Affinage

CRIPTO

Protein Cripto · UniProt P13385

Length
188 aa
Mass
21.2 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRIPTO (CR-1/TDGF1) is a GPI-anchored cell-surface glycoprotein (PMID:10640699, PMID:8006041) that acts as an obligate co-receptor for Nodal-class TGF-β ligands and, independently, as a multifunctional modulator of growth-factor signaling controlling embryonic development, tissue regeneration, and tumorigenesis (PMID:11389842, PMID:27586544). As a Nodal co-receptor, CRIPTO engages the type I receptor ALK4 through its CFC motif—an interaction structurally mapped to residues H120/W124 and required both for Nodal binding to the ALK4/ActRIIB complex and for downstream Smad2 activation (PMID:11389842, PMID:19035567); its co-receptor and secreted co-ligand functions depend on O-linked fucosylation of the EGF-CFC region and on intact GPI anchorage for cis and trans activity (PMID:12052855, PMID:17925387). CRIPTO further organizes Nodal biogenesis by binding the proprotein convertases Furin and PACE4, coupling Nodal processing to endocytic trafficking in detergent-resistant membranes (PMID:18772886), and can itself be shed as a soluble paracrine factor through GPI-PLD activity (PMID:17720976). Beyond Nodal, CRIPTO drives Src/MAPK/PI3K-Akt signaling via Glypican-1 and cell-surface GRP78 (PMID:12649175, PMID:19421146, PMID:10493495), directly binds TGF-β1 to block TβRI assembly and suppress cytostatic/senescence responses (PMID:17030617, PMID:18337457), promotes Notch1 S1 maturation by recruiting it into lipid rafts (PMID:19948478), and potentiates Wnt/β-catenin signaling by binding LRP5/6 and stabilizing Dishevelled-3 (PMID:23022962, PMID:29445127). Through these activities CRIPTO sustains stem-cell self-renewal and pluripotency in a pathway-selective manner (PMID:27586544), governs gastrulation and cardiac development (PMID:14581455, PMID:26811383, PMID:23747598), and controls satellite-cell-driven muscle regeneration and macrophage plasticity by antagonizing TGF-β/myostatin signaling (PMID:23129614, PMID:32107853). CRIPTO transcription is directly activated by HIF-1α under hypoxia and MEF2C in the heart field, and repressed by GCNF during differentiation, with β-catenin/TCF driving a short isoform (PMID:16954206, PMID:17291450, PMID:19834060, PMID:26811383).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 Medium

    Established that CR-1 is a secreted/cell-associated glycoprotein acting through a route distinct from the EGF receptor, ruling out the obvious candidate and framing the search for its true mechanism.

    Evidence Glycosidase/tunicamycin shifts and EGF radioreceptor competition in proliferation assays

    PMID:8006041

    Open questions at the time
    • No receptor identified
    • Signaling pathway undefined
  2. 1999 Medium

    Showed CRIPTO drives PI3K-Akt/GSK-3β survival signaling and engages ErbB-4 indirectly, hinting at receptor-independent oncogenic outputs distinct from the later-defined Nodal axis.

    Evidence Phospho-assays with PI3K inhibitor and rescue; crosslinking and ErbB-4 blockade in carcinoma cells

    PMID:10085099 PMID:10493495

    Open questions at the time
    • The 130/60 kDa crosslinked receptor not identified
    • Single cell line; relation to GRP78/Glypican-1 axis unresolved at the time
  3. 2000 High

    Defined CRIPTO as GPI-anchored, establishing the membrane topology that would prove essential for its spatial co-receptor function.

    Evidence Biochemical fractionation, PI-PLC, immunofluorescence

    PMID:10640699

    Open questions at the time
    • Functional consequence of GPI anchorage not yet tested
    • Shedding mechanism unknown
  4. 2001 High

    Identified the CFC-domain interaction with ALK4 as the molecular basis for Cripto-dependent Nodal signaling, defining its obligate co-receptor role.

    Evidence Co-IP, receptor binding and Smad2 reporter assays in cell culture

    PMID:11389842

    Open questions at the time
    • Stoichiometry and structure of the ternary complex unknown
    • Whether ALK4 binding alone is sufficient unresolved
  5. 2002 High

    Distinguished CRIPTO's cis co-receptor from trans co-ligand activity and showed both require O-fucosylation, revealing post-translational control of ligand-receptor assembly.

    Evidence Coculture and reporter assays, glycosylation inhibition; FACS/co-IP with ALK4 and Smad2 phosphorylation

    PMID:11909953 PMID:12052855

    Open questions at the time
    • MAPK/Akt arm shown Nodal/ALK4-independent but mediator not yet identified
    • In vivo relevance of fucosylation untested
  6. 2003 High

    Resolved the Nodal-independent arm by identifying Glypican-1 as a CRIPTO partner driving c-Src/MAPK/Akt and transformation, and placed the Nodal/Cripto/ALK4 axis in cardiomyogenic differentiation.

