An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases

Chou, Chia-Lin; Huang, Yung-Cheng; Kuo, Ting-Ting; Liu, Jing-Pei; Sher, Yuh‐Pyng

doi:10.3390/ijms21207790

Cited by 65 publications

(44 citation statements)

References 123 publications

(188 reference statements)

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“…Moreover, although p-EGFR is an upstream signaling molecule that activates AKT by phosphorylation, it would be interesting to elucidate other candidate targets, besides EGFR, linked to ADAM 9 activity; one such candidate may be tumor necrosis factor receptor (TNFR) because ADAM 9 was shown to regulate tumor cell apoptosis through the ADAM 9/ TNFR1 pathway [32]. Several members of the ADAM family, particularly ADAM 9, are known to have a role in shedding TNF-α and activating its downstream signaling pathway [33]. Our results showed that silencing expression of ADAM9 resulted in significantly reduced expression of TNFα mRNA in HN6 and HN15 cell lines, suggesting that activation of ADAM 9 can stimulate expression of TNF-α in certain oral cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the A disintegrin and metalloproteinase 9 in oral cancer cell invasion

Buranaphatthana

Makeudom

et al. 2021

European J Oral Sciences

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The aims of this study were to determine the functional roles of the transmembrane glycoprotein, Disintegrin and metalloproteinase domain-containing protein 9 (ADAM 9), in the phosphorylation of epidermal growth factor receptor (EGFR) and AKT and in the aggressiveness of oral cancer cells. Immunohistochemistry and immunoblotting were conducted to determine expression of ADAM 9 and the levels of EGFR phosphorylated at the tyrosine 1173 residue (p-EGFR tyr1173 ) and AKT phosphorylated at the serine 473 residue (p-AKT ser473 ) in oral cancer tissues and in the oral cancer cell lines HN5, HN6, HN15, and HN008. Small interfering RNA (siRNA) was used to inhibit expression of ADAM9 mRNA, and thus production of ADAM9 protein, in oral cancer cells. ADAM9-knockdown cells were examined for p-EGFR tyr1173 and p-AKT ser473 levels and used for cell proliferation and invasion assays. A positive correlation among overexpression of ADAM 9, p-EGFR tyr1173 , and p-AKT ser473 was found in oral cancer tissues.

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Section: Discussionmentioning

confidence: 99%

Involvement of the A disintegrin and metalloproteinase 9 in oral cancer cell invasion

Buranaphatthana

Makeudom

et al. 2021

European J Oral Sciences

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“…Interestingly, the accumulation of amyloid peptides is a hallmark of sarcoid granulomas [91]. Two genes of the F-SARC-CoV2 and control panels (FKBP10 or FK506-binding protein 10, a molecular chaperone with peptidyl-prolyl isomerase activity, which binds the immunosuppressive drug FK506 or tacrolimus) and ADAM9 (A disintegrin and a metalloprotease 9), interact with cellular factors involved in UPR (unfolded protein response) [92,93]. UPR is a molecular process maintaining cellular homeostasis and having a crucial role in the host's defense against viral infection.…”

Section: Endoplasmic Reticulum Stress-related Pathwaysmentioning

confidence: 99%

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

Pachéco

Valeyre

Jammal

et al. 2021

Cells

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Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

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“…Among the five driver genes identified by structural causal modeling, we primarily focused on experimentally determining the role of ADAM9 (a disintegrin and a metalloprotease 9) in COVID-19 etiology because (i) it was the gene with the greatest degree of causal influence in the SCM DAG, (ii) it was the only driver gene that was previously shown to interact with SARS-CoV-2 through a global interactomics approach (Gordon et al, 2020a(Gordon et al, , 2020b and (iii) it is an entry factor for another RNA virus, the encephalomyocarditis virus (Bazzone et al, 2019). ADAM9 is a metalloprotease with various functions that are mediated either by its disintegrin domain for adhesion or by its metalloprotease domain for the shedding of a large range of cell surface proteins (Chou et al, 2020). The ADAM9 gene encodes two isoforms, which encode membrane-bound and secreted proteins.…”

Section: Adam9 Is a Major Driver Of Ards In Critical Covid-19 Patientsmentioning

confidence: 99%

Identification of driver genes for severe forms of COVID-19 in a deeply phenotyped young patient cohort

Carapito

Helms

et al. 2021

Preprint

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The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (age and co-morbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major co-morbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 “critical” (in the ICU under mechanical ventilation) and 25 “non-critical” (in a noncritical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammation, perturbed lymphoid/myeloid compartments, coagulation and viral cell biology. Within a unique gene signature that differentiated critical from noncritical patients, several driver genes promoted severe COVID-19 among which the upregulated metalloprotease ADAM9 was key. This gene signature was replicated in an independent cohort of 81 critical and 73 recovered COVID-19 patients, as were ADAM9 transcripts, soluble form and proteolytic activity. Ex vivo ADAM9 inhibition affected SARS-CoV-2 uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, COVID-19 cohort, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. The key driver, ADAM9, interfered with SARS-CoV-2 biology. A repositioning strategy for anti-ADAM9 therapeutic is feasible.One sentence summaryEtiopathogenesis of severe COVID19 in a young patient population devoid of comorbidities.

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An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases

Cited by 65 publications

References 123 publications

Involvement of the A disintegrin and metalloproteinase 9 in oral cancer cell invasion

Involvement of the A disintegrin and metalloproteinase 9 in oral cancer cell invasion

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

Identification of driver genes for severe forms of COVID-19 in a deeply phenotyped young patient cohort

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