Cripto

Last updated
CFC1B
2J5H.pdb.jpg
Identifiers
Aliases CFC1B , entrez:653275, cripto, FRL-1, cryptic family 1B
External IDs MGI: 109448 HomoloGene: 50007 GeneCards: CFC1B
Orthologs
SpeciesHumanMouse
Entrez

653275

12627

Ensembl

ENSG00000152093

ENSMUSG00000026124

UniProt

P0CG36

P97766

RefSeq (mRNA)

NM_001079530

NM_007685

RefSeq (protein)

NP_001072998

NP_031711

Location (UCSC) Chr 2: 130.52 – 130.53 Mb Chr 1: 34.57 – 34.58 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cripto is an EGF-CFC or epidermal growth factor-CFC, which is encoded by the Cryptic family 1 gene. [5] Cryptic family protein 1B is a protein that in humans is encoded by the CFC1B gene. [6] [7] 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. [5] The extracellular protein which Cripto encodes plays a crucial role in the development of left and right division of symmetry. [8]

Contents

Crypto is a glycosylphosphatidylinositol-anchored co-receptor that binds nodal and the activin type I ActRIB (ALK)-4 receptor (ALK4). [5] [9] [10]

Structure

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, [11] which makes it a potentially essential element in the signaling pathway directing vertebrate embryo development. [12] 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. [11]

Function

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. [5]

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. [13] Other results of Cripto disruption include the lack of posterior structures. [14] and a block on the differentiation of cardiac myocyte,. [15] 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, [14] explaining the failure of posterior structures to form in the absence of Cripto.

The role in cancer

The high expression of Cripto-1 was detected in many types of cancer such as pancreatic, breast and colon cancer. The high expression levels were linked to poor survival rate in cancer patients. Its role was suggested to be through promotion of epithelial-to-mesenchymal transition (EMT). The Wnt signaling pathway/β-catenin and TGF-B/Smad pathway was shown to control epithelial-to-mesenchymal transition in cancer. [16] [17] Recently, Cripto-1 was proposed as cancer stem cell marker.

Clinical significance

CFC1B has oncogene potential [11] due to the tumor cell proliferation through initiation by autocrine or paracrine signaling. [5] Furthermore, the cryptic protein is highly over-expressed in many tumors [11] such as colorectal, gastric, breast, and pancreatic cancers in homosapiens. [5] Cripto is one of the key regulators of embryonic stem cells differentiation into cardiomyocyte vs. neuronal fate. [18] Expression levels of cripto are associated with resistance to EGFR inhibitors. [19]

See also

Teratocarcinoma-derived growth factor 1

Related Research Articles

<span class="mw-page-title-main">Gastrulation</span> Stage in embryonic development in which germ layers form

Gastrulation is the stage in the early embryonic development of most animals, during which the blastula, or in mammals the blastocyst, is reorganized into a two-layered or three-layered embryo known as the gastrula. Before gastrulation, the embryo is a continuous epithelial sheet of cells; by the end of gastrulation, the embryo has begun differentiation to establish distinct cell lineages, set up the basic axes of the body, and internalized one or more cell types including the prospective gut.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. EMT is essential for numerous developmental processes including mesoderm formation and neural tube formation. EMT has also been shown to occur in wound healing, in organ fibrosis and in the initiation of metastasis in cancer progression.

<span class="mw-page-title-main">T-box transcription factor T</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the TBXT gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian animals that have been screened, as well as the freshwater cnidarian Hydra.

<span class="mw-page-title-main">Intermediate mesoderm</span> Layer of cells in mammalian embryos

Intermediate mesoderm or intermediate mesenchyme is a narrow section of the mesoderm located between the paraxial mesoderm and the lateral plate of the developing embryo. The intermediate mesoderm develops into vital parts of the urogenital system.

Lefty are a class of proteins that are closely related members of the TGF-beta superfamily of growth factors. These proteins are secreted and play a role in left-right asymmetry determination of organ systems during development. Mutations of the genes encoding these proteins have been associated with left-right axis malformations, particularly in the heart and lungs.

<span class="mw-page-title-main">Mesenchyme</span> Type of animal embryonic connective tissue

Mesenchyme is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every organ in the developing embryo.

<span class="mw-page-title-main">TGF alpha</span> Protein

Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors capable of protein kinase activity for cellular signaling.

<span class="mw-page-title-main">Epiregulin</span> Protein found in humans

Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.

<span class="mw-page-title-main">SHC1</span> Protein-coding gene in humans

SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.

<span class="mw-page-title-main">SNAI1</span> Protein

Zinc finger protein SNAI1 is a protein that in humans is encoded by the SNAI1 gene. Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.