    Evidence Binding/co-IP, Src kinase and transformation/migration assays; ES cell differentiation with ActRIB rescue and Nodal antagonists

    PMID:12649175 PMID:14581455

    Open questions at the time
    • How Glypican-1 couples to Src not mechanistically detailed
    • Link between the two signaling arms unclear
  7. 2006 High

    Revealed a ligand-trap function: CRIPTO binds TGF-β1 and blocks TβRI assembly, antagonizing cytostatic TGF-β signaling and offering an oncogenic mechanism independent of Nodal.

    Evidence Direct binding, receptor assembly co-IP, reporter and cytostasis assays with siRNA

    PMID:17030617

    Open questions at the time
    • Structural basis of TGF-β1 binding undefined
    • Selectivity among TGF-β isoforms not fully mapped
  8. 2007 High

    Demonstrated that GPI anchorage is functionally required for paracrine and autocrine Nodal co-receptor activity and that GPI-PLD-mediated shedding produces a distinct soluble paracrine factor.

    Evidence Omega-site/truncation mutagenesis, PI-PLC ablation, paracrine reporter assays; GPI-PLD knockdown/overexpression with migration and sprouting assays

    PMID:17720976 PMID:17925387

    Open questions at the time
    • Physiological triggers of shedding in vivo unknown
    • Relative contribution of membrane vs soluble CRIPTO context-dependent
  9. 2008 High

    Connected CRIPTO to Nodal biogenesis machinery by showing it recruits Furin/PACE4 to localize Nodal processing and endocytosis, and identified caveolin-1 as a negative regulator of CRIPTO oncogenic signaling.

    Evidence Co-IP, BFA, density gradient fractionation and trafficking imaging; Cav-1 co-IP and Cav-1-null/MMTV-CR-1 mouse signaling assays

    PMID:18202186 PMID:18772886

    Open questions at the time
    • How CRIPTO selects Nodal for raft microdomains unclear
    • Cav-1 regulatory mechanism (sequestration vs signaling block) not resolved
  10. 2008 Medium

    Extended the TGF-β1-inhibitory mechanism to skin epithelium, showing CRIPTO blocks TGF-β1-induced Smad2/3 signaling and senescence.

    Evidence Receptor binding blockade, Smad2/3 phosphorylation, reporter and senescence assays in keratinocytes

    PMID:18337457

    Open questions at the time
    • Single cell type
    • Whether membrane-bound or soluble CRIPTO mediates the effect not separated
  11. 2009 High

    Identified cell-surface GRP78 as a required mediator of CRIPTO's MAPK/PI3K signaling and modulation of multiple TGF-β ligands, and mapped CRIPTO-Notch1 interaction promoting S1 maturation, broadening its signaling reach.

    Evidence shRNA/GRP78 immunoneutralization with functional readouts; Y2H, co-IP, raft fractionation and S1 cleavage assays for Notch1

    PMID:19421146 PMID:19948478

    Open questions at the time
    • GRP78-to-kinase coupling mechanism undefined
    • Whether Notch enhancement operates in vivo untested
  12. 2009 High

    Placed CRIPTO under direct hypoxic transcriptional control by HIF-1α and showed this drives hypoxia-induced cardiomyogenesis, linking the gene's expression to the microenvironment.

    Evidence ChIP for HIF-1α at the promoter and ES cell differentiation under hypoxia with loss-of-function

    PMID:19834060

    Open questions at the time
    • Other hypoxia-responsive cofactors not examined
    • Relevance to tumor hypoxia not directly tested here
  13. 2009 Medium

    Provided structural and affinity detail of the CFC-ALK4 interface and showed CFC does not bind ActRIIB, refining the receptor-engagement model.

    Evidence NMR of synthetic CFC domain, SPR binding, molecular docking

    PMID:19035567

    Open questions at the time
    • Isolated domain, not full-length protein
    • Ternary complex structure with Nodal absent
  14. 2006 Medium

    Defined transcriptional repression of CRIPTO by GCNF during differentiation and β-catenin/TCF-driven induction of a short isoform, establishing how CRIPTO levels track developmental state.

    Evidence EMSA, ChIP, reporter and GCNF-VP16 fusion assays; TCF/LEF site mutation reporter assays

    PMID:16954206 PMID:17291450

    Open questions at the time
    • Function of the short isoform not characterized
    • Interplay between repressive and activating inputs unresolved
  15. 2012 Medium

    Established CRIPTO as a positive Wnt/β-catenin modulator by binding LRP5/6 and facilitating Wnt3a signaling, adding a third major signaling axis.

    Evidence Co-IP, β-catenin stabilization and TCF reporter, invasion/colony assays

    PMID:23022962

    Open questions at the time
    • Mechanism of LRP enhancement unclear
    • Single lab
  16. 2012 High

    Defined an in vivo regenerative role: CRIPTO in satellite cells promotes myogenic proliferation/determination by antagonizing myostatin, demonstrating physiological TGF-β ligand-trap function.

    Evidence Conditional KO and gain-of-function in satellite cells, muscle regeneration assays, myostatin antagonism

    PMID:23129614

    Open questions at the time
    • Direct myostatin-CRIPTO binding not shown here
    • Receptor context for antagonism undefined
  17. 2013 Medium

    Showed CRIPTO is required during gastrulation for endoderm formation and primitive streak organization, partly through Fgf8-Fgfr1 and p38 pathways.

