activity may prevent other autocrine/paracrine regulation processes leading to germ cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

TACE/ADAM17 is involved in germ cell apoptosis during rat spermatogenesis

Lizama¹,

Rojas-Benítez²,

Antonelli³

et al. 2010

Reproduction

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The pathways leading to male germ cell apoptosis in vivo are poorly understood, but are highly relevant for the comprehension of sperm production regulation by the testis. In this work, we show the evidence of a mechanism where germ cell apoptosis is induced through the inactivation and shedding of the extracellular domain of KIT (c-kit) by the protease TACE/a disintegrin and metalloprotease 17 (ADAM17) during the first wave of spermatogenesis in the rat. We show that germ cells undergoing apoptosis lacked the extracellular domain of the KIT receptor. TACE/ADAM17, a membrane-bound metalloprotease, was highly expressed in germ cells undergoing apoptosis as well. On the contrary, cell surface presence of ADAM10, a closely related metalloprotease isoform, was not associated with apoptotic germ cells. Pharmacological inhibition of TACE/ADAM17, but not ADAM10, significantly prevented germ cell apoptosis in the male pubertal rat. Induction of TACE/ADAM17 by the phorbol-ester phorbol 12-myristate 13-acetate (PMA) induced germ cell apoptosis, which was prevented when an inhibitor of TACE/ADAM17 was present in the assay. Ex-vivo rat testis culture showed that PMA induced the cleavage of the KIT extracellular domain. Isolation of apoptotic germ cells showed that even though protein levels of TACE/ADAM17 were higher in apoptotic germ cells than in nonapoptotic cells, the contrary was observed for ADAM10. These results suggest that TACE/ADAM17 is one of the elements triggering physiological germ cell apoptosis during the first wave of spermatogenesis.

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TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass

Chen

Aiken

Saw

et al. 2018

Journal of Bone and Mineral Research

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Deregulated proteolysis invariably underlies most human diseases including bone pathologies. Metalloproteinases constitute the largest of the five protease families, and the metzincin metalloproteinases are inhibited by the four tissue inhibitors of metalloproteinase called TIMPs. We hypothesized that Timp genes are essential for skeletal homeostasis. We bred individual Timp knockout mice to generate unique mouse models, the quadruple Timp null strain (QT) as well as mice harboring only a single Timp3 allele (QT3 ). QT mice are grossly smaller and exhibit a dramatic reduction of trabeculae in long bones by μCT imaging with a corresponding increase in metalloproteinase activity. At the cellular level, Timp deficiency compromised differentiation markers, matrix deposition and mineralization in neonatal osteoblasts from calvariae, as well as the fibroblastic colony-forming unit (CFU-F) capacity of bone marrow-derived stromal cells. In contrast, we observed that osteoclasts were overactive in the Timp null state, consistent with the noted excessive bone resorption of QT bones. Immunohistochemistry (IHC) and immunofluorescence (IF) analyses of bone sections revealed higher Cathepsin K and RANKL signals upon Timp loss. Seeking the molecular mechanism, we identified abnormal TNFα bioactivity to be a central event in Timp-deficient mice. Specifically, TNFα triggered induction of the Wnt signaling inhibitor Dkk1 in the osteoblasts at the mRNA and protein levels, with a simultaneous increase in RANKL. Neutralizing TNFα antibody was capable of rescuing the induction of Dkk1 as well as RANKL. Therefore, the generation of novel Timp-deficient systems allowed us to uncover the essential and collective function of TIMP proteins in mammalian long-bone homeostasis. Moreover, our study discovers a functional TIMP/metalloproteinase-TNFα-Dkk1/RANKL nexus for optimal control of the bone microenvironment, which dictates coexistence of the osteoblast and osteoclast lineages. © 2018 American Society for Bone and Mineral Research.

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Identification of ADAM10 as a major TNF sheddase in ADAM17-deficient fibroblasts

Cited by 48 publications

References 28 publications

Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway

Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway

TACE/ADAM17 is involved in germ cell apoptosis during rat spermatogenesis

TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass

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