Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis

• Published in: FEBS letters Vol. 586; no. 14; pp. 1836 - 1845
• Main Authors: Gray, Peter C., Vale, Wylie
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 04.07.2012
• Subjects: Animals; BMP; bone morphogenetic protein; Cancer; Cell Membrane - metabolism; Cripto; Endoplasmic Reticulum Chaperone BiP; fibroblast growth factor (FGF) receptor ligand-1; FRL-1; GDF; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; glcyosylphosphatidylinositol; glucose regulated protein 78 kDa; GPI; GPI-Linked Proteins - metabolism; growth and differentiation factor; GRP78; Heat-Shock Proteins - metabolism; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Mice; Models, Biological; Neoplasm Proteins - metabolism; Neoplasms - metabolism; Plasticity; Protein Structure, Tertiary; Signal Transduction; Stem cell; Stem Cells - cytology; TDGF1; teratocarcinoma-derived growth factor 1; TGF-β; Transforming Growth Factor beta - metabolism; GPI; BMP; FRL-1; Stem cell; Plasticity; GDF; GRP78; TGF-β; TDGF1; Cripto; Cancer
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2012.01.051

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.