Decrypting the role of Cripto in tumorigenesis

Abstract

The cell-surface associated molecule Cripto is overexpressed in a wide range of epithelial cancers, yet little is known about potential mechanisms by which Cripto expression might enhance tumorigenesis. A new study reveals that binding of Cripto to the TGF-beta ligand Activin B can block Activin B-mediated suppression of cell proliferation. Furthermore, this study also demonstrates that antibody blockade of Cripto function may prove useful in the inhibition of tumorigenesis.

Figure 1

Schematic models for the role of Cripto in Activin and Nodal signaling. For simplicity, TGF-β ligands and receptors are represented as monomers. (a) Activin signaling utilizes ActRIB and ActRII or ActRIIB, resulting in an active receptor complex and phosphorylation (P) of the type I receptor. (b) Nodal signaling requires Cripto, which is GPI-linked, in addition to ActRIB and ActRIIB. Nodal interacts with Cripto through the EGF motif, and requires the presence of an O-fucose modification (red F) on Cripto. (c–f) Four possible inactive complexes resulting in inhibition of Activin signaling by Cripto. Gray and colleagues (12) propose an inactive Cripto/Activin/ActRII complex (c) and do not detect direct interaction between Cripto and Activin (f). In contrast, Adkins and colleagues (1) propose three potential inactive complexes that do not include ActRII (d–f).