TACE Activation by MAPK-Mediated Regulation of Cell Surface Dimerization and TIMP3 Association

Xu, Pinglong; Liu, Jianming; Sakaki-Yumoto, Masayo; Derynck, Rik

doi:10.1126/scisignal.2002689

Cited by 135 publications

(124 citation statements)

References 60 publications

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“…Because of this, optimization of the initial lead antibody utilized a cell-based functional screen. The PMA-regulated accessibility of the epitope recognized by MEDI3622 is consistent with previous reports demonstrating that phosphorylation of the intracellular domain of ADAM17 orchestrates a transition from inactive dimer to active monomer and the release of the extracellular inhibitory molecule TIMP3 (21).…”

Section: Discussionsupporting

confidence: 78%

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A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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ADAM17 is the primary sheddase for HER pathway ligands. We report the discovery of a potent and specific ADAM17 inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent tumor models. The inhibitory activity of MEDI3622 correlated with EGFR activity both in a series of tumor models across several indications as well in as a focused set of head and neck patient-derived xenograft models. The antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in the OE21 esophageal model and the COLO205 colorectal model suggesting additional activity outside of the EGFR pathway. Combination of MEDI3622 and cetuximab in the OE21 model was additive and eradicated tumors. Proteomics analysis revealed novel ADAM17 substrates that function outside of the HER pathways and may contribute toward the antitumor activity of the monoclonal antibody.

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Section: Discussionsupporting

confidence: 78%

“…Cellular regulation of ADAM17 shedding activity is a complex process modulated by the ADAM17 redox state (18), protein processing (19), signal transduction pathways downstream of PKC (20), and binding to the naturally occurring ADAM17 antagonist protein TIMP3 (21). ADAM17 sheddase activity is stimulated by the PKC mimetic PMA.…”

Section: Resultsmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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“…Our study suggest that cell adhesion disruption by the activation of ADAMs plays an important role in necroptotic cell death. Although the detailed mechanism of ADAM activation is still poorly understood, a recent study reported that ADAM10 and ADAM17 form homodimers on the cell surface and the transition of ADAM10 or 17 homodimers to monomers is critical for metalloprotease activation [27]. We show that MLKL forms a complex with multiple ADAMs upon necroptotic stimulus.…”

Section: Discussionmentioning

confidence: 83%

“…Moreover, MLKL only complexed with ADAM9 in ADAM10 shRNA knockdown cells ( Figure 4D), suggesting a possible redundant function of ADAM9 and ADAM10 in mediating the cleavage of cell-surface proteins [26]. Previous studies suggested that the activation of ADAM10/17 is regulated by the conformational change from oligomer to monomer on cell surface [27,28]. We then performed a blue native PAGE to determine the oligomeric status of ADAM10 during necroptosis.…”

Section: Mlkl Forms Complex With Adams To Mediate Activation Of Adam mentioning

confidence: 99%

Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration

et al. 2016

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Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. TNF-induced necroptosis is mediated by receptor-interacting protein kinases, RIP1 and RIP3, and the mixed lineage kinase domain-like (MLKL). After being phosphorylated by RIP3, MLKL is translocated to the plasma membrane and mediates necroptosis. However, the execution of necroptosis and its role in inflammation and other cellular responses remain largely elusive. In this study, we report that MLKL-mediated activation of cell-surface proteases of the a disintegrin and metalloprotease (ADAM) family promotes necroptosis, inflammation and cell migration. ADAMs are specifically activated at the early stage of necroptosis when MLKL is phosphorylated and translocated to the cell plasma membrane. Activation of ADAMs induces ectodomain shedding of diverse cell-surface proteins including adhesion molecules, receptors, growth factors and cytokines. Importantly, the shedding of cell-surface proteins disrupts cell adhesion and accelerates necroptosis, while the soluble fragments of the cleaved proteins trigger the inflammatory responses. We also demonstrate that the shedding of E-cadherin ectodomain from necroptotic cells promotes cell migration. Thus, our study provides a novel mechanism of necroptosis-induced inflammation and new insights into the physiological and pathological functions of this unique form of cell death.

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“…28 Alternatively, changes in quantity of TIMP3 expression and activation have been shown to alter intracellular signaling of the MAPK pathways, suggesting that imbalances in ECM remodeling induce important cell regulatory pathways. 29 Aberrant MAPK signaling has been recently implicated in AMD pathology. 30 Increased TIMP3 protein in Bruch's membrane and drusen of AMD eyes is also correlated with AMD disease pathology.…”

Section: Discussionmentioning

confidence: 99%

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

et al. 2013

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Age-related macular degeneration (AMD) is a leading cause of irreversible central visual loss in the elderly. A recent genomewide association studies (GWAS) reported that rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3)/synapsin III (SYN3) region of 22q12.3 is associated with AMD. In this study, we characterize its phenotypic influence on AMD using three independent study cohorts: case-control studies from the National Eye Institute Clinical Center (NEI, n ¼ 397) and the AgeRelated Eye Disease Study (n ¼ 523) as well as a nested case-control study from Blue Mountains Eye Study (BMES, n ¼ 852).Comparisons between cases and controls show no association between rs9621532 and AMD in the three sample sets. However, stratifying NEI cases uncovers a moderate protective role of rs9621532 in neovascular AMD (nAMD) and the association adhered to a dominant model (odds ratios ¼ 0.32; 95% CI: 0.11-0.89; P ¼ 0.02). The BMES data followed the same pattern of association with nAMD as that seen in the NEI sample but did not reach statistical significance. Polychotomous logistic regression showed a trend that rs9621532 correlates with less severe disease, for example, with the majority of carriers having intermediate AMD rather than nAMD/geographic atrophy AMD. Functionally, rs9621532 influences TIMP3 mRNA expression in cultured primary human fetal retinal pigment epithelium (hfRPE) cells. In hfRPE donors carrying the protective rs9625132 allele, we measured a reduction in TIMP3 mRNA by quantitative RT-PCR. Our data suggest that rs9621532 carriers have a lower risk of developing nAMD, potentially because of decreased transcription of TIMP3.

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TACE Activation by MAPK-Mediated Regulation of Cell Surface Dimerization and TIMP3 Association

Cited by 135 publications

References 60 publications

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

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