scholarly journals Inactive rhomboid proteins RHBDF1 and RHBDF2 (iRhoms): a decade of research in murine models

2021 ◽  
Author(s):  
Lisa M. Burzenski ◽  
Benjamin E. Low ◽  
Vivek Kohar ◽  
Leonard D. Shultz ◽  
Michael V. Wiles ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Serine Proteases ◽  
Skin Diseases ◽  
Protein Domains ◽  
Normal Growth ◽  
Growth Factor Signaling ◽  
Murine Models ◽  
The Past ◽  
Rhomboid Proteases ◽  
Parkinson’S Diseases

AbstractRhomboid proteases, first discovered in Drosophila, are intramembrane serine proteases. Members of the rhomboid protein family that are catalytically deficient are known as inactive rhomboids (iRhoms). iRhoms have been implicated in wound healing, cancer, and neurological disorders such as Alzheimer’s and Parkinson’s diseases, inflammation, and skin diseases. The past decade of mouse research has shed new light on two key protein domains of iRhoms—the cytosolic N-terminal domain and the transmembrane dormant peptidase domain—suggesting new ways to target multiple intracellular signaling pathways. This review focuses on recent advances in uncovering the unique functions of iRhom protein domains in normal growth and development, growth factor signaling, and inflammation, with a perspective on future therapeutic opportunities.

scholarly journals An internally quenched peptide as a new model substrate for rhomboid intramembrane proteases

2018 ◽  
Vol 399 (12) ◽  
pp. 1389-1397 ◽  
Author(s):  
Elena Arutyunova ◽  
Zhenze Jiang ◽  
Jian Yang ◽  
Ayodeji N. Kulepa ◽  
Howard S. Young ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Catalytic Mechanism ◽  
Mass Spectrometry Analysis ◽  
Aqueous Environment ◽  
Growth Factor Signaling ◽  
Rhomboid Protease ◽  
Spectrometry Analysis ◽  
Intramembrane Proteases ◽  
Rhomboid Proteases ◽  
Lipid Environment

AbstractRhomboids are ubiquitous intramembrane serine proteases that cleave transmembrane substrates. Their functions include growth factor signaling, mitochondrial homeostasis, and parasite invasion. A recent study revealed that theEscherichia colirhomboid protease EcGlpG is essential for its extraintestinal pathogenic colonization within the gut. Crystal structures of EcGlpG and theHaemophilus influenzaerhomboid protease HiGlpG have deciphered an active site that is buried within the lipid bilayer but exposed to the aqueous environment via a cavity at the periplasmic face. A lack of physiological transmembrane substrates has hampered progression for understanding their catalytic mechanism and screening inhibitor libraries. To identify a soluble substrate for use in the study of rhomboid proteases, an array of internally quenched peptides were assayed with HiGlpG, EcGlpG and PsAarA fromProvidencia stuartti. One substrate was identified that was cleaved by all three rhomboid proteases, with HiGlpG having the highest cleavage efficiency. Mass spectrometry analysis determined that all enzymes hydrolyze this substrate between norvaline and tryptophan. Kinetic analysis in both detergent and bicellular systems demonstrated that this substrate can be cleaved in solution and in the lipid environment. The substrate was subsequently used to screen a panel of benzoxazin-4-one inhibitors to validate its use in inhibitor discovery.

scholarly journals Peroxiredoxins as Potential Targets for Cardiovascular Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1244
Author(s):  
Se-Jin Jeong ◽  
Jong-Gil Park ◽  
Goo Taeg Oh
Keyword(s):  
Cardiovascular Disease ◽  
Intracellular Signaling ◽  
Toxic Substance ◽  
Regulatory Proteins ◽  
The Past ◽  
Glutathione Peroxidases ◽  
Intracellular Signals ◽  
Common Etiology ◽  
Cardiovascular Cells

Increased oxidative stress (OS) is considered a common etiology in the pathogenesis of cardiovascular disease (CVD). Therefore, the precise regulation of reactive oxygen species (ROS) in cardiovascular cells is essential to maintain normal physiological functions. Numerous regulators of cellular homeostasis are reportedly influenced by ROS. Hydrogen peroxide (H2O2), as an endogenous ROS in aerobic cells, is a toxic substance that can induce OS. However, many studies conducted over the past two decades have provided substantial evidence that H2O2 acts as a diffusible intracellular signaling messenger. Antioxidant enzymes, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins (Prdxs), maintain the balance of ROS levels against augmentation of ROS production during the pathogenesis of CVD. Especially, Prdxs are regulatory sensors of transduced intracellular signals. The intracellular abundance of Prdxs that specifically react with H2O2 act as regulatory proteins. In this review, we focus on the role of Prdxs in the regulation of ROS-induced pathological changes in the development of CVD.

scholarly journals Itch in Atopic Dermatitis – What Is New?

