ArticleScience signaling2015
Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake.
Article in Science signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 41 citations in OpenAlex.
- Fatty acids metabolic reprogramming and tumor microenvironment in pancreatic cancer: targeting pathways.Clinical and experimental medicine · 2026Review
- Emerging roles of the metabolic regulator 3-hydroxy-3-methylglutaryl coenzyme-CoA reductase in human cancers: From biology to therapeutics.Genes & diseases · 2026Review
- Regulation of sebaceous gland homeostasis and sebum secretion by the ERBB receptor family.iScience · 2026Review
- Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis.Cancer & metabolism · 2025Article
- Functional interaction between immune checkpoints and lipid metabolism in the development of arteriosclerosis obliterans.Frontiers in immunology · 2025Review
- Dysregulation of Cholesterol Homeostasis in Ovarian Cancer.Current oncology (Toronto, Ont.) · 2023Review
- Excavation and characterization of key circRNAs for milk fat percentage in Holstein cattle.Journal of animal science · 2023Article
- The IDI1/SREBP2 axis drives intrahepatic cholestasis and is a treatment target of San-Huang-Cai-Zhu formula identified by sequencing and experiments.Frontiers in pharmacology · 2023Article
- Inflammation Induced by Lipopolysaccharide and Palmitic Acid Increases Cholesterol Accumulation via Enhancing Myeloid Differentiation Factor 88 Expression in HepG2 Cells.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Regulation of low-density lipoprotein receptor expression in triple negative breast cancer by EGFR-MAPK signaling.Scientific reports · 2021Article
- Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.Theranostics · 2021Article
- Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy.Frontiers in oncology · 2021Review
- Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer.Cells · 2020Review
- Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice.International journal of molecular sciences · 2020Article
- Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Article
- Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy.Frontiers in oncology · 2020Review
- Lipoprotein Drug Delivery Vehicles for Cancer: Rationale and Reason.International journal of molecular sciences · 2019Review
- Anti-cancer effect of doxorubicin is mediated by downregulation of HMG-Co A reductase via inhibition of EGFR/Src pathway.Laboratory investigation; a journal of technical methods and pathology · 2019Article
- Alcohol Induces More Severe Fatty Liver Disease by Influencing Cholesterol Metabolism.Evidence-based complementary and alternative medicine : eCAM · 2019Article
- Neuregulin 4 Is a Novel Marker of Beige Adipocyte Precursor Cells in Human Adipose Tissue.Frontiers in physiology · 2019Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Cholesterol is a lipid that is critical for steroid hormone production and the integrity of cellular membranes, and, as such, it is essential for cell growth. The epidermal growth factor receptor (EGFR) family member ERBB4, which forms signaling complexes with other EGFR family members, can undergo ligand-induced proteolytic cleavage to release a soluble intracellular domain (ICD) that enters the nucleus to modify transcription. We found that ERBB4 activates sterol regulatory element binding protein-2 (SREBP-2) to enhance low-density lipoprotein (LDL) uptake and cholesterol biosynthesis. Expression of the ERBB4 ICD in mammary epithelial cells or activation of ERBB4 with the ligand neuregulin 1 (NRG1) induced the expression of SREBP target genes involved in cholesterol biosynthesis, including HMGCR and HMGCS1, and lipid uptake, LDLR, which encodes the LDL receptor. Addition of NRG1 increased the abundance of the cleaved, mature form of SREBP-2 through a pathway that was blocked by addition of inhibitors of PI3K (phosphatidylinositol 3-kinase) or dual inhibition of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, but not by inhibition of AKT or mTORC1. Pharmacological inhibition of the activity of SREBP site 1 protease or of all EGFR family members (with lapatinib), but not EGFR alone (with erlotinib), impaired NRG1-induced expression of cholesterol biosynthesis genes. Collectively, our findings indicated that activation of ERBB4 promotes SREBP-2-regulated cholesterol metabolism. The connections of EGFR and ERBB4 signaling with SREBP-2-regulated cholesterol metabolism are likely to be important in ERBB-regulated developmental processes and may contribute to metabolic remodeling in ERBB-driven cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.