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IRhom2

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https://www.readbyqxmd.com/read/27601030/irhom2-regulates-csf1r-cell-surface-expression-and-non-steady-state-myelopoiesis-in-mice
#1
Xiaoping Qing, Lindsay D Rogers, Arthur Mortha, Yonit Lavin, Patricia Redecha, Priya D Issuree, Thorsten Maretzky, Miriam Merad, David R McIlwain, Tak W Mak, Christopher M Overall, Carl P Blobel, Jane E Salmon
CSF1R (colony stimulating factor 1 receptor) is the main receptor for CSF1 and has crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by ADAM17 (A disintegrin and metalloprotease 17). Here, we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells...
September 7, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27599715/stimulated-release-and-functional-activity-of-surface-expressed-metalloproteinase-adam17-in-exosomes
#2
Esther Groth, Jessica Pruessmeyer, Aaron Babendreyer, Julian Schumacher, Tobias Pasqualon, Daniela Dreymueller, Shigeki Higashiyama, Inken Lorenzen, Joachim Grötzinger, Didier Cataldo, Andreas Ludwig
By mediating proteolytic shedding on the cell surface the disintegrin and metalloproteinases ADAM10 and ADAM17 function as critical regulators of growth factors, cytokines and adhesion molecules. We here report that stimulation of lung epithelial A549 tumor cells with phorbol-12-myristate-13-acetate (PMA) leads to the downregulation of the surface expressed mature form of ADAM17 without affecting ADAM10 expression. This reduction could not be sufficiently explained by metalloproteinase-mediated degradation, dynamin-mediated internalization or microdomain redistribution of ADAM17...
November 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27428826/irhom2-is-essential-for-innate-immunity-to-dna-viruses-by-mediating-trafficking-and-stability-of-the-adaptor-sting
#3
Wei-Wei Luo, Shu Li, Chen Li, Huan Lian, Qing Yang, Bo Zhong, Hong-Bing Shu
STING is a central adaptor in the innate immune response to DNA viruses. However, the manner in which STING activity is regulated remains unclear. We identified iRhom2 ('inactive rhomboid protein 2') as a positive regulator of DNA-virus-triggered induction of type I interferons. iRhom2 deficiency markedly impaired DNA-virus- and intracellular-DNA-induced signaling in cells, and iRhom2-deficient mice were more susceptible to lethal herpes simplex virus type 1 (HSV-1) infection. iRhom2 was constitutively associated with STING and acted in two distinct processes to regulate STING activity...
September 2016: Nature Immunology
https://www.readbyqxmd.com/read/27393687/irhom2-uncv-mutation-blocks-bulge-stem-cells-assuming-the-fate-of-hair-follicle
#4
Leilei Yang, Wenlong Li, Bing Liu, Shaoxia Wang, Lin Zeng, Cuiping Zhang, Yang Li
iRhom2 is necessary for maturation of TNFα-converting enzyme, which is required for the release of tumor necrosis factor. In the previous study, we found that the iRhom2 (Uncv) mutation in N-terminal cytoplasmic domain-encoding region (iRhom2 (Uncv) ) leads to aberrant hair shaft and inner root sheath differentiation, thus results in a hairless phenotype in homozygous iRhom2 (Uncv/Uncv) BALB/c mice. In this study, we found iRhom2 mutation decreased hair matrix proliferation, however, iRhom2 (Uncv/Uncv) mice displayed hyperproliferation and hyperkeratosis in the interfollicular epidermis along with hypertrophy in the sebaceous glands...
September 2016: Archives of Dermatological Research
https://www.readbyqxmd.com/read/27330189/met-signaling-in-keratinocytes-activates-egfr-and-initiates-squamous-carcinogenesis
#5
Christophe Cataisson, Aleksandra M Michalowski, Kelly Shibuya, Andrew Ryscavage, Mary Klosterman, Lisa Wright, Wendy Dubois, Fan Liu, Anne Zhuang, Kameron B Rodrigues, Shelley Hoover, Jennifer Dwyer, Mark R Simpson, Glenn Merlino, Stuart H Yuspa
The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance in tumorigenesis is not clear. We found that the incidence of carcinogen-induced skin squamous tumors was substantially increased in transgenic MT-HGF (mouse metallothionein-hepatocyte growth factor) mice, which have increased abundance of the MET ligand HGF. Squamous tumors also erupted spontaneously on the skin of MT-HGF mice that were promoted by wounding or the application of 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C...
