scholarly journals iRhom2: An Emerging Adaptor Regulating Immunity and Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6570 ◽  
Author(s):  
Mazin A. Al-Salihi ◽  
Philipp A. Lang
Keyword(s):  
Critical Role ◽  
Growth Factor Receptor ◽  
Biologically Active ◽  
Necrosis Factor Alpha ◽  
Dna Viruses ◽  
Catalytic Center ◽  
Intramembrane Proteases ◽  
Epidermal Growth ◽  
Factor Alpha

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.

scholarly journals The role of endothelial PI3Kγ activity in neutrophil trafficking

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 150-157 ◽  
Author(s):  
Kamal D. Puri ◽  
Teresa A. Doggett ◽  
Ching-Yu Huang ◽  
Jason Douangpanya ◽  
Joel S. Hayflick ◽  
...  
Keyword(s):  
Critical Role ◽  
Fold Increase ◽  
Necrosis Factor Alpha ◽  
Catalytic Subunits ◽  
Injury Model ◽  
Lung Injury Model ◽  
Factor Alpha ◽  
Phosphoinositide 3 Kinase

Phosphoinositide 3-kinase gamma (PI3Kγ) in neutrophils plays a critical role in the directed migration of these cells into inflamed tissues. In this study, we demonstrate the importance of the endothelial component of PI3Kγ activity relative to its leukocyte counterpart in supporting neutrophil interactions with the inflamed vessel wall. Despite the reconstitution of class-Ib PI3K function in neutrophils of p110γ–/– mice, we observed a 45% reduction in accumulation of these cells in an acute lung injury model. Mechanistically, this appears to result from a perturbation in selectin-mediated adhesion as manifested by a 70% reduction in wild-type (WT) neutrophil attachment to and 17-fold increase in rolling velocities on p110γ–/– microvessels in vivo in response to tumor necrosis factor alpha (TNFα). This alteration in adhesion was further augmented by a deficiency in p110δ, suggesting that the activity of both catalytic subunits is required for efficient capture of neutrophils by cytokine-stimulated endothelium. Interestingly, E-selectin–mediated adhesion in p110γ–/– mice was impaired by more than 95%, but no defect in nuclear factor kappa B (NF-κB)–induced gene expression was observed. These findings suggest a previously unrecognized partnership between class-I PI3Ks expressed in leukocytes and endothelium, the combination of which is required for the efficient trafficking of immunocompetent cells to sites of inflammation.

scholarly journals The Critical Role of the Epidermal Growth Factor Receptor in Endochondral Ossification

2011 ◽  
Vol 26 (11) ◽  
pp. 2622-2633 ◽  
Author(s):  
Xianrong Zhang ◽  
Valerie A Siclari ◽  
Shenghui Lan ◽  
Ji Zhu ◽  
Eiki Koyama ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endochondral Ossification ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Epidermal Growth

scholarly journals Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice

2010 ◽  
Vol 207 (8) ◽  
pp. 1617-1624 ◽  
Author(s):  
Athena Chalaris ◽  
Nina Adam ◽  
Christian Sina ◽  
Philip Rosenstiel ◽  
Judith Lehmann-Koch ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Intestinal Barrier ◽  
Systemic Availability ◽  
Epidermal Growth ◽  
Targeting Strategy ◽  
Necrosis Factor ◽  
Increased Susceptibility

The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17ex/ex were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17ex/ex mice was normal, ADAM17ex/ex mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target.

scholarly journals TNFAIP1 is differentially expressed in the primary tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Differentially Expressed ◽  
Expression Data ◽  
Breast Cancer Patients ◽  
Necrosis Factor Alpha ◽  
Primary Tumors ◽  
Epidermal Growth ◽  
Factor Alpha ◽  
Necrosis Factor

Trastuzumab, a monoclonal antibody targeted against the human epidermal growth factor receptor 2 (HER2) is utilized for the treatment of human breast cancer (1, 2), but a complete understanding of how tumor signal transduction is modulated by trastuzumab treatment is lacking. By mining published and public microarray and gene expression data (3, 4) from the primary tumors of patients treated with trastuzumab, we found that the tumor necrosis factor alpha-induced protein 1, TNFAIP1, was among the genes most differentially expressed in the primary tumors of patients treated with trastuzumab, and expressed at lower levels in the tumors of patients treated with trastuzumab. Thus, the use of trastuzumab in patients with breast cancer is associated with decreased expression of a gene (5) that can induce apoptosis of cancer cells (6).

scholarly journals Intracellular Adhesion Molecule 1 Plays a Key Role in Acquired Immunity to Salmonellosis

2003 ◽  
Vol 71 (10) ◽  
pp. 5881-5891 ◽  
Author(s):  
Simon Clare ◽  
Robert Goldin ◽  
Christine Hale ◽  
Richard Aspinall ◽  
Cameron Simmons ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Critical Role ◽  
Interleukin 2 ◽  
Sublethal Dose ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Intracellular Adhesion Molecule ◽  
Serovar Typhimurium ◽  
Factor Alpha

ABSTRACT This study investigated the role of intracellular adhesion molecule 1 (ICAM-1) during Salmonella enterica serovar Typhimurium infection of mice. We show that ICAM-1 is expressed in and around granulomas on day 4 of infection in wild-type mice. However, when naive ICAM-1−/− mice were challenged with a sublethal dose of serovar Typhimurium, there were no detectable differences in systemic bacterial burden over the first 9 days of infection compared to wild-type control mice. When mice were immunized with the S. enterica serovar Typhimurium vaccine strain SL2361 and then challenged with the virulent S. enterica serovar Typhimurium strain C5, 100% of the ICAM-1−/− mice succumbed to infection, compared to 30% of wild-type mice. T-cell responses, as measured by activation via interleukin-2 production, as well as antibody responses were comparable in the ICAM-1−/− and wild-type mice. Following challenge, counts in organs were significantly higher in the ICAM-1−/− mice, and histological examination of organs showed pathological differences. Strain SL3261-immunized wild-type mice had cellular infiltrate and normal granuloma formation in the liver and spleen on days 5 and 10 after challenge with strain C5. ICAM-1−/− mice had a similar infiltrate on day 5, whereas on day 10 the infiltrate was more widespread and there were fewer macrophages associated with the granulomas. High circulating levels of tumor necrosis factor alpha and gamma interferon, as well as a high burden of strain C5 in the blood, accompanied the differences in histopathology. In this study we show that ICAM-1 plays a critical role during rechallenge of immunized mice with virulent S. enterica serovar Typhimurium.

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