CRIPTO3 encodes a functional EGF-CFC family protein that activates Nodal-dependent signaling pathways 1. Despite being initially classified as a pseudogene with only six amino acid differences from CRIPTO1, CRIPTO3 is a bona fide translated protein expressed in human tissues and cancer samples 2. Both CRIPTO3 and CRIPTO1 compete for binding to key signaling molecules including Nodal, GRP78, and activin receptor-like kinase 4 (ALK4), indicating functional overlap in cell signaling 1. During embryonic development, CRIPTO3 expression is regulated by germ cell nuclear factor (GCNF), which represses it during differentiation of stem cells, suggesting roles in maintaining pluripotency 3. Notably, CRIPTO3 and CRIPTO1 display distinct subcellular localizations and tissue-specific expression patterns; for example, CRIPTO3 localizes cytoplasmically while CRIPTO1 shows nuclear localization in placental tissue, and their relative expression levels vary across fetal tissues 4. CRIPTO3 is particularly expressed in certain cancers where it may function as an oncogene through activation of retrogene-mediated Nodal signaling 2. These findings suggest CRIPTO3 has independent functions in both developmental signaling and tumorigenesis, with potential clinical implications for cancer prognosis 1.