2016: Science Signaling
https://www.readbyqxmd.com/read/27256961/regulation-of-a-disintegrin-and-metalloproteinase-adam-family-sheddases-adam10-and-adam17-the-emerging-role-of-tetraspanins-and-rhomboids
#6
Alexandra L Matthews, Peter J Noy, Jasmeet S Reyat, Michael G Tomlinson
A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are ubiquitous transmembrane "molecular scissors" which proteolytically cleave, or shed, the extracellular regions of other transmembrane proteins. ADAM10 is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions. ADAM17 is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor α (TNFα) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function...
June 2, 2016: Platelets
https://www.readbyqxmd.com/read/27076598/endogenous-transmembrane-tnf-alpha-protects-against-premature-senescence-in-endothelial-colony-forming-cells
#7
Linden A Green, Victor Njoku, Julie Mund, Jaime Case, Mervin Yoder, Michael P Murphy, Matthias Clauss
RATIONALE: Transmembrane tumor necrosis factor-α (tmTNF-α) is the prime ligand for TNF receptor 2, which has been shown to mediate angiogenic and blood vessel repair activities in mice. We have previously reported that the angiogenic potential of highly proliferative endothelial colony-forming cells (ECFCs) can be explained by the absence of senescent cells, which in mature endothelial cells occupy >30% of the population, and that exposure to a chronic inflammatory environment induced premature, telomere-independent senescence in ECFCs...
May 13, 2016: Circulation Research
https://www.readbyqxmd.com/read/26869525/irhoms-its-functions-and-essential-roles
#8
Min-Young Lee, Ki-Hoan Nam, Kyung-Chul Choi
In Drosophila, rhomboid proteases are active cardinal regulators of epidermal growth factor receptor (EGFR) signaling pathway. iRhom1 and iRhom2, which are inactive homologs of rhomboid intramembrane serine proteases, are lacking essential catalytic residues. These are necessary for maturation and traffickingof tumor necrosis factor-alpha (TNF-α) converting enzyme (TACE) from endoplasmic reticulum (ER) to plasma membrane through Golgi, and associated with the fates of various ligands for EGFR. Recent studies have clarifiedthat the activation or downregulation of EGFR signaling pathways by alteration of iRhoms are connected to several human diseases including tylosis with esophageal cancer (TOC) which is the autosomal dominant syndrom, breast cancer, and Alzheimer's disease...
March 1, 2016: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/26603928/3d-structure-generation-molecular-dynamics-and-docking-studies-of-irhom2-protein-involved-in-cancer-rheumatoid-arthritis
#9
Utkarsh Raj, Himansu Kumar, Pritish Kumar Varadwaj
A short-lived membrane protein IRHOM2 pedals a cascade of events by regulating Epidermal Growth Factor Receptor (EGFR) signalling in parallel with metalloproteases which results their involvement in cancer as well as in rheumatoid arthritis. Therefore, IRHOM2 is a potential therapeutic drug target for these diseases, but its 3D-structure has not been reported yet. In this study, the three-dimensional structure of the IRHOM2 protein was generated using I-TASSER (Iterative Threading Assembly Refinement) server...
2015: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/26535007/deletions-in-the-cytoplasmic-domain-of-irhom1-and-irhom2-promote-shedding-of-the-tnf-receptor-by-the-protease-adam17
#10
Sathish K Maney, David R McIlwain, Robin Polz, Aleksandra A Pandyra, Balamurugan Sundaram, Dorit Wolff, Kazuhito Ohishi, Thorsten Maretzky, Matthew A Brooke, Astrid Evers, Ananda A Jaguva Vasudevan, Nima Aghaeepour, Jürgen Scheller, Carsten Münk, Dieter Häussinger, Tak W Mak, Garry P Nolan, David P Kelsell, Carl P Blobel, Karl S Lang, Philipp A Lang
The protease ADAM17 (a disintegrin and metalloproteinase 17) catalyzes the shedding of various transmembrane proteins from the surface of cells, including tumor necrosis factor (TNF) and its receptors. Liberation of TNF receptors (TNFRs) from cell surfaces can dampen the cellular response to TNF, a cytokine that is critical in the innate immune response and promotes programmed cell death but can also promote sepsis. Catalytically inactive members of the rhomboid family of proteases, iRhom1 and iRhom2, mediate the intracellular transport and maturation of ADAM17...
