iRhoms in the brain – a new frontier?

Lichtenthaler, Stefan F.; O’Hara, Bruce F.; Blobel, Carl P.

doi:10.1080/15384101.2015.1084187

Cited by 15 publications

(17 citation statements)

References 7 publications

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“…On these premises, it is clear why iRhoms represent a promising therapeutic target in AD. As a consequence of their peculiar tissue expression, with only iRhom1 expressed in neurons, but not iRhom2, and only iRhom2 expressed in microglia, but not iRhom1, the ability of ADAM17 to process TNF or APP can be differentially regulated by either iRhom [ 146 ]. Thus, a potential inhibition of iRhom2 would inactivate ADAM17 in microglia, thereby preventing the pathological cleavage of TNF, but not in neurons, where iRhom1 would still support the ADAM17-dependent non-amyloidogenic process of APP and all the other physiological functions of the protease in the brain.…”

Section: Adam17 In Diseasementioning

confidence: 99%

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

et al. 2021

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For decades, disintegrin and metalloproteinase 17 (ADAM17) has been the object of deep investigation. Since its discovery as the tumor necrosis factor convertase, it has been considered a major drug target, especially in the context of inflammatory diseases and cancer. Nevertheless, the development of drugs targeting ADAM17 has been harder than expected. This has generally been due to its multifunctionality, with over 80 different transmembrane proteins other than tumor necrosis factor α (TNF) being released by ADAM17, and its structural similarity to other metalloproteinases. This review provides an overview of the different roles of ADAM17 in disease and the effects of its ablation in a number of in vivo models of pathological conditions. Furthermore, here, we comprehensively encompass the approaches that have been developed to accomplish ADAM17 selective inhibition, from the newest non-zinc-binding ADAM17 synthetic inhibitors to the exploitation of iRhom2 to specifically target ADAM17 in immune cells.

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Section: Adam17 In Diseasementioning

confidence: 99%

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

et al. 2021

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“…Recently, research has shown that an early, important regulatory mechanism is represented by the interaction with an adapter factor identified as iRhom1 and iRhom2, pseudoproteases of the rhomboid superfamily, which are essential modulators of ADAM17 maturation and activity [ 30 , 31 ]. Subsequently, it was revealed that iRhom1 plays a central role in ADAM17 maturation, particularly in the brain [ 32 , 33 ]. The iRhom proteins seem to show a role in the selectivity of ADAM17 for some, but not all, substrates [ 34 ].…”

Section: The Sheddase Adam17: Biology and Functionmentioning

confidence: 99%

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

Sisto

Ribatti

Lisi

2021

JCM

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For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.

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“…Interestingly, amyloid plaques in the brain of AD patients can lead to the activation of resting microglia . Consistent with this, complex network analyses showed that iRhom2 is connected to the protein tyrosine kinase 2β that is a critical component of signaling cascades involved in regulating the activation of infiltrating Mϕs or microglia . Therefore, it is conceivable that alterations in iRhom2 gene methylation might increase iRhom2 expression in activated microglia, potentially leading to enhanced ADAM17‐dependent release of pro‐inflammatory mediators such as TNF, thereby exacerbating the inflammatory environment in AD …”

Section: Irhoms In Autoimmune and Systemic Inflammatory Diseasesmentioning

confidence: 75%

Novel functions of inactive rhomboid proteins in immunity and disease

Geesala

Issuree

Maretzky

2019

Journal of Leukocyte Biology

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iRhoms are related to a family of intramembrane serine proteinases called rhomboids but lack proteolytic activity. In mammals, there are two iRhoms, iRhom1 and iRhom2, which have similar domain structures and overlapping specificities as well as distinctive functions. These catalytically inactive rhomboids are essential regulators for the maturation and trafficking of the disintegrin metalloprotease ADAM17 from the endoplasmic reticulum to the cell surface, and are required for the cleavage and release of a variety of membrane-associated proteins, including the IL-6 receptor, L-selectin, TNF, and EGFR ligands. iRhom2-dependent regulation of ADAM17 function has been recently implicated in the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy. In this review, we discuss our current understanding of iRhom biology, their implications in autoimmune pathologies, and their potential as therapeutic targets. K E Y W O R D Sa disintegrin and metalloprotease 17 (ADAM17), epidermal growth factor receptor (EGFR), inactive rhomboid 1 (iRHOM1), inactive rhomboid 2 (iRHOM2), rhomboid 5 homolog 1 (RHBDF1), rhomboid 5 homolog 2 (RHBDF2), tumor necrosis factor (TNF) 1 L-selectin from leukocytes and has key roles in their recruitment to sites of inflammation. 10 Moreover, ADAM17 has a wide range of different substrates, 11 including the IL-6 receptor (IL6R), which has important roles in IL6R-dependent pathologies such as multiple myeloma, prostate cancer, and RA. 12,13 The rhomboid 5 homolog proteins iRhom1 and iRhom2 (also known as RHBDF1 and RHBDF2) are proteolytically inactive members of the rhomboid family and act as key regulators of ADAM17-dependent

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iRhoms in the brain – a new frontier?

Cited by 15 publications

References 7 publications

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

Strategies to Target ADAM17 in Disease: From Its Discovery to the iRhom Revolution

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

Novel functions of inactive rhomboid proteins in immunity and disease

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