    Evidence Conditional Cripto KO mouse embryo phenotyping and pathway analysis

    PMID:23747598

    Open questions at the time
    • Whether Fgf/p38 effects are direct or downstream of Nodal unclear
    • Single lab
  18. 2016 High

    Demonstrated pathway-selective control of pluripotency—CRIPTO uses Wnt/β-catenin in mouse ESCs versus Nodal/Smad2 in EpiSCs/human ESCs—and placed Tdgf1 downstream of MEF2C in cardiac outflow tract development.

    Evidence Cripto KO ESCs with Wnt and Smad2 readouts and lineage assays; conditional Mef2c KO with Tdgf1 enhancer reporter and ChIP

    PMID:26811383 PMID:27586544

    Open questions at the time
    • How cell state selects which pathway CRIPTO engages is unresolved
    • Direct enhancer dissection of stage-specific outputs incomplete
  19. 2016 Medium

    Implicated CRIPTO in innate immune signaling by showing it modulates macrophage cytokine output and phagocytosis through NF-κB activation.

    Evidence NF-κB inhibitor, IKK phosphorylation, p65 translocation, cytokine ELISA, phagocytosis assays

    PMID:26476731

    Open questions at the time
    • Upstream receptor coupling to NF-κB undefined
    • Single lab
  20. 2018 Medium

    Extended the Wnt axis in cancer, showing CRIPTO binds FZD7/LRP6/DVL3 and stabilizes DVL3 to confer stemness in hepatocellular carcinoma.

    Evidence Co-IP, DVL3 stability and β-catenin reporter assays, knockdown with constitutively active β-catenin rescue

    PMID:29445127

    Open questions at the time
    • Mechanism of DVL3 stabilization undefined
    • Single lab
  21. 2020 High

    Revealed a myeloid-lineage role: CRIPTO restrains TGFβ/Smad in macrophages to enable anti-inflammatory plasticity, with loss exacerbating dystrophic muscle pathology via EndMT.

    Evidence Myeloid conditional KO, macrophage FACS, TGFβ/Smad assays, EndMT analysis in mdx mice

    PMID:32107853

    Open questions at the time
    • Whether CRIPTO acts cell-autonomously in macrophages vs paracrine unclear
    • Receptor mediating TGFβ restraint not pinned down
  22. 2021 Medium

    Identified a TGF-β–ALK1–Cripto complex driving catabolic SMAD1/5 signaling and chondrocyte hypertrophy in osteoarthritis, expanding CRIPTO's receptor partnerships beyond ALK4.

    Evidence Co-IP of the receptor complex, SMAD1/5 phosphorylation, chondrocyte hypertrophy assays, OA mouse/human expression

