The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer

The EGF-CFC gene family encodes a group of structurally related proteins th at serve as important competence factors during early embryogenesis in Xeno pus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep), mouse cripto (Cr-l) and cryptic, a nd human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essenti al for the formation of mesoderm and endoderm and for correct establishment of the anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right (UR) asymmetry, In zebrafish, there is strong genetic evidence that oep functions as an obligatory cc-factor for the correct signaling of a transforming growth factor-beta (TGF beta)-relat ed gene, nodal, during gastrulation and during UR asymmetry development. Ex pression of Cr-l and cryptic is extinguished in the embryo after day 8 of g estation except for the developing heart where Cr-l expression is necessary for myocardial development. In the mouse, cryptic is not expressed in adul t tissues whereas Cr-l is expressed at a low level in several different tis sues including the mammary gland, In the mammary gland, expression of Cr-l in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-l protein can be detected in hum an milk. Overexpression of Cr-l in mouse mammary epithelial cells can facil itate their in vitro transformation and in vivo these Cr-l-transduced cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or hum an cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompani ed by an epithelial-mesenchymal transition which is associated with a decre ase in beta -catenin function and an increase in vimentin expression. Expre ssion of cripto is increased several-fold in human colon, gastric, pancreat ic and lung carcinomas and in a variety of different types of mouse and hum an breast carcinomas. More importantly, this increase can first be detected in premalignant lesions in some of these tissues. Although a specific rece ptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin-type RIIB and RIB receptor system that functions through Smad-e . Mouse and human cripto have been shown to activate a ras/raf/MAP kinase s ignaling pathway in mammary epithelial cells. Activation of phosphatidylino sitol 3-kinase and Akt are also important for the ability of CR-1 to stimul ate cell migration and to block lactogenic hormone-induced expression of p- casein and whey acidic protein. In mammary epithelial cells, part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or fibroblast growth factor receptor 1 through an src-like tyrosine kinase.