Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Coppola, Ilaria; Brouwers, Bas; Meulemans, Sandra; Ramos‐Molina, Bruno; Creemers, John W.M.

doi:10.3390/ijms22126344

Cited by 7 publications

(12 citation statements)

References 41 publications

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“…72 The less pronounced impairment of pro-insulin receptor cleavage in the liver is supported by observations in mice with liver-specific furin knockout, suggesting a redundant function of other PCs for insulin receptor maturation in this organ. 68 Taken together, this evidence supports the association between furin reduction and diabetes (Figure 3). In an opposite manner, a study with 21 years of follow up demonstrated that baseline plasma furin levels positively correlate with increased risk of diabetes and mortality in humans (Table 2), indicating the role of furin in diabetes development.…”

Section: ■ Diabetes Mellitussupporting

confidence: 83%

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

Wichaiyo,

Koonyosying,

Morales

2024

ACS Pharmacol. Transl. Sci.

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Furin plays a major role in post-translational modification of several biomolecules, including endogenous hormones, growth factors, and cytokines. Recent reports have demonstrated the association of furin and cardio-cerebrovascular diseases (CVDs) in humans. This review describes the possible pathogenic contribution of furin and its substrates in CVDs. Early-stage hypertension and diabetes mellitus show a negative correlation with furin. A reduction in furin might promote hypertension by decreasing maturation of B-type natriuretic peptide (BNP) or by decreasing shedding of membrane (pro)renin receptor (PRR), which facilitates activation of the renin−angiotensin−aldosterone system (RAAS). In diabetes, furin downregulation potentially leads to insulin resistance by reducing maturation of the insulin receptor. In contrast, the progression of other CVDs is associated with an increase in furin, including dyslipidemia, atherosclerosis, ischemic stroke, myocardial infarction (MI), and heart failure. Upregulation of furin might promote maturation of membrane type 1-matrix metalloproteinase (MT1-MMP), which cleaves low-density lipoprotein receptor (LDLR), contributing to dyslipidemia. In atherosclerosis, elevated levels of furin possibly enhance maturation of several substrates related to inflammation, cell proliferation, and extracellular matrix (ECM) deposition and degradation. Neuronal cell death following ischemic stroke has also been shown to involve furin substrates (e.g., MT1-MMP, hepcidin, and hemojuvelin). Moreover, furin and its substrates, including tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1), and transforming growth factor-β1 (TGF-β1), are capable of mediating inflammation, hypertrophy, and fibrosis in MI and heart failure. Taken together, this evidence provides functional significance of furin in CVDs and might suggest a potential novel therapeutic modality for the management of CVDs.

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Section: ■ Diabetes Mellitussupporting

confidence: 83%

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

Wichaiyo,

Koonyosying,

Morales

2024

ACS Pharmacol. Transl. Sci.

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“…A population‐based prospective study involved subjects at high risk for the development of T2DM and revealed that initial high furin serum levels increased the risk for the development of T2DM and premature mortality 20,24 . Mutation in furin induces propagation of insulin resistance (IR) and T2DM due to association with mutation in the insulin pro‐receptors 25 . Indeed, high circulating furin serum level is correlated with dyslipidemia, high body mass index, and development of metabolic syndrome 26 .…”

Section: Furin and Cardiometabolic Disordersmentioning

confidence: 99%

The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review

Al‐kuraishy,

Al‐Maiahy,

Al‐Gareeb

et al. 2023

Cancer Reports

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BackgroundEndometrial adenocarcinoma (EAC) is a malignant tumor of the endometrium. EAC is the most common female malignancy following the menopause period. About 40% of patients with EAC are linked with obesity and interrelated with hypertension, diabetes mellitus, and high circulating estrogen levels. Proprotein convertase (PC) furin was involved in the progression of EAC.Recent findingsFurin is a protease enzyme belonging to the subtilisin PC family called PC subtilisin/kexin type 3 that converts precursor proteins to biologically active forms and products. Aberrant activation of furin promotes abnormal cell proliferation and the development of cancer. Furin promotes angiogenesis, malignant cell proliferation, and tissue invasion by malignant cells through its pro‐metastatic and oncogenic activities. Furin activity is correlated with the malignant proliferation of EAC. Higher expression of furin may increase the development of EAC through overexpression of pro‐renin receptors and disintegrin and metalloprotease 17 (ADAM17). As well, inflammatory signaling in EAC promotes the expression of furin with further propagation of malignant transformation.ConclusionFurin is associated with the development and progression of EAC through the induction of proliferation, invasion, and metastasis of malignant cells of EAC. Furin induces ontogenesis in EAC through activation expression of ADAM17, pro‐renin receptor, CD109, and TGF‐β. As well, EAC‐mediated inflammation promotes the expression of furin with further propagation of neoplastic growth and invasion.

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“…Consequently, furin knockout mice demonstrate impaired insulin content and secretion [ 68 ]. These animals also exhibit abnormal processing of insulin receptor, decreased pancreatic β-cell mass, and proliferation, and ultimately develop progressive, age-dependent glucose intolerance [ 69 , 70 ]. Although the data available on serpinB8 are scant, the restrictive pattern of this serpin’s expression in the pancreas may reflect the function of this molecule to inhibit furin in the islets, thereby implicating it in various aspects of islet biology.…”

Section: The Role Of Clade B Serpins In Diabetesmentioning

confidence: 99%

The Role of Proteases and Serpin Protease Inhibitors in β-Cell Biology and Diabetes

Kryvalap

Czyzyk

2022

Biomolecules

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Regulation of the equilibrium between proteases and their inhibitors is fundamental to health maintenance. Consequently, developing a means of targeting protease activity to promote tissue regeneration and inhibit inflammation may offer a new strategy in therapy development for diabetes and other diseases. Specifically, recent efforts have focused on serine protease inhibitors, known as serpins, as potential therapeutic targets. The serpin protein family comprises a broad range of protease inhibitors, which are categorized into 16 clades that are all extracellular, with the exception of Clade B, which controls mostly intracellular proteases, including both serine- and papain-like cysteine proteases. This review discusses the most salient, and sometimes opposing, views that either inhibition or augmentation of protease activity can bring about positive outcomes in pancreatic islet biology and inflammation. These potential discrepancies can be reconciled at the molecular level as specific proteases and serpins regulate distinct signaling pathways, thereby playing equally distinct roles in health and disease development.

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Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Cited by 7 publications

References 41 publications

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review

The Role of Proteases and Serpin Protease Inhibitors in β-Cell Biology and Diabetes

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