BPS2026 – Vasorin modulates ligand-dependent assembly of TGFβ receptor complexes in live cells

Oncogenic TGFβ signaling depends on ligand-induced assembly of TGFβ type I (TβRI) and type II (TβRII) receptors. However, the biophysical principles governing receptor multimerization and the role of regulatory factors such as membrane density, ligand, or coreceptors, remains poorly defined. Whether TβRI and TβRII form homodimers that later assemble into heteromeric complexes has not been well-established, and previous studies using biochemical and single-molecule approaches have produced conflicting results. Some reports suggest that homodimers exist in resting cells, while others propose that assembly occurs only after ligand stimulation. Such conflicting observations suggest that receptor assembly may not be solely determined by ligand binding but could also be shaped by regulatory factors such as membrane density, ligand availability, or co-receptors like vasorin (VASN). Using pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS), we quantitatively examined receptor interactions at native membrane densities. Our study reveals that TβRI forms ligand-independent homodimers at intermediate expression levels, while TβRII dimerizes only upon ligand binding. We also observed that VASN modulated TGF beta receptor interactions following different treatment conditions. These findings clarify the stoichiometry and assembly dynamics of TGFβ receptors and identify VASN as a hypoxia-responsive modulator. This work integrates live-cell biophysics with cancer biology to reveal a mechanism through which hypoxia enhances invasive behavior in GBM