Fig. 9

A model for the effect of type I receptor competition on the balance of signaling to Smad2/3 vs. Smad1/5/8. All receptors are designated as homodimers. Competition for ACVR2A (blue) is shown to demonstrate the principle. ACVR2A can form complexes with type I receptors that signal to Smad2/3 (e.g., ALK4, yellow) or Smad1/5/8 (e.g., ALK2, green). Excess of a type I receptor which signals to Smad1/5/8 (e.g., ALK2) can compete with ALK4 (which signals to Smad2/3) for binding to ACVR2A, and vice versa. In the case of ActA (left), ligand binding enhances heterocomplex formation with either ALK4 or ALK2 (thicker black arrows), while only the first induces pSmad2/3 formation. The competition by ALK2 inhibits ACVR2A/ALK4 complex formation, thus reducing ActA-mediated signaling to Smad2/3. In an analogous manner, binding of ALK4 to ACVR2A interferes with ACVR2A/ALK2 association (right), inhibiting BMP9-mediated signaling to Smad1/5/8