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. 2020 Jan 21;130(2):582–589. doi: 10.1172/JCI133678

Figure 2. Canonical signaling by SMAD2/3-pathway ligands.

Figure 2

Ligand binding leads to multimerization of type I and type II receptors, in some cases with the assistance of a coreceptor (type III). Activated type I receptors phosphorylate SMAD2 or SMAD3, which dissociate from type I receptor and oligomerize with SMAD4 to form a heterodimeric complex that translocates into the nucleus, thereby regulating the cellular response. SMAD7, whose stability is regulated by microRNAs (miR-21), can exert feedback effects on the pathway through multiple mechanisms, including inhibition of SMAD2/3 activation. See text for details. While TGF-β, GDF11, and activin B have been implicated in ineffective hematopoiesis, additional SMAD2/3-pathway ligands are likely involved. Note that dimeric ligands and receptors are depicted here as monomers for simplicity. ALK4/5/7, activin receptor–like kinases 4, 5, and 7.