    PMID:34357595

    Open questions at the time
    • Direct CFC-ALK1 contact not mapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRIPTO integrates and switches between its multiple signaling axes (Nodal/Smad2, Glypican-1/GRP78/Src, TGF-β1 inhibition, Notch, Wnt) in a cell-state- and context-dependent manner remains unresolved at the structural and systems level.
  • No full-length structure of CRIPTO in any receptor complex
  • Quantitative rules governing pathway selection unknown
  • How membrane vs soluble CRIPTO differentially routes signaling is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
ALK4DVL3FURINGPC1HSPA5LRP6NOTCH1PACE4
Complex memberships
Nodal/Cripto/ALK4/ActRIIB co-receptor complexTGF-β–ALK1–Cripto complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Cripto interacts with the type I receptor ALK4 via its conserved CFC motif. This interaction is necessary both for Nodal binding to the ALK4/ActRIIB receptor complex and for Smad2 activation by Nodal. Co-immunoprecipitation, receptor binding assays, Smad2 activation reporter assays in cell culture Molecular cell High 11389842
2000 Cripto protein is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) moiety, as demonstrated by biochemical characterization and immunofluorescence; GPI-linkage is proposed to be important for spatial specificity of cell-cell interactions. Biochemical fractionation, PI-PLC treatment, immunofluorescence Mechanisms of development High 10640699
2002 Cripto functions as both a coreceptor (in cis) and a secreted coligand (in trans) for Nodal signaling. The ability of Cripto to bind Nodal and mediate Nodal signaling requires addition of an O-linked fucose monosaccharide to a conserved site within EGF-CFC proteins. Luciferase reporter assay, cell coculture assays, glycosylation inhibition studies Molecular and cellular biology High 12052855
2002 Cripto-1 binds to cell surface ALK4 on mammary epithelial cells (shown by FACS and co-immunoprecipitation). In the presence of Nodal and ALK4, CR-1 phosphorylates Smad2. CR-1 activation of MAPK and Akt is independent of Nodal and ALK4, indicating CR-1 modulates distinct signaling pathways. FACS binding assay, co-immunoprecipitation, phage display library screening, Smad2 phosphorylation assay Molecular and cellular biology High 11909953
2003 Cripto-1 specifically binds Glypican-1, a membrane-associated heparan sulfate proteoglycan, and activates tyrosine kinase c-Src, triggering MAPK and Akt signaling pathways independently of Nodal and ALK4. Active Src kinase is necessary for CR-1-induced in vitro transformation and migration. Binding assays, co-immunoprecipitation, kinase activity assays, transformation and migration assays with Src inhibition Cancer research High 12649175
2003 Nodal/Cripto/Alk4 pathway controls cardiomyogenesis in embryonic stem cells. Cripto signaling activates the Smad2 pathway; overexpression of activated ActRIB compensates for loss of Cripto in promoting cardiomyogenesis. Nodal antagonists inhibit Cripto-regulated cardiomyocyte induction. ES cell differentiation assay, genetic epistasis (ActRIB overexpression rescue), Nodal antagonist treatment, Smad2 activation assay The Journal of cell biology High 14581455
2006 Cripto binds TGF-β and reduces the association of TGF-β with its type I receptor TβRI, thereby suppressing TGF-β signaling and diminishing the cytostatic effects of TGF-β in mammary epithelial cells. siRNA knockdown of endogenous Cripto enhanced TGF-β signaling. Direct binding assay, receptor assembly co-immunoprecipitation, TGF-β reporter assay, siRNA knockdown, cytostasis assay Molecular and cellular biology High 17030617
2007 GPI attachment of Cripto-1 is required for its paracrine (trans) activity as a Nodal co-receptor. Soluble COOH-terminal-truncated forms of CR-1 have significantly lower activity than GPI-anchored CR-1 for inducing Nodal signaling in trans and in cis. PI-PLC treatment removes cell-surface CR-1 and renders cells refractory to Nodal. GPI omega-site identification, truncation mutant functional assays, PI-PLC treatment, Nodal signaling reporter assays, fluorescent cell-labeling paracrine assay The Journal of biological chemistry High 17925387
2007 CR-1 shedding from the membrane to a soluble form is mediated by GPI-phospholipase D (GPI-PLD) activity at the GPI-anchorage site. Growth factors (EGF, LPA, serum) trigger shedding. Soluble CR-1 promotes endothelial cell migration as a paracrine factor, while membrane-bound CR-1 stimulates endothelial sprouting through direct cell-cell contact. siRNA knockdown of GPI-PLD, GPI-PLD overexpression, conditioned medium migration assays, co-culture sprouting assays The Journal of biological chemistry High 17720976
2008 Cripto binds the proprotein convertases Furin and PACE4 and localizes Nodal processing at the cell surface. Cripto and uncleaved Nodal associate during secretion; Cripto guides the Nodal precursor in detergent-resistant membranes to endocytic microdomains marked by GFP-Flotillin, coupling Nodal processing and endocytosis. Co-immunoprecipitation, brefeldin A treatment, density gradient fractionation, antibody uptake experiments, fluorescence imaging The EMBO journal High 18772886
