After being secreted, the mature Nodal-Gdf3 heterodimer (red and blue) diffuses through the extracellular space to the surface of the receiving cell, where it binds a co-receptor called Oep (short for one-eyed-pinhead; Gritsman et al., 1999) and two receptors (Acvr1b and Acvr2; Wrana et al., 1994) to assemble a signaling complex. Within this complex, the Acvr2 receptors phosphorylate the Acvr1b receptors, which in turn phosphorylate proteins called Smad2 and Smad3 (Gu et al., 1998; Dubrulle et al., 2015). The phosphorylated Smad2 or Smad3 then forms a heterotrimer with Smad4 and accumulates in the nucleus, where it activates the transcription of various genes. The signaling complex shown here was first suggested by Calvanese et al. (2010).