Schematic models for the role of Cripto in Activin and Nodal signaling. For simplicity, TGF-β ligands and receptors are represented as monomers. (a) Activin signaling utilizes ActRIB and ActRII or ActRIIB, resulting in an active receptor complex and phosphorylation (P) of the type I receptor. (b) Nodal signaling requires Cripto, which is GPI-linked, in addition to ActRIB and ActRIIB. Nodal interacts with Cripto through the EGF motif, and requires the presence of an O-fucose modification (red F) on Cripto. (c–f) Four possible inactive complexes resulting in inhibition of Activin signaling by Cripto. Gray and colleagues (12) propose an inactive Cripto/Activin/ActRII complex (c) and do not detect direct interaction between Cripto and Activin (f). In contrast, Adkins and colleagues (1) propose three potential inactive complexes that do not include ActRII (d–f).