2009 Cell surface GRP78 is a necessary mediator of Cripto signaling. Targeted disruption of the Cripto/GRP78 complex using shRNAs or GRP78 immunoneutralization blocks Cripto activation of MAPK/PI3K pathways and modulation of activin-A, activin-B, Nodal and TGF-β1 signaling, and prevents Cripto-mediated proliferation, E-cadherin downregulation, and decreased cell adhesion. shRNA knockdown, GRP78 immunoneutralization, phospho-signaling assays, proliferation and adhesion assays Oncogene High 19421146
2009 Cripto-1 binds all four mammalian Notch receptors (confirmed by co-immunoprecipitation). The CFC domain of Cripto-1 and the C-terminal EGF-like repeats of Notch1 mediate the interaction, occurring mainly in the ER-Golgi network. Cripto-1 recruits Notch1 into lipid raft microdomains and enhances furin-like protease-mediated S1 cleavage (proteolytic maturation) of Notch1, sensitizing it to ligand-induced Notch signaling activation. Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, lipid raft fractionation, S1 cleavage assay, knockdown of Cripto-1 The Journal of cell biology High 19948478
1999 Cripto-1 induces phosphorylation of AKT and GSK-3β via a PI3K-dependent pathway in human cervical carcinoma cells. PI3K inhibition blocks Cripto-1-mediated AKT and GSK-3β phosphorylation and leads to apoptosis, which can be partially rescued by exogenous CR-1. Phosphorylation assays, PI3K inhibitor (LY294002) treatment, apoptosis assay, rescue experiment Cancer research Medium 10493495
1999 Cripto-1 indirectly induces tyrosine phosphorylation of ErbB-4 but not ErbB-2 or ErbB-3. Down-regulation of ErbB-4 impairs CR-1-mediated MAPK activation. Chemical cross-linking of 125I-CR-1 identifies two specific binding bands at 130 kDa and 60 kDa distinct from known ErbB receptors. Tyrosine phosphorylation assay, anti-ErbB-4 blocking antibody, hammerhead ribozyme, chemical crosslinking of radiolabeled CR-1 The Journal of biological chemistry Medium 10085099
1994 CR-1 is a glycoprotein: N-glycosidase F digestion shifts the 27–29 kDa human CR-1 protein to 20 kDa, and tunicamycin treatment produces a similar shift. CR-1 growth stimulatory activity is not mediated through the EGF receptor, as anti-EGF receptor antibody did not inhibit CR-1 action and CR-1 failed to inhibit 125I-EGF binding. Western blot, immunoprecipitation, N-glycosidase F digestion, tunicamycin treatment, 125I-EGF radioreceptor assay, EGF receptor blocking antibody, proliferation assay The Journal of biological chemistry Medium 8006041
2006 Germ cell nuclear factor (GCNF) directly represses CRIPTO-1 transcription by binding to a DR0 element in the CRIPTO-1 promoter during differentiation. GCNF binding was confirmed in vitro (EMSA) and in vivo (ChIP); GCNF-VP16 fusion prevented retinoic acid-induced downregulation of CRIPTO-1. EMSA, chromatin immunoprecipitation, luciferase reporter assay, GCNF overexpression and GCNF-VP16 fusion expression The Journal of biological chemistry High 16954206
2007 β-Catenin/TCF/LEF directly regulate expression of the short form of human Cripto-1 through an intronic-exonic enhancer element containing three tandem TCF/LEF binding sites within the CR-1 gene. Luciferase reporter assay, TCF/LEF binding site identification and mutation, chromatin analysis in colon carcinoma and hepatoma cell lines Biochemical and biophysical research communications Medium 17291450
2009 HIF-1α directly regulates Cripto-1 expression by binding to hypoxia-responsive elements in the Cripto-1 promoter. Cripto-1 is required for hypoxia to induce cardiomyocyte differentiation from mouse ES cells; hypoxia fails to induce cardiomyogenesis in Cripto-1-deficient mES cells. ChIP for HIF-1α at Cripto-1 promoter, ES cell differentiation assay under hypoxia, Cripto-1 knockout/knockdown in mES cells The American journal of pathology High 19834060
2012 Cripto-1 binds to Wnt co-receptors LRP5 and LRP6, facilitating Wnt3a binding to LRP5/6 and enhancing Wnt3a signaling through cytoplasmic β-catenin stabilization and elevated β-catenin/Tcf transcriptional activation. Co-immunoprecipitation, β-catenin cytoplasmic stabilization assay, TCF/β-catenin reporter assay, invasion and colony formation assays Cellular signalling Medium 23022962
2012 Conditional inactivation of Cripto in adult satellite cells compromises skeletal muscle regeneration, while gain of function accelerates regeneration and leads to muscle hypertrophy. Cripto promotes myogenic cell proliferation and determination by antagonizing the TGF-β ligand myostatin. Conditional knockout in satellite cells, gain-of-function overexpression, muscle regeneration assays, myostatin antagonism functional assay Proceedings of the National Academy of Sciences of the United States of America High 23129614
2009 The CFC domain of Cripto interacts with the ALK4 receptor extracellular domain with a KD in the micromolar range. Residues H120 and W124 of the CFC domain, previously identified by mutagenesis, are positioned to interact at the CFC-ALK4 interface. The CFC domain does not interact with ActRIIB. NMR structural characterization of synthetic CFC domain, SPR binding studies, molecular docking Journal of peptide science Medium 19035567
