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

FEBS Lett. 2012 Jul 4;586(14):1836-45. doi: 10.1016/j.febslet.2012.01.051. Epub 2012 Feb 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • GPI-Linked Proteins / metabolism*
  • Gene Expression Regulation, Developmental*
  • Gene Expression Regulation, Neoplastic*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Models, Biological
  • Neoplasm Proteins / metabolism*
  • Neoplasms / metabolism
  • Protein Structure, Tertiary
  • Signal Transduction
  • Stem Cells / cytology
  • Transforming Growth Factor beta / metabolism*

Substances

  • GPI-Linked Proteins
  • Heat-Shock Proteins
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • TDGF1 protein, human
  • Transforming Growth Factor beta
  • molecular chaperone GRP78