The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition

Abstract Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that can function either in cis (autocrine) or in trans (paracrine). The cell membrane cis form is found in lipid rafts and endosomes while the trans acti...

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Published in:Seminars in cancer biology 2014-12, Vol.29, p.51-58
Main Authors: Klauzinska, Malgorzata, Castro, Nadia P, Rangel, Maria Cristina, Spike, Benjamin T, Gray, Peter C, Bertolette, Daniel, Cuttitta, Frank, Salomon, David
Format: Article
Language:English
Subjects:
Activin Receptors, Type I - metabolism
beta Catenin - metabolism
Cancer
Cell Membrane - metabolism
Cripto-1
Epithelial-mesenchymal transition
Epithelial-Mesenchymal Transition - genetics
GPI-Linked Proteins - genetics
GRP78
Heat-Shock Proteins - metabolism
Hematology, Oncology and Palliative Medicine
Humans
Intercellular Signaling Peptides and Proteins - genetics
Membrane Proteins - genetics
Neoplasm Invasiveness - genetics
Neoplasm Proteins - genetics
Neoplasms - genetics
Neoplasms - pathology
Neoplastic Stem Cells - cytology
Neovascularization, Pathologic - genetics
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Notch - metabolism
Smad2 Protein - metabolism
Smad3 Protein - metabolism
Smad4 Protein - metabolism
Stem cells
TGF-beta Superfamily Proteins - metabolism
Transforming Growth Factor beta - metabolism
Wnt Proteins - metabolism
Wnt Signaling Pathway - genetics
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Summary:Abstract Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that can function either in cis (autocrine) or in trans (paracrine). The cell membrane cis form is found in lipid rafts and endosomes while the trans acting form lacking the GPI anchor is soluble. As a member of the epidermal growth factor (EGF)/Cripto-1-FRL-1-Cryptic (CFC) family, CR-1 functions as an obligatory co-receptor for the transforming growth factor-β (TGF-β) family members, Nodal and growth and differentiation factors 1 and 3 (GDF1/3) by activating Alk4/Alk7 signaling pathways that involve Smads 2, 3 and 4. In addition, CR-1 can activate non-Smad-dependent signaling elements such as PI3K, Akt and MAPK. Both of these pathways depend upon the 78 kDa glucose regulated protein (GRP78). Finally, CR-1 can facilitate signaling through the canonical Wnt/β-catenin and Notch/Cbf-1 pathways by functioning as a chaperone protein for LRP5/6 and Notch, respectively. CR-1 is essential for early embryonic development and maintains embryonic stem cell pluripotentiality. CR-1 performs an essential role in the etiology and progression of several types of human tumors where it is expressed in a population of cancer stem cells (CSCs) and facilitates epithelial-mesenchymal transition (EMT). In this context, CR-1 can significantly enhance tumor cell migration, invasion and angiogenesis. Collectively, these facts suggest that CR-1 may be an attractive target in the diagnosis, prognosis and therapy of several types of human cancer.
ISSN:1044-579X
1096-3650
DOI:10.1016/j.semcancer.2014.08.003