International Journal of Molecular Sciences

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4 pages, 168 KiB

Open AccessEditorial

A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis

by Thorsten Maretzky

Int. J. Mol. Sci. 2021, 22(16), 8762; https://doi.org/10.3390/ijms22168762 - 16 Aug 2021

Cited by 1 | Viewed by 1324

Abstract

In the late 1980s, Paul Primakoff and colleagues showed that fertilization could be blocked in an in vitro sperm–egg fusion assay by inoculating them in the presence of a disintegrin and metalloprotease (ADAM)-specific antibody [...] Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

Research

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16 pages, 2542 KiB

Open AccessArticle

Members of the Fibroblast Growth Factor Receptor Superfamily Are Proteolytically Cleaved by Two Differently Activated Metalloproteases

by Garima Dixit, Willow Schanz, Benjamin A. Pappas and Thorsten Maretzky

Int. J. Mol. Sci. 2021, 22(6), 3165; https://doi.org/10.3390/ijms22063165 - 20 Mar 2021

Cited by 8 | Viewed by 2928

Abstract

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that have been associated not only with various cellular processes, such as embryonic development and adult wound healing but also enhanced tumor survival, angiogenesis, and metastatic spread. Proteolytic cleavage of these [...] Read more.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that have been associated not only with various cellular processes, such as embryonic development and adult wound healing but also enhanced tumor survival, angiogenesis, and metastatic spread. Proteolytic cleavage of these single-pass transmembrane receptors has been suggested to regulate biological activities of their ligands during growth and development, yet little is known about the proteases responsible for this process. In this study, we monitored the release of membrane-anchored FGFRs 1, 2, 3, and 4 in cell-based assays. We demonstrate here that metalloprotease-dependent metalloprotease family, ADAM10 and ADAM17. Loss- and gain-of-function studies in murine embryonic fibroblasts showed that constitutive shedding as well as phorbol-ester-induced processing of FGFRs 1, 3, and 4 is mediated by ADAM17. In contrast, treatment with the calcium ionophore ionomycin stimulated ADAM10-mediated FGFR2 shedding. Cell migration assays with keratinocytes in the presence or absence of soluble FGFRs suggest that ectodomain shedding can modulate the function of ligand-induced FGFR signaling during cell movement. Our data identify ADAM10 and ADAM17 as differentially regulated FGFR membrane sheddases and may therefore provide new insight into the regulation of FGFR functions. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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15 pages, 1657 KiB

Open AccessArticle

Role of ADAM10 and ADAM17 in Regulating CD137 Function

by Jana Seidel, Sinje Leitzke, Björn Ahrens, Maria Sperrhacke, Sucharit Bhakdi and Karina Reiss

Int. J. Mol. Sci. 2021, 22(5), 2730; https://doi.org/10.3390/ijms22052730 - 8 Mar 2021

Cited by 20 | Viewed by 3791

Abstract

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 [...] Read more.

Human CD137 (4-1BB), a member of the TNF receptor family, and its ligand CD137L (4-1BBL), are expressed on immune cells and tumor cells. CD137/CD137L interaction mediates bidirectional cellular responses of potential relevance in inflammatory diseases, autoimmunity and oncology. A soluble form of CD137 exists, elevated levels of which have been reported in patients with rheumatoid arthritis and various malignancies. Soluble CD137 (sCD137) is considered to represent a splice variant of CD137. In this report, however, evidence is presented that A Disintegrin and Metalloproteinase (ADAM)10 and potentially also ADAM17 are centrally involved in its generation. Release of sCD137 by transfected cell lines and primary T cells was uniformly inhibitable by ADAM10 inhibition. The shedding function of ADAM10 can be blocked through inhibition of its interaction with surface exposed phosphatidylserine (PS), and this effectively inhibited sCD137 generation. The phospholipid scramblase Anoctamin-6 (ANO6) traffics PS to the outer membrane and thus modifies ADAM10 function. Overexpression of ANO6 increased stimulated shedding, and hyperactive ANO6 led to maximal constitutive shedding of CD137. sCD137 was functionally active and augmented T cell proliferation. Our findings shed new light on the regulation of CD137/CD137L immune responses with potential impact on immunotherapeutic approaches targeting CD137. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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20 pages, 2656 KiB

Open AccessArticle

Constitutive and Regulated Shedding of Soluble FGF Receptors Releases Biologically Active Inhibitors of FGF-2

by Anne Hanneken, Maluz Mercado and Pamela Maher

Int. J. Mol. Sci. 2021, 22(5), 2712; https://doi.org/10.3390/ijms22052712 - 8 Mar 2021

Cited by 7 | Viewed by 2219

Abstract

The identification of soluble fibroblast growth factor (FGF) receptors in blood and the extracellular matrix has led to the prediction that these proteins modulate the diverse biological activities of the FGF family of ligands in vivo. A recent structural characterization of the soluble [...] Read more.

