Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis.
Cripto is a small, GPI-anchored signaling protein that regulates cellular survival, proliferation, differentiation and migration during normal developmental processes and tumorigenesis. Cripto functions as an obligatory co-receptor for the TGF-β ligands Nodal, GDF1 and GDF3 but attenuates signaling of others such as activin-A, activin-B and TGF-β1. Soluble, secreted forms of Cripto also activate Src, ras/raf/MAPK and PI3K/Akt pathways via a mechanism that remains largely obscure. This review describes the biological roles and signaling mechanisms of Cripto, highlighting our identification of the 78 kDa glucose regulated protein (GRP78) as a cell surface receptor/co-factor required for Cripto signaling via both TGF-β and Src/MAPK/PI3K pathways. We discuss emerging evidence indicating that Cripto/GRP78 signaling regulates normal somatic stem cells and their tumorigenic counterparts.
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, United States. gray@salk.edu
Peter C
PC
Gray
Wylie
W
Vale
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D058851:GPI-Linked Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; D058851:GPI-Linked Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; D016212:Transforming Growth Factor beta