RIN3 Is a Negative Regulator of Mast Cell Responses to SCF

Janson, Christine; Kasahara, Noriyuki; Prendergast, George C.; Colicelli, John

doi:10.1371/journal.pone.0049615

Cited by 20 publications

(13 citation statements)

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“…RIN3 is a Rab5 GTPase binding protein expressed in many tissues, including the lung, and is involved in transport from plasma membranes to early endosomes 69,70 . High levels of expression of RIN3 have been found on human mast cells 71 , a cell type that may be of interest in COPD 72–74 . Furthermore, we demonstrated, in a small number of lung tissue samples, that RIN3 expression differs between COPD cases versus controls.…”

Section: Discussionmentioning

confidence: 99%

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Cho

McDonald

Zhou

et al. 2014

The Lancet Respiratory Medicine

304

307

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Background The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. Methods Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis. Findings Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls. Interpretation In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup. Funding National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.

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Section: Discussionmentioning

confidence: 99%

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Cho

McDonald

Zhou

et al. 2014

The Lancet Respiratory Medicine

304

307

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“…Studies in HeLa cells have shown that RIN3 is involved in vesicular trafficking to early endosomes and interacts with amphiphysin II, a protein involved in the regulation of endocytosis [Kajiho et al, ]. RIN3 also participates in the internalization of receptor tyrosine kinase KIT in mast cells [Janson et al, ]. Although the role of RIN3 in bone cells has not been studied it is an interesting candidate for PDB given the crucial role that small GTPases play in osteoclast function [Itzstein et al, 2011].…”

Section: Molecular Pathology Of Pdbmentioning

confidence: 99%

Biology and Treatment of Paget's Disease of Bone

Vallet

Ralston

2015

J. Cell. Biochem.

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Paget's disease of bone (PDB) is a common skeletal disorder characterized by increased and disorganized bone remodeling affecting one or more skeletal sites. Although some patients are asymptomatic others develop complications such as bone pain, deformity, nerve compression syndromes, and fragility fractures. Genetic factors play an important role in the pathogenesis of PDB and there is strong evidence that susceptibility is determined by variants within or close to genes that regulate osteoclast function. Environmental factors also play a key role but the nature of the environmental triggers is less clear. Bisphosphonates are a highly effective treatment for the elevations in bone turnover that are characteristic of PDB but it is unclear at present if they alter the natural history of the disease. Here, we review the epidemiology, clinical, cellular, and molecular abnormalities in PDB as well as environmental and genetic triggers, and current available treatment options.

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“…RIN3 is highly expressed and enriched in human mast cells. RIN3 may function as an inhibitor of mast cells migration to sites of infection and injury [ 71 , 156 ].…”

Section: Appendixmentioning

confidence: 99%

Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics

Kurakin

Bredesen

2020

Aging

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Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks. Using algorithms for hypothesis independent search and expert-assisted synthesis of heterogeneous data, we attempted to reconcile multimodal clinical profiles of early-stage AD patients and accumulated research data within a parsimonious framework. Results of our analysis suggest that Alzheimer’s may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis. The latter can be caused by various endogenous and exogenous factors, such as chronic inflammatory conditions, infections, vascular dysfunction, head trauma, environmental toxicity, and immune disorders. Whether originating in the brain or on the periphery, chronic stress, toxicity, and inflammation are communicated to the central nervous system (CNS) via humoral and neural routes, preferentially targeting high-centrality regulatory nodes and circuits of the nervous system, and eventually manifesting as a neurodegenerative CNS disease. In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer’s disease.

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RIN3 Is a Negative Regulator of Mast Cell Responses to SCF

Cited by 20 publications

References 50 publications

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Biology and Treatment of Paget's Disease of Bone

Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics

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