Human Cripto-1 (CR-1), also known as teratocarcinoma-derived growth factor-1 (TDGF-1) is a member of the Epidermal Growth Factor (EGF)-Cripto-1/FRL-1/Cryptic (CFC) protein family (Bianco et al., 2005a; Strizzi et al., 2005). Structurally the EGF-CFC family consists of extracellular soluble or cell membrane-associated proteins that contain an NH2-terminal signal peptide, a modified EGF-like region, a conserved cysteinerich domain (the CFC motif), and a short hydrophobic COOH-terminus which, with the exception of FRL-1, contains additional sequences for glycosylphosphatidylinositol (GPI) cleavage and attachment (Bianco et al., 2005a). Unlike the canonical EGF motif that contains three disulfide loops (A, B and C), the variant EGF-like motif in the EGF-CFC proteins lacks the A loop, possesses a truncated B loop and has a complete C loop. Because the EGF-CFC peptides lack the A loop, these proteins do not directly bind to any of the known HER-related tyrosine kinase receptors either as homodimers or heterodimers (Bianco et al., 1999, 2005a). The CFC domain of human CR-1 contains three disulfide bonds in a pattern which structurally resembles the von Willebrand factor C (VWFC)-like domains found within the COOH-terminal extracellular portions of the Notch ligands, Jagged1, and Jagged2 (Foley et al., 2003). Like several of the Notch receptor proteins, all of the EGF-CFC proteins contain a consensus O-linked fucosylation site within the EGF-like motif initially thought to be necessary for their ability to function as a coreceptor for the transforming growth factor β (TGFβ)-related protein, Nodal (Schiffer et al., 2001). However, a recent study demonstrates that it is the amino acid threonine to which fucose is bound and not fucose per se that is required for CR-1 coreceptor activity with Nodal (Shi et al., 2007). Biochemical characterization of human CR-1 identified Asn-79 as being an N-linked glycosylation site with > 90% occupancy, and Ser-40 and Ser-161 as being O-linked glycosylation sites with 80% and 40% occupancy, respectively (Bianco et al., 2005a). Whether mutation of these other glycosylation sites can affect the biological activity of CR-1 is presently unknown.
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Bianco, C., Strizzi, L., De Luca, A., Normanno, N., Salomon, D.S. (2008). Breast and Colon Carcinomas: Detection with Plasma CRIPTO-1. In: Hayat, M.A. (eds) Methods of Cancer Diagnosis, Therapy and Prognosis. Methods of Cancer Diagnosis, Therapy and Prognosis, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8369-3_15
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