The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B

Kara, I.; Poggi, Marjorie; Bonardo, Bernadette; Govers, Roland; Landrier, Jean‐François; Tian, Sun; Leibiger, Ingo B.; Day, Robert; Creemers, John W.M.; Peiretti, Franck

doi:10.1074/jbc.m114.592543

Cited by 23 publications

(10 citation statements)

References 51 publications

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“…The short isoform (INSR-A) is predominantly expressed in undifferentiated cells and contributes to prenatal development and tissue growth, whereas the expression of the long isoform (INSR-B) is enhanced in post-mitotic and differentiated cells and is largely responsible for the systemic metabolic action of insulin in adults [116]. The differential expression of INSR isoforms derives from a tight regulation of mRNA maturation by several splicing factors, such as heterogeneous nuclear ribonucleoprotein (hnRNP) F promoting INSR-B expression and hnRNP A1 promoting INSR-A expression, or at post-translational level with furin involved in INSR-A cleavage and PACE4 supporting INSR-B maturation [117,118]. These events are also affected by growth factors, including insulin itself [119].…”

Section: Insr In Atmentioning

confidence: 99%

Insulin and Insulin Receptors in Adipose Tissue Development

Cignarelli

Genchi

Perrini

et al. 2019

IJMS

159

104

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Insulin is a major endocrine hormone also involved in the regulation of energy and lipid metabolism via the activation of an intracellular signaling cascade involving the insulin receptor (INSR), insulin receptor substrate (IRS) proteins, phosphoinositol 3-kinase (PI3K) and protein kinase B (AKT). Specifically, insulin regulates several aspects of the development and function of adipose tissue and stimulates the differentiation program of adipose cells. Insulin can activate its responses in adipose tissue through two INSR splicing variants: INSR-A, which is predominantly expressed in mesenchymal and less-differentiated cells and mainly linked to cell proliferation, and INSR-B, which is more expressed in terminally differentiated cells and coupled to metabolic effects. Recent findings have revealed that different distributions of INSR and an altered INSR-A:INSR-B ratio may contribute to metabolic abnormalities during the onset of insulin resistance and the progression to type 2 diabetes. In this review, we discuss the role of insulin and the INSR in the development and endocrine activity of adipose tissue and the pharmacological implications for the management of obesity and type 2 diabetes.

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Section: Insr In Atmentioning

confidence: 99%

Insulin and Insulin Receptors in Adipose Tissue Development

Cignarelli

Genchi

Perrini

et al. 2019

IJMS

159

104

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“…Another possible approach is to take advantage of the differential regulation of IR isoform protein maturation. Indeed, furin and paired basic amino acid-cleaving enzyme 4 enzymes, seems to be differentially required for IR-A and IR-B maturation ( 328 , 329 ), and furin can be inhibited by a number of polyphenols ( 330 ).…”

Section: Inhibitors Of Insulin/ir-a Signalingmentioning

confidence: 99%

Insulin Resistance: Any Role in the Changing Epidemiology of Thyroid Cancer?

et al. 2017

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In the past few decades, the incidence of thyroid cancer (TC), namely of its papillary hystotype (PTC), has shown a steady increase worldwide, which has been attributed at least in part to the increasing diagnosis of early stage tumors. However, some evidence suggests that environmental and lifestyle factors can also play a role. Among the potential risk factors involved in the changing epidemiology of TC, particular attention has been drawn to insulin-resistance and related metabolic disorders, such as obesity, type 2 diabetes, and metabolic syndrome, which have been also rapidly increasing worldwide due to widespread dietary and lifestyle changes. In accordance with this possibility, various epidemiological studies have indeed gathered substantial evidence that insulin resistance-related metabolic disorders might be associated with an increased TC risk either through hyperinsulinemia or by affecting other TC risk factors including iodine deficiency, elevated thyroid stimulating hormone, estrogen-dependent signaling, chronic autoimmune thyroiditis, and others. This review summarizes the current literature evaluating the relationship between metabolic disorders characterized by insulin resistance and the risk for TC as well as the possible underlying mechanisms. The potential implications of such association in TC prevention and therapy are discussed.

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“…The tetrabasic sequence is most likely removed afterward by carboxypeptidase D, a process that has been shown to be required for full activation of the insulin-like growth factor 1 receptor [5]. The endoproteolytic cleavage step has been shown to be performed by the proprotein convertase (PC) family members FURIN, PACE4, PC5/6 (isoforms A and B), and PC7 in overexpression experiments [6]. However, FURIN was put forward as the physiological PC for processing of the proIR in the secretory pathway and PACE4 at the cell surface when FURIN activity is reduced [6].…”

Section: Introductionmentioning

confidence: 99%

“…The endoproteolytic cleavage step has been shown to be performed by the proprotein convertase (PC) family members FURIN, PACE4, PC5/6 (isoforms A and B), and PC7 in overexpression experiments [6]. However, FURIN was put forward as the physiological PC for processing of the proIR in the secretory pathway and PACE4 at the cell surface when FURIN activity is reduced [6]. In colorectal cell lines and in mouse mammary gland tissue, genetic ablation of Furin indeed blocked proIR processing, suggesting non-redundant cleavage by FURIN [7,8].…”

Section: Introductionmentioning

confidence: 99%

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

Coppola

Brouwers

Meulemans

et al. 2021

IJMS

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The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific Furin knockout (βFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in βFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis.

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The Paired Basic Amino Acid-cleaving Enzyme 4 (PACE4) Is Involved in the Maturation of Insulin Receptor Isoform B

Cited by 23 publications

References 51 publications

Insulin and Insulin Receptors in Adipose Tissue Development

Insulin and Insulin Receptors in Adipose Tissue Development

Insulin Resistance: Any Role in the Changing Epidemiology of Thyroid Cancer?

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

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