ArticleMolecular neurobiology2021
APP Binds to the EGFR Ligands HB-EGF and EGF, Acting Synergistically with EGF to Promote ERK Signaling and Neuritogenesis.
Article in Molecular neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- HBEGF/EGFR pathway activation by hUC-MSCs improves cognitive outcomes in anti-NMDAR encephalitis.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Epidermal growth factor receptor modulation for neural repair: Implications for neurodegenerative disease therapy.Frontiers in molecular neuroscience · 2026Review
- The pathogenic APP N-terminal Val225Ala mutation alters tau protein liquid-liquid phase separation and exacerbates synaptic damage.Molecular psychiatry · 2025Article
- Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Analysis of complete and incomplete response to neoadjuvant therapy in rectum cancer patients.Gastroenterology and hepatology from bed to bench · 2025Article
- Genetic overlap between Alzheimer's disease and immune-mediated diseases: an atlas of shared genetic determinants and biological convergence.Molecular psychiatry · 2024Article
- Cytokine polarized, alternatively activated bone marrow neutrophils drive axon regeneration.Nature immunology · 2024Article
- Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model.bioRxiv : the preprint server for biology · 2024Article
- Serum NfL and EGFR/NfL ratio mRNAs as biomarkers for phenotype and disease severity of myelin oligodendrocyte glycoprotein IgG-associated disease.Frontiers in immunology · 2024Article
- Genetic overlap between Alzheimer's disease and immune-mediated diseases: An atlas of shared genetic determinants and biological convergence.Research square · 2023Article
- Amyloid precursor protein and its interacting proteins in neurodevelopment.Biochemical Society transactions · 2023Review
- MiR-760 targets HBEGF to control cartilage extracellular matrix degradation in osteoarthritis.Journal of orthopaedic surgery and research · 2023Article
- Integration of multiple-omics data to reveal the shared genetic architecture of educational attainment, intelligence, cognitive performance, and Alzheimer's disease.Frontiers in genetics · 2023Article
- miR-4443/MMP2 suppresses the migration and invasion of trophoblasts through the HB-EGF/EGFR pathway in preeclampsia.Cell cycle (Georgetown, Tex.) · 2022Article
- Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer's disease.Neural regeneration research · 2022Review
- Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer's disease and normal physiology.Frontiers in cell and developmental biology · 2022Review
- Therapeutic Targeting of Repurposed Anticancer Drugs in Alzheimer's Disease: Using the Multiomics Approach.ACS omega · 2021Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The amyloid precursor protein (APP) is a transmembrane glycoprotein central to Alzheimer's disease (AD) with functions in brain development and plasticity, including in neurogenesis and neurite outgrowth. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are well-described neurotrophic and neuromodulator EGFR ligands, both implicated in neurological disorders, including AD. Pro-HB-EGF arose as a putative novel APP interactor in a human brain cDNA library yeast two-hybrid screen. Based on their structural and functional similarities, we first aimed to verify if APP could bind to (HB-)EGF proforms. Here, we show that APP interacts with these two EGFR ligands, and further characterized the effects of APP-EGF interaction in ERK activation and neuritogenesis. Yeast co-transformation and co-immunoprecipitation assays confirmed APP interaction with HB-EGF. Co-immunoprecipitation also revealed that APP binds to cellular pro-EGF. Overexpression of HB-EGF in HeLa cells, or exposure of SH-SY5Y cells to EGF, both resulted in increased APP protein levels. EGF and APP were observed to synergistically activate the ERK pathway, crucial for neuronal differentiation. Immunofluorescence analysis of cellular neuritogenesis in APP overexpression and EGF exposure conditions confirmed a synergistic effect in promoting the number and the mean length of neurite-like processes. Synergistic ERK activation and neuritogenic effects were completely blocked by the EGFR inhibitor PD 168393, implying APP/EGF-induced activation of EGFR as part of the mechanism. This work shows novel APP protein interactors and provides a major insight into the APP/EGF-driven mechanisms underlying neurite outgrowth and neuronal differentiation, with potential relevance for AD and for adult neuroregeneration.
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