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Cripto is an EGF-CFC or epidermal growth factor-CFC, which is encoded by the Cryptic family 1 gene.[1] Cryptic family protein 1B is a protein that in humans is encoded by the CFC1B gene.[2][3] Cryptic family protein 1B acts as a receptor for the TGF beta signaling pathway. It has been associated with the translation of an extracellular protein for this pathway.[1] The extracellular protein which Cripto encodes plays a crucial role in the development of left and right division of symmetry. Mutations of it could cause congenital heart disease.[4]

Crypto is a glycosylphosphatidylinositol-anchored co-receptor that binds nodal and the activin type I ActRIB (ALK)-4 receptor (ALK4).[1][5]


Cripto is composed of two adjacent cysteine-rich motifs: the EGF-like and the CFC of an N-terminal signal peptide and of a C-terminal hydrophobic region attached by a GPI anchor,[6] which makes it a potentially essential element in the signaling pathway directing vertebrate embryo development.[7] NMR data confirm that the CFC domain has a C1-C4, C2-C6, C3-C5 disulfide pattern and show that structures are rather flexible and globally extended, with three non-canonical anti-parallel strands.[6]


In the Nodal signaling pathway of embryonic development, Cripto has been shown to have dual function as a co-receptor as well as ligand. Particularly in cell cultures, it has been shown to act as a signaling molecule with the capabilities of a growth factor, and in co-culture assays, it has displayed the property of a co-ligand to Nodal. Glycosylation is responsible for mediating this interface with Nodal. EGF-CFC proteins’ composition as a receptor complex is further solidified by the GPI linkage, making the cell membrane connection able to regulate growth factor signaling of Nodal.[1]

Expression during embryonic development

High concentrations of Cripto are found in both the trophoblast and inner cell mass, along the primitive streak as the second epithelial-mesenchymal transformation event occurs to form the mesoderm, and in the myocardium of the developing heart. Though no specific defect has been formally associated with mutations in Cripto, in vitro studies that disrupt gene function at various times during development have provided glimpses of possible malformations. For example, inactivation of Cripto during gastrulation disrupted the migration of newly formed mesenchymal mesoderm cells, resulting in the accumulation of cells around the primitive streak and eventual embryonic death.[8] Other results of Cripto disruption include the lack of posterior structures.[9][10] and a block on the differentiation of cardiac myocyte,.[11] both of which lead to embryonic death.

Cripto’s functions have been hypothesized from these null mutation studies. It is now known that Cripto is similar to other morphogens originating from the primitive streak in that it is asymmetrically expressed, specifically in a proximal-distal gradient,[9] explaining the failure of posterior structures to form in the absence of Cripto.

Clinical significance

CFC1B has oncogene potential [6] due to the tumor cell proliferation through initiation by autocrine or paracrine signaling.[1] Furthermore, the cryptic protein is highly over-expressed in many tumors [6] such as colorectal, gastric, breast, and pancreatic cancers in homosapiens.[1] Cripto is one of the key regulators of embryonic stem cells differentiation into cardiomyocyte vs. neuronal fate.[12] Expression levels of cripto are associated with resistance to EGFR inhibitors.[13]


  1. 1.0 1.1 1.2 1.3 1.4 1.5 Yan YT, Liu JJ, Luo Y, E C, Haltiwanger RS, Abate-Shen C, Shen MM (2002). "Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway". Mol. Cell. Biol. 22 (13): 4439–4449. doi:10.1128/MCB.22.13.4439-4449.2002. PMC 133918. PMID 12052855.
  2. "Entrez Gene: cripto".
  3. Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
  4. "CFC1". Retrieved April 2015. Check date values in: |accessdate= (help)
  5. Lonardo E, Parish CL, Ponticelli S, Marasco D, Ribeiro D, Ruvo M, De Falco S, Arenas E, Minchiotti G (Aug 2010). "A small synthetic cripto blocking Peptide improves neural induction, dopaminergic differentiation, and functional integration of mouse embryonic stem cells in a rat model of Parkinson's disease". Stem Cells. 28 (8): 1326–37. doi:10.1002/stem.458. PMID 20641036.
  6. 6.0 6.1 6.2 6.3 Calvanese L, Saporito A, Marasco D, D'Auria G, Minchiotti G, Pedone C, Paolillo L, Falcigno L, Ruvo M (Nov 2006). "Solution structure of mouse Cripto CFC domain and its inactive variant Trp107Ala". Journal of Medicinal Chemistry. 49 (24): 7054–62. doi:10.1021/jm060772r. PMID 17125258.
  7. Minchiotti G, Manco G, Parisi S, Lago CT, Rosa F, Persico MG (2001). "Structure-function analysis of the EGF-CFC family member Cripto identifies residues essential for nodal signalling". Development. 128: 4501–4510.
  8. Jin JZ, Ding J (Sep 2013). "Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation". Developmental Biology. 381 (1): 170–8. doi:10.1016/j.ydbio.2013.05.029. PMC 4657735. PMID 23747598.
  9. 9.0 9.1 Jin JZ, Ding J (Oct 1998). "Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation". Nature. 395: 702–7. doi:10.1038/27215. PMID 9790191.
  10. Ding J, Yang L, Yan YT, Chen A, Desai N, Wynshaw-Boris A, Shen MM (Oct 1998). "Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo". Nature. 395 (6703): 702–7. doi:10.1038/27215. PMID 9790191.
  11. Persico MG, Liguori GL, Parisi S, D'Andrea D, Salomon DS, Minchiotti G (Dec 2001). "Cripto in tumors and embryo development". Biochimica et Biophysica Acta. 1552 (2): 87–93. doi:10.1016/S0304-419X(01)00039-7. PMID 11825688.
  12. Chambery A, Vissers JP, Langridge JI, Lonardo E, Minchiotti G, Ruvo M, Parente A (Feb 2009). "Qualitative and quantitative proteomic profiling of cripto(-/-) embryonic stem cells by means of accurate mass LC-MS analysis". Journal of Proteome Research. 8 (2): 1047–58. doi:10.1021/pr800485c. PMID 19152270.
  13. Park KS, Raffeld M, Moon YW, Xi L, Bianco C, Pham T, Lee LC, Mitsudomi T, Yatabe Y, Okamoto I, Subramaniam D, Mok T, Rosell R, Luo J, Salomon DS, Wang Y, Giaccone G (Jul 2014). "CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance". The Journal of Clinical Investigation. 124 (7): 3003–15. doi:10.1172/JCI73048. PMC 4071378. PMID 24911146.

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