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Molecular and physiological functions of LRIG proteins and netrin-1 in health and disease
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.ORCID-id: 0000-0001-8849-6810
2021 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family has three members, LRIG1, LRIG2, and LRIG3, that encode three structurally similar transmembrane proteins. LRIG1 is a receptor tyrosine kinase regulator, tumor suppressor, and stem cell marker in the skin, intestine, and brain. LRIG2 and LRIG3 have been less studied but shown to interact with LRIG1. The different roles and mechanisms of action of LRIG proteins have not yet been fully elucidated. In Caenorhabditis elegans (C. elegans), the LRIG homolog SMA-10 regulates bone morphogenetic protein (BMP) signaling; however, this function has not been demonstrated for mammalian LRIG proteins. In mice, the gene encoding the neurodevelopmental guidance cue netrin-1, Ntn1, interacts with Lrig3 in inner ear development. The physical interactions between LRIG proteins and other proteins are mostly unknown. 

Here, we describe an LRIG1-centered protein interaction network that regulates growth factor receptor levels. The LRIG1 interactome comprised LRIG2 and LRIG3 as well as many unanticipated proteins. 

An unbiased pathological examination of female mice with different Lrig3 genotypes (homozygous, heterozygous, or knockout) revealed a reduced incidence of spontaneous fatty liver and lymphocytic hyperplasia of the spleen in Lrig3-null mice. Female Lrig3-null mice also had a lower incidence of microvesicular cytoplasm in the liver after eight weeks on a high-fat diet. 

To further explore the molecular and physiological functions of LRIG proteins, we generated Lrig-null (Lrig1-/-;Lrig2-/-;Lrig3-/-) mouse embryonic fibroblasts (MEFs), which displayed a deficiency in adipogenesis caused by impaired BMP signaling. LRIG1 and LRIG3, but not LRIG2, sensitized cells to BMP and rescued the adipogenesis deficiency in Lrig-null MEFs. In C. elegans, the LRIG homolog sma-10 was needed for proper lipid accumulation. By analyzing data from the UK Biobank and GENiAL cohort, we found that certain LRIG1 gene variants were associated with a higher body mass index (BMI) yet protected against type 2 diabetes. This effect was probably mediated by altered adipocyte morphology. 

CRISPR/Cas9-mediated ablation of Ntn1 revealed that the BMP-promoting function of LRIG1 and LRIG3 was opposed by netrin-1, which functioned as an inhibitor of BMP signaling via its receptor neogenin.

In summary, the present thesis describes a novel LRIG protein interaction network, the regulation of BMP signaling by LRIG proteins and netrin-1, and an important function of LRIG proteins in regulating fat metabolism with implications for human metabolic health.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå Universitet , 2021. , s. 68
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2150
Nyckelord [en]
LRIG, Netrin-1, LRIG1, LRIG2, LRIG3, Type 2 diabetes
Nationell ämneskategori
Cancer och onkologi Endokrinologi och diabetes Cellbiologi
Forskningsämne
onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-186845ISBN: 978-91-7855-621-2 (tryckt)ISBN: 978-91-7855-622-9 (digital)OAI: oai:DiVA.org:umu-186845DiVA, id: diva2:1587443
Disputation
2021-09-17, Bergasalen, Norrlands Universitetssjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Anmärkning

The thesis will be defended via zoom link: https://umu.zoom.us/j/68144103623

Tillgänglig från: 2021-08-27 Skapad: 2021-08-24 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
Delarbeten
1. A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors
Öppna denna publikation i ny flik eller fönster >>A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors
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2018 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, nr 9, s. 3421-3435Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a tumor suppressor and a negative regulator of several receptor tyrosine kinases. The molecular mechanisms by which LRIG1 mediates its tumor suppressor effects and regulates receptor tyrosine kinases remain incompletely understood. Here, we performed a yeast two-hybrid screen to identify novel LRIG1-interacting proteins and mined data from the BioPlex (biophysical interactions of ORFeome-based complexes) protein interaction data repository. The putative LRIG1 interactors identified in the screen were functionally evaluated using a triple co-transfection system in which HEK293 cells were co-transfected with platelet-derived growth factor receptor α, LRIG1, and shRNAs against the identified LRIG1 interactors. The effects of the shRNAs on the ability of LRIG1 to down-regulate platelet-derived growth factor receptor α expression were evaluated. On the basis of these results, we present an LRIG1 protein interaction network with many newly identified components. The network contains the apparently functionally important LRIG1-interacting proteins RAB4A, PON2, GAL3ST1, ZBTB16, LRIG2, CNPY3, HLA-DRA, GML, CNPY4, LRRC40, and LRIG3, together with GLRX3, PTPRK, and other proteins. In silico analyses of The Cancer Genome Atlas data sets revealed consistent correlations between the expression of the transcripts encoding LRIG1 and its interactors ZBTB16 and PTPRK and inverse correlations between the transcripts encoding LRIG1 and GLRX3. We further studied the LRIG1 function–promoting paraoxonase PON2 and found that it co-localized with LRIG1 in LRIG1-transfected cells. The proposed LRIG1 protein interaction network will provide leads for future studies aiming to understand the molecular functions of LRIG1 and the regulation of growth factor signaling.

Ort, förlag, år, upplaga, sidor
The American Society for Biochemistry and Molecular Biology, 2018
Nyckelord
LRIG1, PDGFRA, PON2, PTPRK, ZBTB16, platelet-derived growth factor-C (PDGF-C), protein expression, protein-protein interaction, receptor tyrosine kinase, yeast two-hybrid
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-147386 (URN)10.1074/jbc.M117.807487 (DOI)000426562800032 ()29317492 (PubMedID)2-s2.0-85042930541 (Scopus ID)
Tillgänglig från: 2018-05-02 Skapad: 2018-05-02 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
2. Lrig3 affects liver fat accumulation in female mice
Öppna denna publikation i ny flik eller fönster >>Lrig3 affects liver fat accumulation in female mice
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:umu:diva-186829 (URN)
Tillgänglig från: 2021-08-24 Skapad: 2021-08-24 Senast uppdaterad: 2024-07-02
3. LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes
Öppna denna publikation i ny flik eller fönster >>LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes
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2021 (Engelska)Ingår i: Communications Biology, E-ISSN 2399-3642, Vol. 4, nr 1, artikel-id 90Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-beta) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease. Herdenberg et al. show that adipogenesis and BMP signaling are altered in mouse cells deficient in LRIG (Leucine-rich repeats and immunoglobulin-like domains) proteins. They find that mutant LRIG/sma-10 variant worms exhibit lipid storage defects and that human LRIG1 variants are associated with higher body mass index, yet protect against type 2 diabetes. This study suggests an evolutionarily conserved role of LRIG proteins for lipid metabolism and BMP signaling.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2021
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-180823 (URN)10.1038/s42003-020-01613-w (DOI)000613509200014 ()33469151 (PubMedID)2-s2.0-85099541477 (Scopus ID)
Tillgänglig från: 2021-02-26 Skapad: 2021-02-26 Senast uppdaterad: 2024-07-02Bibliografiskt granskad
4. Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling
Öppna denna publikation i ny flik eller fönster >>Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling
2021 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikel-id 8585Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Netrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2021
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-182911 (URN)10.1038/s41598-021-87949-7 (DOI)000644194200021 ()33883596 (PubMedID)2-s2.0-85104705931 (Scopus ID)
Tillgänglig från: 2021-05-28 Skapad: 2021-05-28 Senast uppdaterad: 2024-07-02Bibliografiskt granskad

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Herdenberg, Carl

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