<span class="mw-page-title-main">Teratocarcinoma-derived growth factor 1</span> Protein-coding gene in the species Homo sapiens

Teratocarcinoma-derived growth factor 1 is a protein that in humans is encoded by the TDGF1 gene. The protein is an extracellular, membrane-bound signaling protein that plays an essential role in embryonic development and tumor growth. Mutations in this gene are associated with forebrain defects. Pseudogenes of this gene are found on chromosomes 2, 3, 6, 8, 19 and X. Alternate splicing results in multiple transcript variants.

<span class="mw-page-title-main">FGF10</span> Protein-coding gene in humans

Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.

<span class="mw-page-title-main">Nodal homolog</span> Mammalian protein found in Homo sapiens

Nodal homolog is a secretory protein that in humans is encoded by the NODAL gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the primitive node, in the anterior primitive streak, to lateral plate mesoderm (LPM).

<span class="mw-page-title-main">ANKS1A</span> Protein-coding gene in the species Homo sapiens

Ankyrin repeat and SAM domain-containing protein 1A (ANKS1A), also known as ODIN, is a protein that in humans is encoded by the ANKS1A gene on chromosome 6.

<span class="mw-page-title-main">EGFL7</span> Protein-coding gene in the species Homo sapiens

EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene. Intron 7 of EGFL7 hosts the miR-126 microRNA gene.

The Nodal signaling pathway is a signal transduction pathway important in regional and cellular differentiation during embryonic development.

<span class="mw-page-title-main">Cryptic protein</span> Protein-coding gene in the species Homo sapiens

Cryptic protein, also cryptic family member 1 is a protein that in humans is encoded by the CFC1 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000152093 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026124 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 Yan YT, Liu JJ, Luo Y, E C, Haltiwanger RS, Abate-Shen C, Shen MM (July 2002). "Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway". Molecular and Cellular Biology. 22 (13): 4439–49. doi:10.1128/MCB.22.13.4439-4449.2002. PMC   133918 . PMID   12052855.
  6. ↑ "Entrez Gene: cripto".
  7. ↑ Bonaldo MF, Lennon G, Soares MB (September 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.
  8. ↑ "CFC1".
  9. ↑ Lonardo E, Parish CL, Ponticelli S, Marasco D, Ribeiro D, Ruvo M, et al. (August 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. S2CID   19533260.
  10. ↑ Ravisankar, V.; Singh, Taran P.; Manoj, Narayanan (August 2011). "Molecular evolution of the EGF–CFC protein family". Gene. 482 (1–2): 43–50. doi:10.1016/j.gene.2011.05.007. PMID   21640172.
  11. 1 2 3 4 Calvanese L, Saporito A, Marasco D, D'Auria G, Minchiotti G, Pedone C, et al. (November 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.
  12. ↑ Minchiotti G, Manco G, Parisi S, Lago CT, Rosa F, Persico MG (November 2001). "Structure-function analysis of the EGF-CFC family member Cripto identifies residues essential for nodal signalling". Development. 128 (22): 4501–10. doi:10.1242/dev.128.22.4501. PMID   11714675.
  13. ↑ Jin JZ, Ding J (September 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.
  14. 1 2 Ding J, Yang L, Yan YT, Chen A, Desai N, Wynshaw-Boris A, Shen MM (October 1998). "Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo". Nature. 395 (6703): 702–7. Bibcode:1998Natur.395..702D. doi:10.1038/27215. PMID   9790191. S2CID   4415496.
  15. ↑ Persico MG, Liguori GL, Parisi S, D'Andrea D, Salomon DS, Minchiotti G (December 2001). "Cripto in tumors and embryo development". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1552 (2): 87–93. doi:10.1016/S0304-419X(01)00039-7. PMID   11825688.
  16. ↑ Liu Y, Qin Z, Yang K, Liu R, Xu Y (March 2017). "Cripto-1 promotes epithelial-mesenchymal transition in prostate cancer via Wnt/β-catenin signaling". Oncology Reports. 37 (3): 1521–1528. doi: 10.3892/or.2017.5378 . PMID   28098905.
  17. ↑ Gao X, Xu Q, Zhang RH, Lu T, Pan BJ, Liao Q, et al. (November 1975). "Modification of arginine and lysine in proteins with 2,4-pentanedione". Biochemistry. 14 (23): 5194–9. doi:10.3881/j.issn.1000-503X.12734 (inactive 2024-04-26). PMID   33966694.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
  18. ↑ Chambery A, Vissers JP, Langridge JI, Lonardo E, Minchiotti G, Ruvo M, Parente A (February 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.
  19. ↑ Park KS, Raffeld M, Moon YW, Xi L, Bianco C, Pham T, et al. (July 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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