Cripto is a glycosylphosphatidylinositol (GPI)-anchored Type I cell membrane protein that belongs to the epidermal growth factor (EGF)-Cripto-1-FRL-1-Cryptic (CFC) family of proteins (EGF-CFC). In addition to Cripto, another three members of the EGF-CRC family have been described: Criptic, Xenopus FRL-1, and zebrafish one-eyed pinhead (0EP). Cripto contains a signal sequence, an EGF-like domain, a cysteine-rich region motif (CFC domain), and a hydrophobic COOH-terminus. Cripto plays an important role in maintaining embryonic stem cell pluripotency and tumorigenesis. Cripto acts as a co-receptor for Nodal, a TGFb family member that plays a crucial role in mesoderm and endoderm formation. Nodal and Cripto form complex with type I Activin receptors, Alk4/7 (ACVR1B/ACVR1C), and type II Activin receptors, ActRIIA/ActRIIB (ACVR2A/ACVR2B). Cripto is also known to bind Furin and Pace4 that process Nodal proteolytic maturation and supports Nodal signaling. A soluble form of Cripto is secreted by tumor cells and it lacks the GPI anchor region which is removed by GPI-phospholipase D. The soluble Cripto promotes endothelial cell migration and possibly tumor angiogenesis. More recent data showed that a GPI phospholipase A2 called post-glycosylphosphatidylinositol attachment to proteins 6 (PGAP6) in involved in the in the shedding of Cripto. PGAP6 produces Cripto bearing lyso-GPI which is released from the membrane, and subsequently Cripto is released from the lyso-GPI by GPI-phospholipase D. The action of PGAP6 regulates Nodal signaling.