November 3, 2015: Science Signaling
https://www.readbyqxmd.com/read/25918388/irhoms-1-and-2-are-essential-upstream-regulators-of-adam17-dependent-egfr-signaling
#11
Xue Li, Thorsten Maretzky, Gisela Weskamp, Sébastien Monette, Xiaoping Qing, Priya Darshinee A Issuree, Howard C Crawford, David R McIlwain, Tak W Mak, Jane E Salmon, Carl P Blobel
The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17(-/-) mice die perinatally with open eyes, like Egfr(-/-) mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain...
May 12, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25546423/irhom2-mutation-leads-to-aberrant-hair-follicle-differentiation-in-mice
#12
Yang Leilei, Liu Bing, Li Yang, Wang Shaoxia, Xu Yuan, Wang Dongping, Ye Huahu, Shang Shichen, Zhang Guangzhou, Peng Ruiyun, Zeng Lin, Li Wenlong
iRhom1 and iRhom2 are inactive homologues of rhomboid intramembrane serine proteases lacking essential catalytic residues, which are necessary for the maturation of TNFα-converting enzyme (TACE). In addition, iRhoms regulate epidermal growth factor family secretion. The functional significance of iRhom2 during mammalian development is largely unclear. We have identified a spontaneous single gene deletion mutation of iRhom2 in Uncv mice. The iRhom2Uncv/Uncv mice exhibit hairless phenotype in a BALB/c genetic background...
2014: PloS One
https://www.readbyqxmd.com/read/25395669/genetic-interaction-implicates-irhom2-in-the-regulation-of-egf-receptor-signalling-in-mice
#13
Owen M Siggs, Adam Grieve, Hongmei Xu, Paul Bambrough, Yonka Christova, Matthew Freeman
iRhoms are closely related to rhomboid intramembrane proteases but lack catalytic activity. In mammals iRhoms are known to regulate the trafficking of TACE, the protease that cleaves the membrane bound inflammatory cytokine TNF. We have mapped a spontaneously occurring mouse mutation with a loss of hair phenotype, curly bare (cub), to the Rhbdf2 locus, which encodes the iRhom2 protein. The cub deletion removes the first 268 amino acids of the iRhom2 protein but is not a loss of function. We have also identified a previously reported suppressor of cub, called Mcub (modifier of curly bare), and find it to be a loss of function allele of the amphiregulin gene (Areg)...
November 13, 2014: Biology Open
https://www.readbyqxmd.com/read/24825892/rhbdf2-mutations-increase-its-protein-stability-and-drive-egfr-hyperactivation-through-enhanced-secretion-of-amphiregulin
#14
Vishnu Hosur, Kenneth R Johnson, Lisa M Burzenski, Timothy M Stearns, Richard S Maser, Leonard D Shultz
The rhomboid 5 homolog 2 (Rhbdf2) gene encodes an inactive rhomboid (iRhom) protease, iRhom2, one of a family of enzymes containing a long cytosolic N terminus and a dormant peptidase domain of unknown function. iRhom2 has been implicated in epithelial regeneration and cancer growth through constitutive activation of epidermal growth factor receptor (EGFR) signaling. However, little is known about the physiological substrates for iRhom2 or the molecular mechanisms underlying these functions. We show that iRhom2 is a short-lived protein whose stability can be increased by select mutations in the N-terminal domain...