2016 MEF2C transcription factor directly activates Tdgf1 (Cripto) transcription in the anterior second heart field via an AHF-restricted Tdgf1 enhancer. Loss of Mef2c in the AHF causes outflow tract alignment defects, placing TDGF1 downstream of MEF2C in cardiac development. Conditional Mef2c knockout in AHF, Tdgf1 enhancer reporter assay, ChIP for MEF2C binding, genetic epistasis Development (Cambridge, England) High 26811383
2018 Cripto-1 binds Frizzled-7 (FZD7), LRP6, and Dishevelled-3 (DVL3) of the Wnt/β-catenin pathway and stabilizes DVL3 protein, activating the Wnt/β-catenin signaling cascade to confer stemness in hepatocellular carcinoma. Forced expression of constitutively active β-catenin partially rescues stemness suppression upon Cripto-1 knockdown. Co-immunoprecipitation of FZD7/LRP6/DVL3, DVL3 protein stability assay, β-catenin reporter assay, Cripto-1 knockdown, constitutively active β-catenin rescue Cell death and differentiation Medium 29445127
2016 Cripto sustains mouse ESC self-renewal by modulating Wnt/β-catenin signaling, while it maintains mouse EpiSC and human ESC pluripotency through Nodal/Smad2 signaling. Cripto deficiency permits ESC transdifferentiation into trophectoderm lineage and attenuates ESC lineage restriction, demonstrating pathway-specific roles in different pluripotency states. Cripto knockout ES cells, Wnt/β-catenin reporter assay, Smad2 phosphorylation assay, lineage differentiation assays in vitro and in vivo, trophectoderm marker analysis Nature communications High 27586544
2008 Cripto-1 interacts with caveolin-1 (Cav-1) in COS7 cells and mammary epithelial cells. Cav-1 coexpression with Cr-1 markedly reduces Cr-1-mediated migration, invasion, branching, and inhibits Cr-1-mediated activation of c-Src and MAPK. In Cav-1 null/MMTV-CR-1 transgenic mammary cells, enhanced motility and MAPK/c-Src activation are observed. Co-immunoprecipitation, overexpression and co-expression studies, Cav-1 knockout mouse model (Cav-1 null/MMTV-CR-1), migration and invasion assays, signaling assays The American journal of pathology Medium 18202186
2008 Cripto-1 blocks TGF-β1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-β-responsive reporter activity, and TGF-β1-mediated senescence of keratinocytes, indicating Cripto-1 inhibits TGF-β1 signaling in skin epithelial cells. TGF-β receptor binding blockade assay, Smad2/3 phosphorylation assay, luciferase reporter assay, senescence assay, Cripto-1 treatment of primary keratinocytes Molecular cancer research : MCR Medium 18337457
2013 Conditional inactivation of Cripto during mouse gastrulation leads to accumulation of mesenchymal cells around the primitive streak and defects in definitive endoderm formation and allocation. Both the Fgf8-Fgfr1 pathway and p38 MAP kinase activation are partially affected by loss of Cripto function. Conditional Cripto knockout mouse, embryo phenotypic analysis, Fgf8-Fgfr1 pathway and p38 signaling assays Developmental biology Medium 23747598
2017 Computational modeling and molecular dynamics simulations demonstrate that Cripto binding to GRP78 completely changes GRP78 membrane dynamics, preventing GRP78 from dissociating from the membrane and thereby enabling GRP78 tumorigenic functions at the cell surface. Molecular dynamics simulation, structural modeling Protein science Low 29226519
2020 Conditional deletion of Cripto in the myeloid lineage (CriptoMy-LOF) impairs macrophage plasticity in injured muscle and mdx dystrophic muscle: CriptoMy-LOF macrophages fail to expand as anti-inflammatory CD206+ macrophages due to aberrant TGFβ/Smad signaling activation. This reduction in plasticity disturbs vascular remodeling by increasing Endothelial-to-Mesenchymal Transition (EndMT) and exacerbates dystrophic phenotype. Cre-loxP conditional knockout in myeloid lineage, macrophage FACS phenotyping, TGFβ/Smad signaling assay, EndMT analysis in mdx mouse model EMBO reports High 32107853
2021 Cripto participates in a TGF-β–ALK1–Cripto receptor complex at the plasma membrane of chondrocytes, inducing catabolic SMAD1/5 signaling and favoring hypertrophic differentiation, contributing to osteoarthritis. Elevated Cripto expression was validated in murine and human OA cartilage. Co-immunoprecipitation of TGF-β/ALK1/Cripto complex, SMAD1/5 phosphorylation assay, in vitro and ex vivo chondrocyte hypertrophy assays, OA mouse model gene expression analysis The Journal of pathology Medium 34357595
2012 Cripto-1 enhances JAK2/STAT3 phosphorylation in mesenchymal stem cells through a GRP78-dependent mechanism. Anti-GRP78 antibody blocks Cripto-mediated JAK2/STAT3 activation, c-Myc and cyclin D1 upregulation, and the pro-survival effects of Cripto against hypoxia/H2O2-induced apoptosis. Phosphorylation assays (p-JAK2, p-STAT3), anti-GRP78 antibody blocking, STAT3 siRNA, apoptosis assay Annals of the New York Academy of Sciences Low 22901256
2016 Cripto-1 modulates macrophage cytokine secretion (IL-10, TNF-α, IL-6, IL-1β) and phagocytic activity via activation of NF-κB signaling, specifically through IκB kinase phosphorylation and p65 nuclear translocation. NF-κB inhibition blocks these Cripto-1-induced effects. NF-κB inhibitor (APDC) treatment, IKK phosphorylation assay, p65 nuclear translocation assay, cytokine ELISA, phagocytosis assay Immunologic research Medium 26476731