The identification of soluble fibroblast growth factor (FGF) receptors in blood and the extracellular matrix has led to the prediction that these proteins modulate the diverse biological activities of the FGF family of ligands in vivo. A recent structural characterization of the soluble FGF receptors revealed that they are primarily generated by proteolytic cleavage of the FGFR-1 ectodomain. Efforts to examine their biological properties are now focused on understanding the functional consequences of FGFR-1 ectodomain shedding and how the shedding event is regulated. We have purified an FGFR-1 ectodomain that is constitutively cleaved from the full-length FGFR-1(IIIc) receptor and released into conditioned media. This shed receptor binds FGF-2; inhibits FGF-2-induced cellular proliferation; and competes with high affinity, cell surface FGF receptors for ligand binding. FGFR-1 ectodomain shedding downregulates the number of high affinity receptors from the cell surface. The shedding mechanism is regulated by ligand binding and by activators of PKC, and the two signaling pathways appear to be independent of each other. Deletions and substitutions at the proposed cleavage site of FGFR-1 do not prevent ectodomain shedding. Broad spectrum inhibitors of matrix metalloproteases decrease FGFR-1 ectodomain shedding, suggesting that the enzyme responsible for constitutive, ligand-activated, and protein kinase C-activated shedding is a matrix metalloprotease. In summary, shedding of the FGFR-1 ectodomain is a highly regulated event, sharing many features with a common system that governs the release of diverse membrane proteins from the cell surface. Most importantly, the FGFR ectodomains are biologically active after shedding and are capable of functioning as inhibitors of FGF-2. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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13 pages, 1498 KiB

Open AccessCommunication

ADAM10 Plasma and CSF Levels Are Increased in Mild Alzheimer’s Disease

by Izabela Pereira Vatanabe, Rafaela Peron, Marina Mantellatto Grigoli, Silvia Pelucchi, Giulia De Cesare, Thamires Magalhães, Patricia Regina Manzine, Marcio Luiz Figueredo Balthazar, Monica Di Luca, Elena Marcello and Marcia Regina Cominetti

Int. J. Mol. Sci. 2021, 22(5), 2416; https://doi.org/10.3390/ijms22052416 - 28 Feb 2021

Cited by 21 | Viewed by 2953

Abstract

ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity [...] Read more.

ADAM10 is the main α-secretase that participates in the non-amyloidogenic cleavage of amyloid precursor protein (APP) in neurons, inhibiting the production of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). Strong recent evidence indicates the importance of the localization of ADAM10 for its activity as a protease. In this study, we investigated ADAM10 activity in plasma and CSF samples of patients with amnestic mild cognitive impairment (aMCI) and mild AD compared with cognitively healthy controls. Our results indicated that plasma levels of soluble ADAM10 were significantly increased in the mild AD group, and that in these samples the protease was inactive, as determined by activity assays. The same results were observed in CSF samples, indicating that the increased plasma ADAM10 levels reflect the levels found in the central nervous system. In SH-SY5Y neuroblastoma cells, ADAM10 achieves its major protease activity in the fraction obtained from plasma membrane lysis, where the mature form of the enzyme is detected, confirming the importance of ADAM10 localization for its activity. Taken together, our results demonstrate the potential of plasma ADAM10 to act as a biomarker for AD, highlighting its advantages as a less invasive, easier, faster, and lower-cost processing procedure, compared to existing biomarkers. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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19 pages, 2531 KiB

Open AccessArticle

Quantitative Proteomics Reveals Changes Induced by TIMP-3 on Cell Membrane Composition and Novel Metalloprotease Substrates

by Anna Paola Carreca, Veronica Maria Pravatà, Danilo D’Apolito, Simone Bonelli, Matteo Calligaris, Elisa Monaca, Stephan A. Müller, Stefan F. Lichtenthaler and Simone Dario Scilabra

Int. J. Mol. Sci. 2021, 22(5), 2392; https://doi.org/10.3390/ijms22052392 - 27 Feb 2021

Cited by 6 | Viewed by 3522

Abstract

Ectodomain shedding is a key mechanism of several biological processes, including cell-communication. Disintegrin and metalloproteinases (ADAMs), together with the membrane-type matrix metalloproteinases, play a pivotal role in shedding transmembrane proteins. Aberrant shedding is associated to several pathological conditions, including arthritis. Tissue inhibitor of [...] Read more.

