ADAM9 is present at endothelial cell - cell junctions and regulates monocyte – endothelial transmigration

English, William R.; Siviter, Richard J.; Hansen, Martin; Murphy, Gillian

doi:10.1016/j.bbrc.2017.09.089

Cited by 13 publications

(5 citation statements)

References 27 publications

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“…In the murine HGF/CDK4 melanoma model, ADAM9 contributes to tumor formation and metastatic load (Giebeler et al ., ). That study also highlighted a pivotal role of ADAM9 in trans‐endothelial migration, which was corroborated by other studies (English et al ., ; Micocci et al ., ). Interaction of tumor–cell ADAM9 with platelet α6β1 integrin fosters platelet activation and tumor cell extravasation (Mammadova‐Bach et al ., ).…”

Section: Introductionmentioning

confidence: 99%

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

et al. 2019

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A disintegrin and a metalloprotease (ADAM)‐9 is a metzincin cell‐surface protease with strongly elevated expression in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). In this study, we performed immunohistochemistry (IHC) of a tissue microarray (TMA) to examine the expression of ADAM9 in a cohort of >100 clinically annotated PDAC cases. We report that ADAM9 is prominently expressed by PDAC tumor cells, and increased ADAM9 expression levels correlate with poor tumor grading (P = 0.027) and the presence of vasculature invasion (P = 0.017). We employed gene expression silencing to generate a loss‐of‐function system for ADAM9 in two established PDAC cell lines. In vitro analysis showed that loss of ADAM9 does not impede cellular proliferation and invasiveness in basement membrane. However, ADAM9 plays a crucial role in mediating cell migration and adhesion to extracellular matrix substrates such as fibronectin, tenascin, and vitronectin. This effect appears to depend on its catalytic activity. In addition, ADAM9 facilitates anchorage‐independent growth. In AsPC1 cells, but not in MiaPaCa‐2 cells, we noted a pronounced yet heterogeneous impact of ADAM9 on the abundance of various integrins, a process that we characterized as post‐translational regulation. Sprout formation of human umbilical vein endothelial cells (HUVECs) is promoted by ADAM9, as examined by transfer of cancer cell conditioned medium; this finding further supports a pro‐angiogenic role of ADAM9 expressed by PDAC cancer cells. Immunoblotting analysis of cancer cell conditioned medium highlighted that ADAM9 regulates the levels of angiogenic factors, including shed heparin‐binding EGF‐like growth factor (HB‐EGF). Finally, we carried out orthotopic seeding of either wild‐type AsPC‐1 cells or AsPC‐1 cells with silenced ADAM9 expression into murine pancreas. In this in vivo setting, ADAM9 was also found to foster angiogenesis without an impact on tumor cell proliferation. In summary, our results characterize ADAM9 as an important regulator in PDAC tumor biology with a strong pro‐angiogenic impact.

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Section: Introductionmentioning

confidence: 99%

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

et al. 2019

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“…The mechanism increasing sNRP1 levels in obese T2D in response to hypoglycemia is unclear; however, posthypoglycemic ADAM9 levels were also higher at similar timepoints as the elevated sNRP1 levels in T2D cases. ADAM9 is a disintegrin and metalloproteinase involved in a wide array of cellular processes, especially those involving cell to cell interactions, adhesion, cell-matrix interactions, growth factor and cytokine signalling (30)(31)(32). Membrane-bound NRP1 is proteolytically cleaved by ADAM9 (or ADAM10) to produce its soluble form, sNRP1 (4).…”

Section: Discussionmentioning

confidence: 99%

Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection?

et al. 2021

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IntroductionNeuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection.MethodsA case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9).ResultsBaseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia.ConclusionHypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT03102801.

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“…ADAM9 was found to co-localize with VE-cadherin at cell–cell junctions in confluent endothelial monolayers. In addition, ADAM9 must be expressed on both adjacent cells to localize to the cell–cell junctions, indicating the ability to self-associate through ectodomain interactions [ 9 ].…”

Section: Structure and Molecular Function Of Adam9mentioning

confidence: 99%

“…A majority of ADAMs—all except ADAM10 and ADAM17—also have an epidermal growth factor (EGF)-like domain, whose function is yet to be clarified [ 2 , 5 , 6 ]. ADAM proteins have been reported in numerous biological functions involving development, fertility, ectodomain shedding, cell adhesion, cell–cell interaction, vascular endothelial cell function, inflammation, immunity, signaling transduction, neurodegenerative disease, and cancer biology [ 1 , 7 , 8 , 9 ]. Therefore, ADAMs have important roles in diverse physiological contexts.…”

Section: Introductionmentioning

confidence: 99%

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

Chou

Huang

Kuo

et al. 2020

IJMS

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ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin domain for adhesion and the metalloprotease domain for ectodomain shedding of a wide variety of cell surface proteins. ADAM9 influences the developmental process, inflammation, and degenerative diseases. Recently, increasing evidence has shown that ADAM9 plays an important role in tumor biology. Overexpression of ADAM9 has been found in several cancer types and is correlated with tumor aggressiveness and poor prognosis. In addition, through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies. In this review, we summarize the current understanding of ADAM9 in biological function, pathophysiological diseases, and various cancers. Recent advances in therapeutic strategies using ADAM9-related pathways are presented as well.

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ADAM9 is present at endothelial cell - cell junctions and regulates monocyte – endothelial transmigration

Cited by 13 publications

References 27 publications

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

ADAM9 contributes to vascular invasion in pancreatic ductal adenocarcinoma

Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection?

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

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