VASN

Vasorin (VASN) is a type I transmembrane glycoprotein that functions as a multivalent signaling modulator in vascular biology, autophagy, and cancer through distinct extracellular and intracellular mechanisms. Its extracellular domain, shed by ADAM17, acts as a soluble TGF-β trap whose binding affinity is tuned by ST3Gal1-mediated sialylation, thereby attenuating TGF-β/Smad2/3 signaling in vascular smooth muscle cells and endothelial cells (PMID:15247411, PMID:21170088, PMID:30252131). VASN stabilizes Notch1 at the plasma membrane by competitively blocking Numb-mediated lysosomal degradation through its EGF-like domain, activating Notch signaling in glioma stem cells and endothelial cells, and also physically interacts with YAP to inhibit its phosphorylation, thereby co-activating YAP/TAZ-TEAD and PI3K/AKT pathways in multiple carcinomas (PMID:29198941, PMID:40297901, PMID:36468780). At the lysosome, VASN interacts with MTOR and STK11IP, displacing STK11IP from V-ATPase to promote lysosomal acidification, autophagic flux, and mitophagy, linking TGF-β-induced VASN to autophagy regulation in erythropoiesis and KRAS-driven tumorigenesis (PMID:41630427).

1. 2004 High

   The identification of VASN as a TGF-β-binding transmembrane protein in vascular smooth muscle cells established its foundational role as a ligand trap that attenuates TGF-β signaling and limits injury-induced neointima formation.

   Evidence Signal sequence trap cloning, direct TGF-β pulldown, in vitro signaling assays, and adenoviral restoration in a rat carotid injury model

   PMID:15247411

   Open questions at the time

   • Mechanism by which VASN binds TGF-β at the structural level was not resolved
   • Whether the membrane-bound versus soluble form differed in function was unknown
2. 2010 High

   Demonstrating that ADAM17-mediated ectodomain shedding is required for VASN's TGF-β-inhibitory activity resolved the paradox of how a transmembrane protein acts as a soluble cytokine trap and linked metalloprotease regulation to TGF-β/EMT control.

   Evidence ADAM17 substrate screen, metalloprotease cleavage assay, comparison of membrane-bound vs. soluble VASN in TGF-β signaling and EMT readouts

   PMID:21170088

   Open questions at the time

   • Cleavage site on VASN not mapped at residue resolution
   • Regulation of ADAM17-dependent shedding in vivo not addressed
3. 2012 Medium

   Reporter knock-in and partial deletion studies in mice established VASN's developmental expression pattern in vasculature, skeleton, kidney, and lung, and revealed an anti-apoptotic role against TNFα- and hypoxia-induced cell death.

   Evidence Vasn(lacZ) knock-in reporter, whole-mount in situ hybridization, partial coding deletion with TNFα apoptosis assay in hepatocytes

   PMID:22426063

   Open questions at the time

   • Mitochondrial localization reported but mechanism of mitochondrial targeting not defined
   • Full knockout phenotype not described in this study
4. 2017 High

   Discovery that VASN stabilizes Notch1 by competitively blocking Numb binding revealed a second major signaling axis — independent of TGF-β trapping — through which VASN sustains glioma stem cell self-renewal under hypoxia.

   Evidence Reciprocal Co-IP, Numb competition assay, shRNA knockdown, HIF-1α/STAT3 co-activator studies, and mouse glioblastoma survival model

   PMID:29198941

   Open questions at the time

   • Whether Notch1 stabilization occurs in non-cancer vascular cells was untested
   • Domain on VASN required for Numb displacement was not mapped
5. 2019 High

   Characterization of ST3Gal1-dependent sialylation as a negative regulator of VASN–TGF-β1 binding affinity introduced post-translational glycan editing as a tuning mechanism for VASN's trap function and connected it to angiogenesis via HUVEC tube formation.