Ectodomain shedding is a key mechanism of several biological processes, including cell-communication. Disintegrin and metalloproteinases (ADAMs), together with the membrane-type matrix metalloproteinases, play a pivotal role in shedding transmembrane proteins. Aberrant shedding is associated to several pathological conditions, including arthritis. Tissue inhibitor of metalloproteases 3 (TIMP-3), an endogenous inhibitor of ADAMs and matrix metalloproteases (MMPs), has been proven to be beneficial in such diseases. Thus, strategies to increase TIMP-3 bioavailability in the tissue have been sought for development of therapeutics. Nevertheless, high levels of TIMP-3 may lead to mechanism-based side-effects, as its overall effects on cell behavior are still unknown. In this study, we used a high-resolution mass-spectrometry-based workflow to analyze alterations induced by sustained expression of TIMP-3 in the cell surfaceome. In agreement with its multifunctional properties, TIMP-3 induced changes on the protein composition of the cell surface. We found that TIMP-3 had differential effects on metalloproteinase substrates, with several that accumulated in TIMP-3-overexpressing cells. In addition, our study identified potentially novel ADAM substrates, including ADAM15, whose levels at the cell surface are regulated by the inhibitor. In conclusion, our study reveals that high levels of TIMP-3 induce modifications in the cell surfaceome and identifies molecular pathways that can be deregulated via TIMP-3-based therapies. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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17 pages, 2131 KiB

Open AccessArticle

Analysis of the Conditions That Affect the Selective Processing of Endogenous Notch1 by ADAM10 and ADAM17

by Rolake O. Alabi, Jose Lora, Arda B. Celen, Thorsten Maretzky and Carl P. Blobel

Int. J. Mol. Sci. 2021, 22(4), 1846; https://doi.org/10.3390/ijms22041846 - 12 Feb 2021

Cited by 12 | Viewed by 2623

Abstract

Notch signaling is critical for controlling a variety of cell fate decisions during metazoan development and homeostasis. This unique, highly conserved signaling pathway relies on cell-to-cell contact, which triggers the proteolytic release of the cytoplasmic domain of the membrane-anchored transcription factor Notch from [...] Read more.

Notch signaling is critical for controlling a variety of cell fate decisions during metazoan development and homeostasis. This unique, highly conserved signaling pathway relies on cell-to-cell contact, which triggers the proteolytic release of the cytoplasmic domain of the membrane-anchored transcription factor Notch from the membrane. A disintegrin and metalloproteinase (ADAM) proteins are crucial for Notch activation by processing its S2 site. While ADAM10 cleaves Notch1 under physiological, ligand-dependent conditions, ADAM17 mainly cleaves Notch1 under ligand-independent conditions. However, the mechanism(s) that regulate the distinct contributions of these ADAMs in Notch processing remain unclear. Using cell-based assays in mouse embryonic fibroblasts (mEFs) lacking ADAM10 and/or ADAM17, we aimed to clarify what determines the relative contributions of ADAM10 and ADAM17 to ligand-dependent or ligand-independent Notch processing. We found that EDTA-stimulated ADAM17-dependent Notch1 processing is rapid and requires the ADAM17-regulators iRhom1 and iRhom2, whereas the Delta-like 4-induced ligand-dependent Notch1 processing is slower and requires ADAM10. The selectivity of ADAM17 for EDTA-induced Notch1 processing can most likely be explained by a preference for ADAM17 over ADAM10 for the Notch1 cleavage site and by the stronger inhibition of ADAM10 by EDTA. The physiological ADAM10-dependent processing of Notch1 cannot be compensated for by ADAM17 in Adam10-/- mEFs, or by other ADAMs shown here to be able to cleave the Notch1 cleavage site, such as ADAMs9, 12, and 19. Collectively, these results provide new insights into the mechanisms underlying the substrate selectivity of ADAM10 and ADAM17 towards Notch1. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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17 pages, 1973 KiB

Open AccessArticle

TGF-β Induced CTGF Expression in Human Lung Epithelial Cells through ERK, ADAM17, RSK1, and C/EBPβ Pathways

by Shu-Ching Ou, Kuan-Jen Bai, Wun-Hao Cheng, Jing-Yun Chen, Chien-Huang Lin, Heng-Ching Wen and Bing-Chang Chen

Int. J. Mol. Sci. 2020, 21(23), 9084; https://doi.org/10.3390/ijms21239084 - 29 Nov 2020

Cited by 25 | Viewed by 3169

Abstract

Background: Lung epithelial cells play critical roles in idiopathic pulmonary fibrosis. Methods: In the present study, we investigated whether transforming growth factor-β (TGF-β)-induced expression of connective tissue growth factor (CTGF) was regulated by the extracellular signal-regulated kinase (ERK)/a disintegrin and metalloproteinase 17 (ADAM17)/ribosomal [...] Read more.

