ArticleCell discovery2023
VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling.
Article in Cell discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway.Nature communications · 2026Article
- Site-specific glycosylation of Sec24D and myoferlin recruit ERGIC to ER exit sites for collagen trafficking.Nature communications · 2026Article
- Label-free imaging of intracellular structures in living mammalian cells via external apodization phase-contrast microscopy.The FEBS journal · 2026Article
- Integrative Omics Defines Metabolic Biomarkers and Genetic Regulatory Mechanisms of Mortality Risk.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Spatiotemporal Expression of IRS-1 During Brain Development and its Role in Neural Stem Cell Differentiation.Neuromolecular medicine · 2025Article
- PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy.Journal of biomedical science · 2025Article
- KPNA3 regulates histone locus body formation by modulating condensation and nuclear import of NPAT.The Journal of cell biology · 2025Article
- Crosstalk Between Phase-Separated Membraneless Condensates and Membrane-Bound Organelles in Cellular Function and Disease.Advances in experimental medicine and biology · 2025Review
- Pathogenic mechanisms of amyotrophic lateral sclerosis-linked VAPB P56S mutation in the degeneration of corticospinal motor neurons.Ageing and neurodegenerative diseases · 2025Article
- Mitochondria-associated endoplasmic reticulum membranes tethering protein VAPB-PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy.CNS neuroscience & therapeutics · 2024Article
- The Drosophila tumour suppressor Lgl and Vap33 activate the Hippo pathway through a dual mechanism.Journal of cell science · 2024Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
The scaffold protein IRS-1 is an essential node in insulin/IGF signaling. It has long been recognized that the stability of IRS-1 is dependent on its endomembrane targeting. However, how IRS-1 targets the intracellular membrane, and what type of intracellular membrane is actually targeted, remains poorly understood. Here, we found that the phase separation-mediated IRS-1 puncta attached to endoplasmic reticulum (ER). VAPB, an ER-anchored protein that mediates tethers between ER and membranes of other organelles, was identified as a direct interacting partner of IRS-1. VAPB mainly binds active IRS-1 because IGF-1 enhanced the VAPB-IRS-1 association and replacing of the nine tyrosine residues of YXXM motifs disrupted the VAPB-IRS-1 association. We further delineated that the Y745 and Y746 residues in the FFAT-like motif of IRS-1 mediated the association with VAPB. Notably, VAPB targeted IRS-1 to the ER and subsequently maintained its stability. Consistently, ablation of VAPB in mice led to downregulation of IRS-1, suppression of insulin signaling, and glucose intolerance. The amyotrophic lateral sclerosis (ALS)-derived VAPB P56S mutant also impaired IRS-1 stability by interfering with the ER-tethering of IRS-1. Our findings thus revealed a previously unappreciated condensate-membrane contact (CMC), by which VAPB stabilizes the membraneless IRS-1 signalosome through targeting it to ER membrane.
Identifiers
What Socratic holds
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 Socratic graph.