TGFβ signaling systems are prone to inhibition and ligand competition by coreceptor
Wisam A Fares1, Kevin A Janes1,2,3
1Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, U.S.A.
Abstract:
Transforming growth factor-β (TGFβ) ligands and receptors interact with overlapping selectivity to form different signaling complexes. This many-to-many wiring provides versatility in how ligands are perceived and cell types become activated, but the systems-level impact of coreceptors, which bind TGFβ ligands yet do not signal, remains unresolved. We examined the role of canonical surface-bound coreceptors by numerically simulating TGFβ ligand-receptor systems of increasing complexity and pairing results with single-cell measurements in acutely stimulated cells. Using sampled combinations of biologically plausible rate parameters and initial conditions, we find that coreceptors inhibit downstream signaling six times more often than they promote it, and the models reconcile this inhibitory bias with the prevailing view that coreceptors either promote or inhibit signaling. In multi-ligand systems, coreceptor inhibition causes stimuli to be perceived differently by altering competition, and this threshold is confirmed in cells engineered to induce a single coreceptor heterogeneously. Coreceptors are among the most variably expressed components of TGFβ signaling, suggesting that cells exploit coreceptors as a way to switch active ligand-receptor landscapes with a single gene.
Insights
Coreceptors significantly inhibit Transforming Growth Factor-beta (TGFβ) signaling more than they promote it. This finding explains how cells fine-tune TGFβ responses by altering ligand-receptor interactions.
Area of Science:
- Cellular biology
- Systems biology
- Biophysics
Background:
- Transforming Growth Factor-beta (TGFβ) signaling involves complex ligand-receptor interactions.
- The role of coreceptors, which bind TGFβ ligands but do not signal, remains unclear.
- Understanding coreceptor function is crucial for deciphering TGFβ pathway versatility.
Purpose of the Study:
- To investigate the systems-level impact of canonical surface-bound coreceptors on TGFβ signaling.
- To determine whether coreceptors predominantly promote or inhibit TGFβ pathway activation.
- To explore how coreceptors influence signal perception in multi-ligand environments.
Main Methods:
- Numerical simulations of TGFβ ligand-receptor systems with increasing complexity.
- Pairing simulation results with single-cell measurements in acutely stimulated cells.
- Utilizing biologically plausible rate parameters and initial conditions for simulations.
Main Results:
- Coreceptors inhibit downstream TGFβ signaling six times more often than they promote it.
- Models reconcile this inhibitory bias with existing knowledge of coreceptor function.
- Coreceptor-mediated inhibition alters ligand competition, leading to differential stimulus perception.
- This threshold effect was confirmed in cells engineered for heterogeneous coreceptor expression.
Conclusions:
- Coreceptors play a predominantly inhibitory role in TGFβ signaling.
- Cells can exploit the variable expression of coreceptors to modulate TGFβ signal landscapes.
- Coreceptors act as key regulators, enabling cells to switch active ligand-receptor interactions.
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