   Evidence LC-MS/MS O-glycan analysis, neuraminidase and ST3GAL1 siRNA, quantitative TGF-β1 binding assay, Smad2/3 phosphorylation, HUVEC tubulogenesis

   PMID:30252131

   Open questions at the time

   • In vivo relevance of sialylation-dependent modulation not tested
   • Whether N-glycans also regulate VASN function was not addressed
6. 2019 Medium

   Linking VASN to YAP/TAZ pathway activation in thyroid and later prostate cancer broadened its oncogenic repertoire beyond TGF-β and Notch, though the direct mechanism was initially unclear.

   Evidence siRNA knockdown with YAP/TAZ and EMT marker Western blots in thyroid cancer; YAP overexpression rescue in prostate cancer cells

   PMID:31312369 PMID:32633347

   Open questions at the time

   • No direct VASN–YAP physical interaction demonstrated in these studies
   • Whether YAP/TAZ activation is independent of or downstream of Notch/TGF-β was unknown
7. 2023 High

   Co-immunoprecipitation of VASN with YAP in colorectal cancer cells, combined with demonstration that VASN inhibits YAP phosphorylation and activates PTEN/PI3K/AKT, established VASN as a direct physical regulator of Hippo pathway output.

   Evidence Reciprocal Co-IP, co-immunofluorescence, YAP phosphorylation Western blot, CTGF readout, YAP knockdown rescue in colorectal cancer cells

   PMID:36468780

   Open questions at the time

   • Binding domain on VASN responsible for YAP interaction not mapped
   • Whether VASN–YAP interaction occurs at the membrane or in the cytosol is unresolved
8. 2025 High

   Conditional endothelial knockout of VASN and identification of its EGF-like domain as the Notch1-interacting module unified the TGF-β-independent vascular role: KLF15-driven VASN expression in endothelium activates Notch1 signaling to suppress angiogenesis, and synthetic EGF-like domain peptides recapitulate this activity.

   Evidence Cdh5-Cre EC-specific KO of KLF15 and VASN, ChIP-seq, retinal angiogenesis assay, tumor vascularization, Co-IP, γ-secretase inhibitor epistasis, EGF-like domain peptide treatment

   PMID:40297901

   Open questions at the time

   • Whether shed VASN also activates Notch1 in trans is not determined
   • Structural basis of EGF-like domain–Notch1 interaction unresolved
9. 2025 High

   Discovery that VASN localizes to lysosomes and displaces STK11IP from MTOR and V-ATPase to promote lysosomal acidification and autophagic flux revealed a mechanistically distinct intracellular function connecting TGF-β-induced VASN to autophagy, mitophagy, erythropoiesis, and KRAS-driven cancer.

   Evidence LysoIP, Co-IP competition assay (VASN–STK11IP–MTOR–V-ATPase), CLEM/FIB-SEM, lysosomal acidification assay, autophagy/mitophagy flux, VASN KO, TGF-β induction

   PMID:41630427

   Open questions at the time

   • How VASN is trafficked from the plasma membrane to lysosomes is not defined
   • Whether lysosomal VASN function is independent of its extracellular shedding is unclear
   • Relevance of lysosomal VASN to vascular biology not yet tested
10. 2025 Medium

    VASN knockout mice develop pathological cardiac hypertrophy progressing to fibrosis, establishing a non-redundant cardioprotective role in vivo and linking VASN loss to inflammatory cytokine upregulation and ECM remodeling.

    Evidence VASN global KO mice, histology, RNA-seq, qPCR, echocardiography

    PMID:39898320

    Open questions at the time

    • Which VASN signaling axis (TGF-β, Notch, YAP, lysosomal) mediates cardioprotection is unknown
    • Cell-type-specific contributions (cardiomyocyte vs. fibroblast vs. endothelial) not dissected

• Key unresolved questions include the structural basis of VASN's multi-ligand interactions (TGF-β, Notch1, YAP, STK11IP), how VASN partitions between plasma membrane shedding and lysosomal trafficking, and whether its distinct signaling outputs (TGF-β trapping, Notch1 stabilization, YAP activation, V-ATPase derepression) operate independently or are coordinated in a cell-type-specific manner.
• No high-resolution structural data for VASN or its complexes
• Trafficking itinerary from ER to plasma membrane to lysosome not mapped
• Relative contribution of each signaling axis in physiological vs. pathological contexts remains undefined