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. Author manuscript; available in PMC: 2022 Feb 1.
Published in final edited form as: Cytokine Growth Factor Rev. 2020 Oct 6;57:39–54. doi: 10.1016/j.cytogfr.2020.09.003

Figure 4. TGF-β family receptor promiscuity and functional outcomes of ligand competition.

Figure 4.

The promiscuous nature of TGF-β ligand-receptor interactions can be visualized by superimposing ligand-receptor complexes. Specifically, the knuckle region of BMP-9 (4FAO 184) was used as template and other ligand-ActRIIA/B complexes were superimposed, including GDF11 (6MAC, beige, 18), BMP-2 ( 2H62, bright orange, 44), Activin A (1NYU, yellow, 18), and BMP7 (1LX5, olive, 185). A. The BMP-9 complex is shown as surface model with BMP-9 colored blue, ALK1 colored grey, and ActRIIB colored orange. The superimposed type II receptor ECDs including ActRIIB in the BMP-9 complex are shown for one protomer as Cα-traces/sticks. The figure to the right represents an orthogonal view of the left image. Ligand competition in the TGF-β family and various possible consequences for R-SMAD-mediated signaling are shown. B. Schematic of canonical BMP/GDF signaling. BMP/GDF (blue) bind type II and type I receptors (light and dark blue, respectively) and activate the SMAD1/5/8 pathway. C. An antagonistic ligand, such as inhibin (red), competes with BMP/GDF for binding to type II receptors but does not recruit type I receptors or activate R-SMAD signaling. Inhibin is an antagonist, as it suppresses BMP/GDF mediated SMAD1/5/8. D. A high affinity ligand, such as activin or myostatin (green), competes for binding to type II receptors and recruits a different type I receptor. Activin/myostatin suppress BMP/GDF mediated SMAD1/5/8 signaling and activate the SMAD2/3 branch causing a switch in signaling pathway use. E. A BMP/GDF ligand (grey) competes with another BMP/GDF (blue) for type II receptor binding and activates SMAD1/5/8 signaling. Different combinations of BMP/GDFs will activate SMAD1/5/8 signaling with distinctive potencies that can be additive, subtractive, or other. F. A high affinity ligand (green), such as activin A, forms a non-signaling complex (NSC) with type II receptors (ActRIIA/B) and the type I receptor ALK2 to inhibit BMP/GDF. Activin A blunts BMP/GDF mediated SMAD1/5/8 signaling in this context.