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Molecular cell 317 11389842
2002 Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Molecular and cellular biology 175 12052855
2009 Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene 153 19421146
2003 Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells. The Journal of cell biology 137 14581455
2005 Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis. Oncogene 136 16123806
2002 Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Molecular and cellular biology 123 11909953
1994 Expression of transforming growth factor alpha, amphiregulin and cripto-1 in human breast carcinomas. British journal of cancer 118 8180021
1993 The murine cripto gene: expression during mesoderm induction and early heart morphogenesis. Development (Cambridge, England) 112 7916676
2000 Membrane-anchorage of Cripto protein by glycosylphosphatidylinositol and its distribution during early mouse development. Mechanisms of development 100 10640699
2010 Role of Cripto-1 in stem cell maintenance and malignant progression. The American journal of pathology 96 20616345
2003 A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src. Cancer research 93 12649175
2014 The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Seminars in cancer biology 92 25153355
2012 Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. The American journal of pathology 89 22542493
1994 Identification and biological characterization of an epidermal growth factor-related protein: cripto-1. The Journal of biological chemistry 89 8006041
2002 A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. Human genetics 85 12073012
2006 Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signaling. Molecular and cellular biology 80 17030617
2001 Cripto-1 enhances migration and branching morphogenesis of mouse mammary epithelial cells. Experimental cell research 77 11339828
1995 Expression of messenger RNA for amphiregulin, heregulin, and cripto-1, three new members of the epidermal growth factor family, in human breast carcinomas. Breast cancer research and treatment 74 7579500
1995 Detection and location of amphiregulin and Cripto-1 expression in the developing postnatal mouse mammary gland. Molecular reproduction and development 74 8588926
2012 Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis. FEBS letters 73 22306319
2006 Identification of cripto-1 as a novel serologic marker for breast and colon cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 71 16951234
1993 Expression of amphiregulin, cripto-1, and heregulin-alpha in human breast-cancer cells. International journal of oncology 70 21573645
2008 Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation. The EMBO journal 69 18772886
2005 Role of human cripto-1 in tumor angiogenesis. Journal of the National Cancer Institute 67 15657343
2002 Transforming growth factor alpha, amphiregulin and cripto-1 are frequently expressed in advanced human ovarian carcinomas. International journal of oncology 65 12370739
1999 Cripto: a novel epidermal growth factor (EGF)-related peptide in mammary gland development and neoplasia. BioEssays : news and reviews in molecular, cellular and developmental biology 65 10070255
1999 Cripto-1 indirectly stimulates the tyrosine phosphorylation of erb B-4 through a novel receptor. The Journal of biological chemistry 65 10085099
2018 Cripto-1 contributes to stemness in hepatocellular carcinoma by stabilizing Dishevelled-3 and activating Wnt/β-catenin pathway. Cell death and differentiation 64 29445127
2005 Cripto-1: an oncofetal gene with many faces. Current topics in developmental biology 64 15949532
2007 Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration. The Journal of biological chemistry 60 17720976
2002 Cripto: a tumor growth factor and more. Journal of cellular physiology 59 11857442
2015 Cripto-1 as a novel therapeutic target for triple negative breast cancer. Oncotarget 58 26059540
2004 Cripto-1 overexpression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells. Journal of cellular physiology 58 14584041
2004 Cripto: a novel target for antibody-based cancer immunotherapy. Cancer research 54 15173016
1999 Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells. Cancer research 54 10493495
2008 Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression. Breast disease 53 19029628
2016 Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency. Nature communications 51 27586544
2010 Cripto-1 is a cell surface marker for a tumorigenic, undifferentiated subpopulation in human embryonal carcinoma cells. Stem cells (Dayton, Ohio) 51 20549704
2015 Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer. Cell death and differentiation 50 26343543
2011 An evolving web of signaling networks regulated by Cripto-1. Growth factors (Chur, Switzerland) 50 22149969
2007 Requirement of glycosylphosphatidylinositol anchor of Cripto-1 for trans activity as a Nodal co-receptor. The Journal of biological chemistry 50 17925387
2005 Nodal-dependant Cripto signaling in ES cells: from stem cells to tumor biology. Oncogene 50 16123800
2016 MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1. Development (Cambridge, England) 49 26811383
2010 Cripto-1: an embryonic gene that promotes tumorigenesis. Future oncology (London, England) 49 20624125
2009 Cripto-1 is required for hypoxia to induce cardiac differentiation of mouse embryonic stem cells. The American journal of pathology 46 19834060
2009 Enhancement of Notch receptor maturation and signaling sensitivity by Cripto-1. The Journal of cell biology 44 19948478
1996 Detection of amphiregulin and Cripto-1 in mammary tumors from transgenic mice. Molecular carcinogenesis 44 8561865
2012 Cripto-1 enhances the canonical Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors. Cellular signalling 43 23022962
2011 Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling. Development (Cambridge, England) 42 21862554
1998 Cripto: roles in mammary cell growth, survival, differentiation and transformation. Cell death and differentiation 42 10200494
2008 Potential for cripto-1 in defining stem cell-like characteristics in human malignant melanoma. Cell cycle (Georgetown, Tex.) 41 18604175
2012 Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin. Proceedings of the National Academy of Sciences of the United States of America 40 23129614
2002 Role of the EGF-CFC gene cripto in cell differentiation and embryo development. Gene 37 11992720
2017 CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer. Oncogene 34 28394345