May 27, 2014: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24762269/with-blood-in-the-joint-what-happens-next-could-activation-of-a-pro-inflammatory-signalling-axis-leading-to-irhom2-tnf%C3%AE-convertase-dependent-release-of-tnf%C3%AE-contribute-to-haemophilic-arthropathy
#15
REVIEW
C Haxaire, C P Blobel
One of the main complications of haemophilia A is haemophilic arthropathy (HA), a debilitating disease with a significant negative impact on motility and quality of life. Despite major advances in the treatment of haemophilia A, many patients still suffer from HA. We wish to develop new treatments for HA, but must first better understand its causes. Our laboratory studies molecular scissors that release the pro-inflammatory cytokine tumour necrosis factor alpha (TNFα) from cells. TNFα is considered the 'fire alarm' of the body - it helps to fight infections, but can also cause diseases such as inflammatory arthritis...
May 2014: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/24738885/insights-into-desmosome-biology-from-inherited-human-skin-disease-and-cardiocutaneous-syndromes
#16
REVIEW
Daniela Nitoiu, Sarah L Etheridge, David P Kelsell
The importance of desmosomes in tissue homeostasis is highlighted by natural and engineered mutations in desmosomal genes, which compromise the skin or heart and in some instances both. Desmosomal gene mutations account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy, and are mutated in an array of other disorders such as striate palmoplantar keratoderma, hypotrichosis with or without skin vesicles and lethal acantholytic epidermolysis bullosa. Recently, we reported loss-of-function mutations in the human ADAM17 gene, encoding for the 'sheddase' ADAM17, a transmembrane protein which cleaves extracellular domains of substrate proteins including TNF-α, growth factors and desmoglein (DSG) 2...
June 2014: Cell Communication & Adhesion
https://www.readbyqxmd.com/read/24667173/proteomic-analysis-of-differentially-expressed-skin-proteins-in-irhom2-uncv-mice
#17
Bing Liu, Yuan Xu, Wen-Long Li, Lin Zeng
A mouse homozygous for the spontaneous mutation uncovered (Uncv) has a hairless phenotype. A 309-bp non-frameshift deletion mutation in the N-terminal cytoplasmic domain of iRhom2 was identified in Uncv mice (iRhom2(Uncv)) using target region sequencing. The detailed molecular basis for how the iRhom2 mutation causes the hairless phenotype observed in the homozygous iRhom2(Uncv) mouse remains unknown. To identify differentially expressed proteins in the skin of wild-type and homozygous iRhom2(Uncv) littermates at postnatal day 5, proteomic approaches, including two-dimensional gel electrophoresis and mass spectrometry were used...
January 2015: BMB Reports
https://www.readbyqxmd.com/read/24643277/irhom2-dependent-regulation-of-adam17-in-cutaneous-disease-and-epidermal-barrier-function
#18
Matthew A Brooke, Sarah L Etheridge, Nihal Kaplan, Charlotte Simpson, Edel A O'Toole, Akemi Ishida-Yamamoto, Olivier Marches, Spiro Getsios, David P Kelsell
iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines...
August 1, 2014: Human Molecular Genetics
https://www.readbyqxmd.com/read/23969955/mammalian-irhoms-have-distinct-physiological-functions-including-an-essential-role-in-tace-regulation
#19
Yonka Christova, Colin Adrain, Paul Bambrough, Ashraf Ibrahim, Matthew Freeman
Loss of iRhom2, a catalytically inactive rhomboid-like protein, blocks maturation of TACE/ADAM17 in macrophages, resulting in defective shedding of the cytokine tumor necrosis factor. Apart from the resulting inflammatory defects, iRhom2-null mice appear normal: they do not show the several defects seen in TACE knockouts, suggesting that TACE maturation is independent of iRhom2 in cells other than macrophages. Here we show that the physiological role of iRhoms is much broader. iRhom1 knockout mice die within 6 weeks of birth...
October 2013: EMBO Reports
https://www.readbyqxmd.com/read/23801765/irhom2-controls-the-substrate-selectivity-of-stimulated-adam17-dependent-ectodomain-shedding
#20
Thorsten Maretzky, David R McIlwain, Priya Darshinee A Issuree, Xue Li, Jordi Malapeira, Sadaf Amin, Philipp A Lang, Tak W Mak, Carl P Blobel
Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNFα release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17...
July 9, 2013: Proceedings of the National Academy of Sciences of the United States of America
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