2021 ◽  
Vol 8 ◽  
Author(s):  
Franz J. Legat
Keyword(s):  
Atopic Dermatitis ◽  
Intracellular Signaling ◽  
Sleep Disturbances ◽  
Skin Diseases ◽  
Immunosuppressive Agents ◽  
Calcineurin Inhibitors ◽  
Inflammatory Skin Diseases ◽  
New Era ◽  
Short And Long Term ◽  
Chronic Pruritus

Atopic dermatitis (AD) is among the most frequent inflammatory skin diseases in humans, affecting up to 20% of children and 10% of adults in higher income countries. Chronic pruritus is a disease-defining symptom of AD, representing the most burdensome symptom for patients. Severe chronic pruritus causes significant sleep disturbances and impaired quality of life, as well as increased anxiety, depression and suicidal behavior. Until recently, skin care, topical corticosteroids, and calcineurin-inhibitors were primarily used to treat mild to moderate AD, while phototherapy and immunosuppressive agents such as corticosteroids, cyclosporine, and methotrexate were used to treat patients with moderate to severe AD. The potential short- and long-term adverse events associated with these treatments or their insufficient therapeutic efficacy limited their use in controlling pruritus and eczema in AD patients over longer periods of time. As our understanding of AD pathophysiology has improved and new systemic and topical treatments have appeared on the market, targeting specific cytokines, receptors, or their intracellular signaling, a new era in atopic dermatitis and pruritus therapy has begun. This review highlights new developments in AD treatment, placing a specific focus on their anti-pruritic effects.

scholarly journals RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models?

2018 ◽  
Vol 9 ◽  
Author(s):  
Vishnu Hosur ◽  
Michelle L. Farley ◽  
Benjamin E. Low ◽  
Lisa M. Burzenski ◽  
Leonard D. Shultz ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Growth Factor ◽  
Human Disease ◽  
Growth Factor Signaling ◽  
Murine Models

Normal Growth despite Combined Pituitary Hormone Deficiency

2019 ◽  
Vol 92 (2) ◽  
pp. 133-142
Author(s):  
Mohamed El Kholy ◽  
Heba Elsedfy ◽  
Laurence Perin ◽  
Walid Abi Habid ◽  
Nathalie Thibaud ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Normal Growth ◽  
Molar Ratio ◽  
Common Mechanism ◽  
Pituitary Hormone ◽  
Serum Factors ◽  
Intracellular Signaling Pathways ◽  
Igfbp 3 ◽  
Variable Penetrance

Background: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH. Case Description: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential. Results: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient’s serum was unable to induce AKT phosphorylation in the MCF-7 cell line. Conclusion: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible.

High Throughput Quantitative Analysis of Atherosclerosis tn Mice

2000 ◽  
Vol 6 (S2) ◽  
pp. 554-555
Author(s):  
David A. Sanan ◽  
Zuleika Ladha ◽  
Dale L. Newland
Keyword(s):  
Vascular Tissue ◽  
Disease Process ◽  
Murine Models ◽  
Quantitative Morphometry ◽  
The Past ◽  
Atherosclerotic Lesions ◽  
En Face ◽  
Lesion Analysis ◽  
And Control ◽  
Key Parameter

For the past 7 years we have been measuring atherosclerosis in murine models of the human disease, constantly honing our methods for quantitating the atherosclerotic response of mice that have been genetically, dietarily or pharmaceutically manipulated to help understand and control the disease process.With the advent of genetically modified mouse models, investigators now have more robust atherosclerotic responses to quantitate. The surface area of lesions along the entire length of the aorta is a key parameter used to evaluate these responses. We routinely perform quantitative morphometry of intimal atherosclerotic lesions in pinned-out mouse aortas, also called en face lesion analysis.The number and scale of mouse atherosclerosis studies has increased beyond the capacity of our core laboratory to provide service. While the “wet” processes involved in preparing vascular tissue for atherosclerosis analysis have already been streamlined, we found considerable scope for improving the computer-dependent “back-end” of the analysis.

scholarly journals Obesity-associated digestive cancers: A review of mechanisms and interventions

