ArticleJournal of cell science2012
APPL1 regulates basal NF-κB activity by stabilizing NIK.
Article in Journal of cell science, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- Increased Neuronal Expression of the Early Endosomal Adaptor APPL1 Replicates Alzheimer's Disease-Related Endosomal and Synaptic Dysfunction with Cholinergic Neurodegeneration.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Review
- Regulation of Bcl-XL by non-canonical NF-κB in the context of CD40-induced drug resistance in CLL.Cell death and differentiation · 2021Article
- The NLRP3-inflammasome as a sensor of organelle dysfunction.The Journal of cell biology · 2020Review
- Elevated pre-activation basal level of nuclear NF-κB in native macrophages accelerates LPS-induced translocation of cytosolic NF-κB into the cell nucleus.Scientific reports · 2019Article
- Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome.Scientific reports · 2019Article
- Cell-free formation and interactome analysis of caveolae.The Journal of cell biology · 2018Article
- Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer's Disease.Free radical biology & medicine · 2018Review
- Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Review
- APPL1 prevents pancreatic beta cell death and inflammation by dampening NFκB activation in a mouse model of type 1 diabetes.Diabetologia · 2017Article
- Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease.Molecular psychiatry · 2016Article
- Expression of APPL1 is correlated with clinicopathologic characteristics and poor prognosis in patients with gastric cancer.Current oncology (Toronto, Ont.) · 2016Article
- APPL proteins promote TGFβ-induced nuclear transport of the TGFβ type I receptor intracellular domain.Oncotarget · 2016Article
- Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study.Molecular & cellular proteomics : MCP · 2015Article
- APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments.The Journal of cell biology · 2015Article
- Protein-Binding Function of RNA-Dependent Protein Kinase Promotes Proliferation through TRAF2/RIP1/NF-κB/c-Myc Pathway in Pancreatic β cells.Molecular medicine (Cambridge, Mass.) · 2015Article
- Delivery of an miR155 inhibitor by anti-CD20 single-chain antibody into B cells reduces the acetylcholine receptor-specific autoantibodies and ameliorates experimental autoimmune myasthenia gravis.Clinical and experimental immunology · 2014Article
- APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM.Cell death & disease · 2014Article
- Absence of Appl2 sensitizes endotoxin shock through activation of PI3K/Akt pathway.Cell & bioscience · 2014Article
- Multifunctional protein APPL2 contributes to survival of human glioma cells.Molecular oncology · 2013Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
APPL1 is a multifunctional adaptor protein that binds membrane receptors, signaling proteins and nuclear factors, thereby acting in endosomal trafficking and in different signaling pathways. Here, we uncover a novel role of APPL1 as a positive regulator of transcriptional activity of NF-κB under basal but not TNFα-stimulated conditions. APPL1 was found to directly interact with TRAF2, an adaptor protein known to activate canonical NF-κB signaling. APPL1 synergized with TRAF2 to induce NF-κB activation, and both proteins were necessary for this process and function upstream of the IKK complex. Although TRAF2 was not detectable on APPL endosomes, endosomal recruitment of APPL1 was required for its function in the NF-κB pathway. Importantly, in the canonical pathway, APPL1 appeared to regulate the proper spatial distribution of the p65 subunit of NF-κB in the absence of cytokine stimulation, since its overexpression enhanced and its depletion reduced the nuclear accumulation of p65. By analyzing the patterns of gene transcription upon APPL1 overproduction or depletion we found altered expression of NF-κB target genes that encode cytokines. At the molecular level, overexpressed APPL1 markedly increased the level of NIK, the key component of the noncanonical NF-κB pathway, by reducing its association with the degradative complex containing TRAF2, TRAF3 and cIAP1. In turn, high levels of NIK triggered nuclear translocation of p65. Collectively, we propose that APPL1 regulates basal NF-κB activity by modulating the stability of NIK, which affects the activation of p65. This places APPL1 as a novel link between the canonical and noncanonical machineries of NF-κB activation.
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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.