VTN

VTN (vitronectin) is a secreted extracellular matrix glycoprotein that integrates protease regulation, integrin-mediated signaling, and immune modulation across tissue remodeling and cancer contexts (PMID:12437099, PMID:38773982). Its N-terminal somatomedin B (SMB) domain provides the major high-affinity binding site for PAI-1, with an additional low-affinity site in the C-terminal region that supports formation of larger PAI-1/VTN complexes, linking VTN to fibrinolytic control (PMID:12437099). VTN engages αV-containing integrins to drive downstream FAK/Src/ERK signaling that promotes cell migration and invasion; this axis is restrained by BPIFB1, which binds VTN, lowers its expression, and disrupts VTN–integrin αV complex formation (PMID:29123267), and VTN-driven FAK signaling acts downstream of FBLN2 to mediate TGF-β1-induced fibroblast proliferation and fibrosis (PMID:36608640). A discrete VTN fragment (aa 381–397) binds αV β6 integrin and competitively blocks αV β6-mediated TGF-β1 activation, modulating TGF-β1 bioavailability (PMID:33526813). In tumor biology, VTN promotes radioresistance through G2/M arrest, DNA repair, and ATM-Chk2/ATR-Chk1 activation (PMID:29568064), and tumor-secreted VTN binds C1qbp on tumor-associated macrophages to inhibit phagocytosis and promote M2-like polarization via Fc γRIIIA/CD16-induced Shp1 recruitment and reduced Syk phosphorylation (PMID:38773982). VTN also supports trophoblast migration, invasion, and tube formation, acting upstream of HEY1 to restrain autophagy (PMID:40516241).

1. 1999 Medium

   Established that VTN serves as an RGD-dependent integrin ligand recognized even by αV β3/αV β5-like receptors on Candida albicans, anchoring the principle that VTN-integrin adhesion is RGD-mediated and competable.

   Evidence Antibody and RGD-peptide inhibition adhesion assays with cytofluorimetric analysis of fungal integrin-like receptors

   PMID:10353874

   Open questions at the time

   • Did not map the human integrin signaling consequences of VTN binding
   • Cross-species/microbial system limits direct relevance to human VTN function
2. 2002 Medium

   Localized the major high-affinity PAI-1 binding site to the N-terminal SMB domain with a secondary C-terminal site, defining the structural basis for VTN's role in PAI-1 sequestration and fibrinolytic regulation.

   Evidence Domain-deletion and peptide-competition binding-site mapping

   PMID:12437099

   Open questions at the time

   • No quantitative affinities or structural model resolved here
   • Functional consequence for in vivo fibrinolysis not directly tested
3. 2017 Medium

   Identified BPIFB1 as a physical VTN partner that suppresses VTN expression and VTN-integrin αV complex assembly, revealing an upstream brake on VTN-driven FAK/Src/ERK pro-migratory signaling.

   Evidence Co-IP/MS partner identification plus western blot, immunofluorescence and migration/invasion assays in NPC cells

   PMID:29123267

   Open questions at the time

   • Mechanism by which BPIFB1 lowers VTN expression not defined
   • Single lab; physiological context outside NPC unclear
4. 2018 Medium

   Showed VTN confers radioresistance via cell-cycle arrest, DNA repair, and ATM-Chk2/ATR-Chk1 activation, extending VTN's role from adhesion into the DNA damage response and cell survival.

   Evidence Colony formation/survival assays, cell-cycle analysis, and pathway western blots with knockdown/overexpression after irradiation

   PMID:29568064

   Open questions at the time

   • Link between extracellular VTN and intracellular ATM/ATR activation not mechanistically bridged
   • Single tumor type
5. 2019 Low

   Placed VTN levels downstream of a miR-30c/PAI-1 axis, suggesting indirect transcriptional/post-transcriptional control of circulating VTN.

   Evidence miRNA transfection, luciferase, qRT-PCR, western blot and ELISA in SMCs and plasma

   PMID:31760103

   Open questions at the time

   • Regulation of VTN is indirect via PAI-1, not a direct VTN mechanism
   • Not independently confirmed
6. 2021 Medium

   Defined a VTN fragment (aa 381–397) as a competitive ligand for αV β6 that blocks αV β6-mediated TGF-β1 activation, identifying a fragment-level mechanism for tuning TGF-β1 bioavailability.

   Evidence Competition binding assay, TGF-β bioassay, flow cytometry and serum fragment quantification by nano-LC/MS-MS in human FLSs

   PMID:33526813

   Open questions at the time

   • Protease generating the 381–397 fragment in vivo not identified
   • Single lab and tissue context
7. 2022 Medium

   Identified FBLN2 as a VTN-binding negative regulator and showed VTN acts downstream of FBLN2 to drive TGF-β1-induced fibroblast fibrosis via FAK, integrating VTN into a defined fibrotic signaling cascade.

   Evidence Co-IP confirmation of FBLN2-VTN interaction plus functional rescue (VTN overexpression) with wound healing, CCK-8 and α-SMA readouts

   PMID:36608640

   Open questions at the time

   • Mechanism of FBLN2-mediated VTN downregulation unresolved
   • Single lab; two orthogonal methods only
8. 2024 High

   Revealed VTN as a tumor-derived anti-phagocytic signal acting through macrophage C1qbp, defining the VTN-C1qbp/FcγRIIIA-Shp1-Syk axis that suppresses phagocytosis and promotes M2 polarization.

   Evidence Genome-wide CRISPR screen followed by Co-IP, MS, immunofluorescence, flow cytometry and in vivo mouse tumor models

   PMID:38773982

   Open questions at the time

   • Structural basis of VTN-C1qbp binding not resolved
   • Whether SMB or integrin-binding regions mediate C1qbp engagement unknown
9. 2025 Medium

   Demonstrated VTN acts upstream of HEY1 to restrain autophagy in trophoblasts, supporting migration, invasion and tube formation, extending VTN signaling into a Notch-target/autophagy circuit.

   Evidence Functional assays in HTR8/SVneo, HUVEC and primary EVTs; transcriptomics; LC3II western blot; HEY1 epistasis and 3-MA rescue

   PMID:40516241

   Open questions at the time

   • How VTN signals to HEY1 mechanistically not defined
   • Direct VTN receptor in trophoblasts not identified
10. 2025 Low

    Showed VTN can act as a tumor suppressor in pancreatic cancer and synergize with anti-PD1 therapy, indicating context-dependent immune-regulatory roles.

    Evidence VTN knockdown/overexpression functional assays, syngeneic mouse model with anti-PD1, and single-cell RNA-seq

    PMID:40433359

    Open questions at the time

    • Mechanistic pathway placement for VTN's suppressive effect not defined
    • Opposite directionality to other cancer contexts unexplained

• How VTN's distinct functional regions (SMB/PAI-1 site, RGD integrin site, the 381–397 αV β6 fragment, and the C1qbp-binding region) are coordinately deployed across fibrinolysis, fibrosis, and immune evasion remains unresolved.
• No unifying structural model linking domain usage to context
• Receptor/partner selection rules across tissues unknown