Background: Lung epithelial cells play critical roles in idiopathic pulmonary fibrosis. Methods: In the present study, we investigated whether transforming growth factor-β (TGF-β)-induced expression of connective tissue growth factor (CTGF) was regulated by the extracellular signal-regulated kinase (ERK)/a disintegrin and metalloproteinase 17 (ADAM17)/ribosomal S6 kinases 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ) signaling pathway in human lung epithelial cells (A549). Results: Our results revealed that TGF-β-induced CTGF expression was weakened by ADAM17 small interfering RNA (ADAM17 siRNA), TNF-α processing inhibitor-0 (TAPI-0, an ADAM17 inhibitor), U0126 (an ERK inhibitor), RSK1 siRNA, and C/EBPβ siRNA. TGF-β-induced ERK phosphorylation as well as ADAM17 phosphorylation was attenuated by U0126. The TGF-β-induced increase in RSK1 phosphorylation was inhibited by TAPI-0 and U0126. TGF-β-induced C/EBPβ phosphorylation was weakened by U0126, ADAM17 siRNA, and RSK1 siRNA. In addition, TGF-β increased the recruitment of C/EBPβ to the CTGF promoter. Furthermore, TGF-β enhanced fibronectin (FN), an epithelial–mesenchymal transition (EMT) marker, and CTGF mRNA levels and reduced E-cadherin mRNA levels. Moreover, TGF-β-stimulated FN protein expression was reduced by ADAM17 siRNA and CTGF siRNA. Conclusion: The results suggested that TGF-β induces CTGF expression through the ERK/ADAM17/RSK1/C/EBPβ signaling pathway. Moreover, ADAM17 and CTGF participate in TGF-β-induced FN expression in human lung epithelial cells. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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19 pages, 3752 KiB

Open AccessArticle

Role of iRhoms 1 and 2 in Endochondral Ossification

by Renpeng Fang, Coline Haxaire, Miguel Otero, Samantha Lessard, Gisela Weskamp, David R. McIlwain, Tak W. Mak, Stefan F. Lichtenthaler and Carl P. Blobel

Int. J. Mol. Sci. 2020, 21(22), 8732; https://doi.org/10.3390/ijms21228732 - 19 Nov 2020

Cited by 6 | Viewed by 2576

Abstract

Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of [...] Read more.

Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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10 pages, 1141 KiB

Open AccessCommunication

Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis

by Hemant K. Mishra, Jing Ma, Daniel Mendez, Robert Hullsiek, Nabendu Pore and Bruce Walcheck

Int. J. Mol. Sci. 2020, 21(18), 6688; https://doi.org/10.3390/ijms21186688 - 12 Sep 2020

Cited by 15 | Viewed by 3046

Abstract

Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is [...] Read more.

Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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18 pages, 2694 KiB

Open AccessArticle

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

by Anke Seifert, Justyna Wozniak, Stefan Düsterhöft, Petr Kasparek, Radislav Sedlacek, Stephan Dreschers, Thorsten W. Orlikowsky, Daniela Yildiz and Andreas Ludwig

Int. J. Mol. Sci. 2020, 21(17), 5978; https://doi.org/10.3390/ijms21175978 - 19 Aug 2020

Cited by 10 | Viewed by 3484

Abstract

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its [...] Read more.

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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Review

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16 pages, 1232 KiB

Open AccessReview

Regulation of ADAM10 by the TspanC8 Family of Tetraspanins and Their Therapeutic Potential

by Neale Harrison, Chek Ziu Koo and Michael G. Tomlinson

Int. J. Mol. Sci. 2021, 22(13), 6707; https://doi.org/10.3390/ijms22136707 - 23 Jun 2021

Cited by 26 | Viewed by 5093

Abstract

The ubiquitously expressed transmembrane protein a disintegrin and metalloproteinase 10 (ADAM10) functions as a “molecular scissor”, by cleaving the extracellular regions from its membrane protein substrates in a process termed ectodomain shedding. ADAM10 is known to have over 100 substrates including Notch, amyloid [...] Read more.

