Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

Abstract

It is increasingly evident that genes known to perform critical roles during early embryogenesis, particularly during stem cell renewal, pluripotentiality and survival, are also expressed during the development of cancer. In this regard, oncogenesis may be considered as the recapitulation of embryogenesis in an inappropriate temporal and spatial manner. The epidermal growth factor-Cripto-1/FRL1/cryptic family of proteins consists of extracellular and cell-associated proteins that have been identified in several vertebrate species. During early embryogenesis, epidermal growth factor-Cripto-1/FRL1/ cryptic proteins perform an obligatory role as coreceptors for the transforming growth factor-beta subfamily of proteins, which includes Nodal. Cripto-1 has also been shown to function as a ligand through a Nodal/Alk4-independent signaling pathway that involves binding to glypican-1 and the subsequent activation through src of phosphoinositol-3 kinase/Akt and ras/mitogen-activated protein kinase intracellular pathways. Expression of Cripto-1 is increased in several human cancers and its overexpression is associated with the development of mammary tumors in mice. Here, we review the role of Cripto-1 during embryogenesis, cell migration, invasion and angiogenesis and how these activities may relate to cellular transformation and tumorigenesis. We also briefly discuss evidence suggesting that Cripto-1 may be involved in stem cell maintenance.

MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines

“…Recent data on the NKX2-5 orthologue tinman indicate it functions as a transcriptional activator or repressor, depending on the occurrence of interactions with co-activator or corepressor, respectively. 40 However, CRIPTO is reportedly overexpressed in certain tumor types, 41 rendering a less plausible target for downregulation by NKX2-5. Both PITX2 and MEF2C are involved in hematopoiesis, 42,43 qualifying both of these as potential leukemogenic factors.…”

Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin

“…To date, de novo expression of Cripto has been associated with several epithelial cancers (16,17), but its role in other pathological conditions, such as injury or degenerative diseases, has not been investigated. Given the physiological activity of Cripto in the instructive events of embryonic mesodermal commitment and differentiation (4), we hypothesized that Cripto expression might be reactivated in response to injury in mesenchymal tissues, such as skeletal muscles.…”

Hepatic Differentiation of Human Embryonic and Induced Pluripotent Stem Cells for Regenerative Medicine

“…The epidermal growth factor family molecule, Cripto-1/FRL1/cryptic, plays a central role as a co-receptor for Nodal. Nodal/ALK signaling in conjunction with Cripto contributes to generate endoderm precursor cells and for the subsequent specification of definitive endoderm (DE) (Strizzi et al 2005). The duration and magnitude of Nodal signaling influence the specification of mesoderm or endoderm.…”

“…In most studies, a high dose of Activin A was used as a substitute for Nodal. Activin shares the same receptors (ActRII and ALK4) with Nodal but does not require the association of Cripto to initiate the Nodal/Smad2 signaling pathway (Strizzi et al 2005). After a few days of Activin treatment, most of the ES cells express definitive endoderm genes (Sox17 and Foxa2), while mesoderm, pluripotency and the extraembryonic endoderm genes are down regulated (D'Amour et al 2005, Kubo et al 2004).…”