LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes

Herdenberg, Carl; Mutie, Pascal M.; Billing, Ola; Abdullah, Ahmad; Strawbridge, Rona J.; Dahlman, Ingrid; Tuck, Simon; Holmlund, Camilla; Arner, Peter; Henriksson, Roger; Franks, Paul W.; Hedman, Håkan

doi:10.1038/s42003-020-01613-w

Cited by 17 publications

(33 citation statements)

References 76 publications

(102 reference statements)

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“…In addition to glucose parameters, body weight was significantly correlated with sLRIG2 levels. Herdenberg et al demonstrated reduced adipocyte differentiation in LRIG null mouse embryonic fibroblasts (MEFs) (19). LRIG2 expression levels were also found to be upregulated during the adipogenic process, indicating that LRIG2 may contribute to adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…However, in a recent study, an EGFR-independent role of LRIG was discovered. Herdenberg et al suggested that the LRIG1 protein is a regulator of bone morphogenetic protein (BMP) signaling, and LRIG1 gene variants were associated with a decreased risk of type 2 diabetes (19). The possibility that LRIG2 participates in metabolic regulation in a different manner than a receptor tyrosine kinase regulator cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…There has been very little research that explores the role of LRIG in metabolism. However, a recent study indicated the association between LRIG1 variant and risk of type 2 diabetes (19). In the present study, the usefulness of serum soluble LRIG2 (sLRIG2) as an EGFR-related diagnostic biomarker of type 2 diabetes was evaluated.…”

Section: Introductionmentioning

confidence: 95%

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Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus

Kim¹,

Joung²,

Lee³

et al. 2021

Ann Transl Med

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Background: Early diagnosis and treatment of type 2 diabetes can delay the onset of microvascular and macrovascular complications. Therefore, the identification of a novel biomarker for diagnosing diabetes is necessary. In the present study, the role of serum soluble leucine-rich repeats and immunoglobulin like domains 2 (sLRIG2) was investigated as a diagnostic biomarker of type 2 diabetes.Methods: A total of 240 subjects with newly diagnosed type 2 diabetes (n=80), prediabetes (n=80), or normal glucose tolerance (NGT; n=80) were included in this study. The fasting serum sLRIG2 level was measured using a quantitative sandwich enzyme immunoassay technique with an enzyme-linked immunosorbent assay (ELISA). Serum sLRIG2 levels were compared among the three groups, and the associations of serum sLRIG2 levels with clinical variables were investigated.Results: Serum sLRIG2 levels were significantly higher in subjects with type 2 diabetes (16.7±8.0 ng/mL) than in subjects without diabetes (NGT group: 12.3±5.3 ng/mL, P<0.001; prediabetes group: 13.2±5.8 ng/mL, P=0.002). Glycosylated hemoglobin (HbA1c: r=0.378, P<0.001) and blood glucose (fasting: r=0.421, P<0.001;2-hour postprandial: r=0.433, P<0.001) correlated more strongly with sLRIG2 than any other clinical variables. Conclusions:The serum sLRIG2 levels correlated with glucose parameters; thus, sLRIG2 might be a novel diagnostic biomarker for type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus

Kim¹,

Joung²,

Lee³

et al. 2021

Ann Transl Med

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“…Recently, LRIG proteins have been shown to be evolutionarily conserved regulators of both lipid metabolism and BMP signalling ( Hedman and Henriksson, 2007 ; Herdenberg et al, 2021 ). Thus, the presence of LRIG levels may be a requirement not only to suppress EGFR signalling, but also to support BMP signalling.…”

Section: Introductionmentioning

confidence: 99%

Lrig1 regulates the balance between proliferation and quiescence in glioblastoma stem cells

Ferguson

Blin²,

Alfazema³

et al. 2022

Front. Cell Dev. Biol.

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Patients with glioblastoma (GBM) face a dismal prognosis. GBMs are driven by glioblastoma stem cells (GSCs) that display a neural stem cell (NSC)-like phenotype. These glioblastoma stem cells are often in a quiescent state that evades current therapies, namely debulking surgery and chemo/radiotherapy. Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signalling across many tissue stem cells. Leucinerichrepeats and immunoglobulin-like domains 1 is highly expressed in gliomas and importantly, polymorphisms have been identified that are risk alleles for patients with GBM, which suggests some functional role in gliomagenesis. We previously reported that Lrig1 is a gatekeeper of quiescence exit in adult mouse neural stem cells, suppressing epidermal growth factor receptor signalling prior to cell cycle re-entry. Here, we perform gain- and loss-of-function studies to understand the function of Leucine-rich repeats and immunoglobulin-like domains 1 in glioblastoma stem cells. Using a novel mouse glioblastoma stem cell model, we show that genetic ablation of Lrig1 in cultured GBM stem cells results in higher proliferation and loss of quiescence. In vivo, mice transplanted with glioblastoma stem cells lacking Lrig1 display lower survival compared to Leucine-rich repeats and immunoglobulin-like domains 1 WT glioblastoma stem cells, with tumours displaying increased proportions of proliferative cells and reduced quiescent subpopulations. In contrast, Lrig1 overexpression in mouse glioblastoma stem cells results in enhanced quiescence and reduced proliferation, with impaired tumour formation upon orthotopic transplantation. Mechanistically, we find that Lrig1. 1-null cells have a deficiency in BMP signalling responses that may underlie their lack of responsiveness to quiescence cues in vivo. These findings highlight important roles for Leucine-rich repeats and immunoglobulin-like domains 1 in controlling responsiveness to both epidermal growth factor receptor and BMPR signalling, and hence the proportions of quiescent and proliferative subpopulations in GBMs.

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“…The exact mechanism behind the tumor suppressive functions of LRIG1 has yet to be determined. However, it has been shown that LRIG1 antagonizes the signaling of several oncogenic receptor tyrosine kinases [12] and enhances cellular sensitivity to bone morphogenetic protein (BMP) [13,14]. Intriguingly, LRIG1 can be shed from cells in a bioactive form, suggesting a possible paracrine function [15].…”

Section: Introductionmentioning

confidence: 99%

Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma

et al. 2022

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Background: Ovarian carcinoma is the eighth most common cause of cancer death in women worldwide. The disease is predominantly diagnosed at a late stage. This contributes to high recurrence rates, eventually leading to the development of treatment-resistant disease. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor and regulator of growth factor signaling. LRIG1 levels have not been investigated in human plasma previously. Materials and methods: A quantitative LRIG1-specific single molecule array assay was developed and validated. LRIG1 levels were quantified in plasma samples from 486 patients with suspicious ovarian masses.Results: Among women with ovarian carcinoma, LRIG1 levels were significantly elevated compared to women with benign or borderline type tumors. High LRIG1 plasma levels were associated with worse overall survival and shorter disease-free survival both in the group of all malignant cases and among the stage 3 cases only. LRIG1 was an independent prognostic factor in patients with stage 3 ovarian carcinoma. Conclusion: LRIG1 plasma levels were elevated in patients with ovarian carcinoma, and high levels were associated with poor prognosis, suggesting that LRIG1 might be an etiologic factor and a potentially useful biomarker in ovarian carcinoma.

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LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes

Cited by 17 publications

References 76 publications

Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus

Soluble LRIG2 is a potential biomarker for type 2 diabetes mellitus

Lrig1 regulates the balance between proliferation and quiescence in glioblastoma stem cells

Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma

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