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769502 ◽  
Author(s):  
Jiachen Zheng ◽  
Ming Zhao ◽  
Jiahui Li ◽  
Guoying Lou ◽  
Yanyan Yuan ◽  
...  
Keyword(s):  
Digestive System ◽  
Survival Rates ◽  
Gene Mutations ◽  
Colorectal Cancers ◽  
Growth Factor Signaling ◽  
Related Gene ◽  
The Past ◽  
Digestive Cancers ◽  
Liver And Pancreas ◽  
Prevalence Of Obesity

The prevalence of obesity has steadily increased over the past few decades. Previous studies suggest that obesity is an oncogenic factor and that over 20% of all cancers are obesity-related. Among such cancers, digestive system malignancies (including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, liver, and pancreas) are reported most frequently. While the 5-year survival rates of cancers of the breast and prostate are 90%, that rate is only 45% for digestive cancers. In this review, the mechanisms of obesity-associated digestive cancers are discussed, with an emphasis on obesity-related gene mutations, insulin and insulin-like growth factor signaling pathways, chronic inflammation, and altered adipokine levels. Evidence that these factors often function interdependently rather than independently in carcinogenesis is presented. Recommended interventions that may reduce the burden of obesity-associated digestive cancers, such as participation in physical activity, diet modulation, and calorie restriction, are also described.

scholarly journals Vascular Anomalies Caused by Abnormal Signaling within Endothelial Cells: Targets for Novel Therapies

2017 ◽  
Vol 34 (03) ◽  
pp. 233-238 ◽  
Author(s):  
Ha-Long Nguyen ◽  
Laurence Boon ◽  
Miikka Vikkula
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Vascular Anomalies ◽  
Paradigm Change ◽  
Novel Therapies ◽  
Endothelial Cell Dysfunction ◽  
Cell Dysfunction ◽  
The Past ◽  
Intracellular Signaling Pathways ◽  
Downstream Effects

AbstractVascular anomalies arise as a consequence of improper development and maintenance of the vasculature. Our knowledge on the pathophysiological bases of vascular anomalies has skyrocketed during the past 5 years. It is becoming clear that common intracellular signaling pathways are often activated by mutations, causing endothelial cell dysfunction. These mutations cause hyperactivation of two major intracellular signaling pathways that may be controlled by inhibitors developed for cancer treatment. Although we do not know yet all the downstream effects, it has become evident that normalization of the abnormal signaling is an interesting target for therapy. This is a major paradigm change, as developmental malformations were considered to be inert to any molecular treatment.

scholarly journals From Science to Success? Targeting Tyrosine Kinase 2 in Spondyloarthritis and Related Chronic Inflammatory Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Dominika Hromadová ◽  
Dirk Elewaut ◽  
Robert D. Inman ◽  
Birgit Strobl ◽  
Eric Gracey
Keyword(s):  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Species Differences ◽  
Inflammatory Diseases ◽  
Symptomatic Relief ◽  
Murine Models ◽  
Pathogenic Role ◽  
Tyrosine Kinase 2 ◽  
Inflammatory Bowel ◽  
Basic Biology

Spondyloarthritis (SpA) is a family of inflammatory arthritic diseases, which includes the prototypes of psoriatic arthritis and ankylosing spondylitis. SpA is commonly associated with systemic inflammatory diseases, such as psoriasis and inflammatory bowel disease. Immunological studies, murine models and the genetics of SpA all indicate a pathogenic role for the IL-23/IL-17 axis. Therapeutics targeting the IL-23/IL-17 pathway are successful at providing symptomatic relief, but may not provide complete protection against progression of arthritis. Thus there is still tremendous interest in the discovery of novel therapeutic targets for SpA. Tyrosine kinase 2 (TYK2) is a member of the Janus kinases, which mediate intracellular signaling of cytokines via signal transducer and activator of transcription (STAT) activation. TYK2 plays a crucial role in mediating IL-23 receptor signaling and STAT3 activation. A plethora of natural mutations in and around TYK2 have provided a wealth of data to associate this kinase with autoimmune/autoinflammatory diseases in humans. Induced and natural mutations in murine Tyk2 largely support human data; however, key inter-species differences exist, which means extrapolation of data from murine models to humans needs to be done with caution. Despite these reservations, novel selective TYK2 inhibitors are now proving successful in advanced clinical trials of inflammatory diseases. In this review, we will discuss TYK2 from basic biology to therapeutic targeting, with an emphasis on studies in SpA. Seminal studies uncovering the basic science of TYK2 have provided sound foundations for targeting it in SpA and related inflammatory diseases. TYK2 inhibitors may well be the next blockbuster therapeutic for SpA.

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