The ubiquitously expressed transmembrane protein a disintegrin and metalloproteinase 10 (ADAM10) functions as a “molecular scissor”, by cleaving the extracellular regions from its membrane protein substrates in a process termed ectodomain shedding. ADAM10 is known to have over 100 substrates including Notch, amyloid precursor protein, cadherins, and growth factors, and is important in health and implicated in diseases such as cancer and Alzheimer’s. The tetraspanins are a superfamily of membrane proteins that interact with specific partner proteins to regulate their intracellular trafficking, lateral mobility, and clustering at the cell surface. We and others have shown that ADAM10 interacts with a subgroup of six tetraspanins, termed the TspanC8 subgroup, which are closely related by protein sequence and comprise Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. Recent evidence suggests that different TspanC8/ADAM10 complexes have distinct substrates and that ADAM10 should not be regarded as a single scissor, but as six different TspanC8/ADAM10 scissor complexes. This review discusses the published evidence for this “six scissor” hypothesis and the therapeutic potential this offers. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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19 pages, 10064 KiB

Open AccessReview

ADAM10 Site-Dependent Biology: Keeping Control of a Pervasive Protease

by Francesca Tosetti, Massimo Alessio, Alessandro Poggi and Maria Raffaella Zocchi

Int. J. Mol. Sci. 2021, 22(9), 4969; https://doi.org/10.3390/ijms22094969 - 7 May 2021

Cited by 12 | Viewed by 3825

Abstract

Enzymes, once considered static molecular machines acting in defined spatial patterns and sites of action, move to different intra- and extracellular locations, changing their function. This topological regulation revealed a close cross-talk between proteases and signaling events involving post-translational modifications, membrane tyrosine kinase [...] Read more.

Enzymes, once considered static molecular machines acting in defined spatial patterns and sites of action, move to different intra- and extracellular locations, changing their function. This topological regulation revealed a close cross-talk between proteases and signaling events involving post-translational modifications, membrane tyrosine kinase receptors and G-protein coupled receptors, motor proteins shuttling cargos in intracellular vesicles, and small-molecule messengers. Here, we highlight recent advances in our knowledge of regulation and function of A Disintegrin And Metalloproteinase (ADAM) endopeptidases at specific subcellular sites, or in multimolecular complexes, with a special focus on ADAM10, and tumor necrosis factor-α convertase (TACE/ADAM17), since these two enzymes belong to the same family, share selected substrates and bioactivity. We will discuss some examples of ADAM10 activity modulated by changing partners and subcellular compartmentalization, with the underlying hypothesis that restraining protease activity by spatial segregation is a complex and powerful regulatory tool. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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22 pages, 1650 KiB

Open AccessReview

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

by Cheng-Wei Chou, Yu-Kai Huang, Ting-Ting Kuo, Jing-Pei Liu and Yuh-Pyng Sher

Int. J. Mol. Sci. 2020, 21(20), 7790; https://doi.org/10.3390/ijms21207790 - 21 Oct 2020

Cited by 49 | Viewed by 6463

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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20 pages, 1194 KiB

Open AccessReview

iRhom2: An Emerging Adaptor Regulating Immunity and Disease

by Mazin A. Al-Salihi and Philipp A. Lang

Int. J. Mol. Sci. 2020, 21(18), 6570; https://doi.org/10.3390/ijms21186570 - 8 Sep 2020

Cited by 18 | Viewed by 4894

Abstract

The rhomboid family are evolutionary conserved intramembrane proteases. Their inactive members, iRhom in Drosophila melanogaster and iRhom1 and iRhom2 in mammals, lack the catalytic center and are hence labelled “inactive” rhomboid family members. In mammals, both iRhoms are involved in maturation and trafficking [...] Read more.

The rhomboid family are evolutionary conserved intramembrane proteases. Their inactive members, iRhom in Drosophila melanogaster and iRhom1 and iRhom2 in mammals, lack the catalytic center and are hence labelled “inactive” rhomboid family members. In mammals, both iRhoms are involved in maturation and trafficking of the ubiquitous transmembrane protease a disintegrin and metalloprotease (ADAM) 17, which through cleaving many biologically active molecules has a critical role in tumor necrosis factor alpha (TNFα), epidermal growth factor receptor (EGFR), interleukin-6 (IL-6) and Notch signaling. Accordingly, with iRhom2 having a profound influence on ADAM17 activation and substrate specificity it regulates these signaling pathways. Moreover, iRhom2 has a role in the innate immune response to both RNA and DNA viruses and in regulation of keratin subtype expression in wound healing and cancer. Here we review the role of iRhom2 in immunity and disease, both dependent and independent of its regulation of ADAM17. Full article

(This article belongs to the Special Issue A Disintegrin and Metalloproteases (ADAMs): Activation, Regulation and Mechanisms of Catalysis)

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