1998 Purification and characterization of a recombinant human cripto-1 protein. Growth factors (Chur, Switzerland) 34 9570042
2006 Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3. The Journal of biological chemistry 33 16954206
2011 The role of Cripto-1 in the tumorigenesis and progression of oral squamous cell carcinoma. Oral oncology 31 21824804
2004 Nodal and Cripto-1: embryonic pattern formation genes involved in mammary gland development and tumorigenesis. Journal of mammary gland biology and neoplasia 31 15300009
2018 Cripto-1 Plasmid DNA Vaccination Targets Metastasis and Cancer Stem Cells in Murine Mammary Carcinoma. Cancer immunology research 30 30143536
2011 Expression and functional role of CRIPTO-1 in cutaneous melanoma. British journal of cancer 30 21863025
2014 Cripto-1 expression in glioblastoma multiforme. Brain pathology (Zurich, Switzerland) 29 24521322
2010 Targeting the embryonic gene Cripto-1 in cancer and beyond. Expert opinion on therapeutic patents 29 21073352
2007 beta-Catenin/TCF/LEF regulate expression of the short form human Cripto-1. Biochemical and biophysical research communications 29 17291450
2005 Context-dependent neuronal differentiation and germ layer induction of Smad4-/- and Cripto-/- embryonic stem cells. Molecular and cellular neurosciences 29 15737733
2021 Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update. Frontiers in pain research (Lausanne, Switzerland) 28 35295489
2018 CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma. The Journal of pathology 28 29604056
2009 Riding shotgun: a dual role for the epidermal growth factor-Cripto/FRL-1/Cryptic protein Cripto in Nodal trafficking. Traffic (Copenhagen, Denmark) 28 19302412
2012 Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF-1α in the hypoxic bone marrow niche. Annals of the New York Academy of Sciences 26 22901256
2009 Cripto-1 overexpression is involved in the tumorigenesis of nasopharyngeal carcinoma. BMC cancer 26 19732464
1996 Transfection with a CRIPTO anti-sense plasmid suppresses endogenous CRIPTO expression and inhibits transformation in a human embryonal carcinoma cell line. International journal of cancer 26 8635871
2018 Cripto Enhances Proliferation and Survival of Mesenchymal Stem Cells by Up-Regulating JAK2/STAT3 Pathway in a GRP78-Dependent Manner. Biomolecules & therapeutics 25 28835002
2015 Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors. Molecular oncology 24 26654129
1996 Characterization of the mouse Tdgf1 gene and Tdgf pseudogenes. Mammalian genome : official journal of the International Mammalian Genome Society 23 8661720
2017 Cripto-1 promotes epithelial-mesenchymal transition in prostate cancer via Wnt/β-catenin signaling. Oncology reports 22 28098905
2016 Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF-κB signaling. Immunologic research 22 26476731
2013 The significance of a Cripto-1 positive subpopulation of human melanoma cells exhibiting stem cell-like characteristics. Cell cycle (Georgetown, Tex.) 22 23574716
2008 Cripto-1 alters keratinocyte differentiation via blockade of transforming growth factor-beta1 signaling: role in skin carcinogenesis. Molecular cancer research : MCR 22 18337457
2019 Cripto-1 expression in patients with clear cell renal cell carcinoma is associated with poor disease outcome. Journal of experimental & clinical cancer research : CR 21 31455359
2016 Cripto-1 vaccination elicits protective immunity against metastatic melanoma. Oncoimmunology 21 27467944
2020 Cripto shapes macrophage plasticity and restricts EndMT in injured and diseased skeletal muscle. EMBO reports 20 32107853
2013 Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors. The International journal of developmental biology 20 23784832
2010 Significance and relationship between Cripto-1 and p-STAT3 expression in gastric cancer and precancerous lesions. World journal of gastroenterology 20 20128024
2010 TDGF1 is a novel predictive marker for metachronous metastasis of colorectal cancer. International journal of oncology 19 20126975
2008 Regulation of Cripto-1 signaling and biological activity by caveolin-1 in mammary epithelial cells. The American journal of pathology 19 18202186
2002 Detection and localization of Cripto-1 binding in mouse mammary epithelial cells and in the mouse mammary gland using an immunoglobulin-cripto-1 fusion protein. Journal of cellular physiology 19 11807813
2009 Teratocarcinoma-derived growth factor 1 (TDGF1) sequence variants in patients with congenital heart defect. International journal of cardiology 18 19853938
2023 CX3CR1+ Macrophage Facilitates the Resolution of Allergic Lung Inflammation via Interacting CCL26. American journal of respiratory and critical care medicine 17 36790376
2019 Development of conformational antibodies targeting Cripto-1 with neutralizing effects in vitro. Biochimie 17 30703478
2011 Altered expression of activin, cripto, and follistatin in the endometrium of women with endometrioma. Fertility and sterility 17 21496809
2021 Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells. International journal of molecular sciences 16 34502188
1999 Expression of cripto and amphiregulin in colon mucosa from high risk colon cancer families. International journal of oncology 16 10024674
2013 Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation. Developmental biology 15 23747598
2021 Cripto favors chondrocyte hypertrophy via TGF-β SMAD1/5 signaling during development of osteoarthritis. The Journal of pathology 14 34357595
2014 Expression of Nodal, Cripto, SMAD3, phosphorylated SMAD3, and SMAD4 in the proliferative endometrium of women with endometriosis. Reproductive sciences (Thousand Oaks, Calif.) 14 25228630
2011 Human recombinant Cripto-1 increases doubling time and reduces proliferation of HeLa cells independent of pro-proliferation pathways. Cancer letters 14 22182448
2009 Structural insights into the interaction between the Cripto CFC domain and the ALK4 receptor. Journal of peptide science : an official publication of the European Peptide Society 14 19035567
2007 Cripto-1 expression in uveal melanoma: an immunohistochemical study. Experimental eye research 14 17412323
2021 Cripto-1 as a Potential Target of Cancer Stem Cells for Immunotherapy. Cancers 13 34065315
2017 Clinical significance of cripto-1 expression in lung adenocarcinoma. Oncotarget 13 29108289
2017 Cripto stabilizes GRP78 on the cell membrane. Protein science : a publication of the Protein Society 13 29226519

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