Fig. 1. Schematic outline of the Nodal signaling pathway. (A) Nodal ligands are expressed as homodimeric proproteins, and can be cleaved extracellularly by the proprotein convertases Furin and Pace4. (B) Mature Nodal ligands, as well as Gdf1 and Gdf3, can bind to an EGF-CFC co-receptor in a complex with type I receptor (ALK4) and type II receptor (ActRII or ActRIIB) dimers. At least in some contexts, uncleaved Nodal proprotein can also signal through a similar receptor complex, although it is currently unknown whether such signaling is EGF-CFC dependent (Ben-Haim et al., 2006). (C) Cerberus and Lefty proteins are soluble antagonists that can interact with Nodal ligands; Lefty proteins can also interact with EGF-CFC co-receptors to inhibit their function. (D) Receptor activation leads to the phosphorylation of the type I receptor by the type II kinase, as well as phosphorylation of Smad2 (or Smad3). Activated Smad2 or Smad3 associates with Smad4 and translocates to the nucleus, whereas the receptor complex undergoes internalization into endosomes and can be targeted by Dpr2 for lysosomal degradation. (E) Within the nucleus, activated Smad2-Smad4 (or Smad3-Smad4) complexes interact with the winged-helix transcription factor FoxH1 or Mixer homeoproteins on target promoters, leading to transcriptional activation through interactions with ARC105 and the Mediator complex. Pathway activity can be inhibited by interaction of Drap1 with FoxH1 or by the Smad phosphatase Ppm1A, which promotes the nuclear export of Smad2 and possibly targets it for proteasomal degradation.