{"gene":"CRIPTO","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2001,"finding":"Cripto interacts with the type I receptor ALK4 via its conserved CFC motif, and this interaction is necessary for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal.","method":"Co-immunoprecipitation, receptor binding assays, Smad2 phosphorylation assays in cell culture","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional signaling assays, widely replicated across multiple labs","pmids":["11389842"],"is_preprint":false},{"year":2002,"finding":"Cripto functions as both a coreceptor and a coligand (secreted signaling factor) for Nodal, and its ability to bind Nodal and mediate Nodal signaling requires O-linked fucosylation at a conserved site within EGF-CFC proteins.","method":"Luciferase reporter assay, cell coculture assays, glycosylation mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — functional assays with glycosylation mutants and cell-based signaling readouts, replicated","pmids":["12052855"],"is_preprint":false},{"year":2000,"finding":"Cripto protein is anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) moiety, as demonstrated by immunofluorescence and biochemical characterization.","method":"Immunofluorescence, biochemical fractionation, PI-PLC treatment","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical characterization with multiple orthogonal methods","pmids":["10640699"],"is_preprint":false},{"year":2003,"finding":"Cripto can form a complex with activin and ActRII/IIB receptors, and inhibits activin signaling by blocking the association of ALK4 with ActRII/IIB; Cripto can simultaneously facilitate Nodal signaling while antagonizing activin signaling.","method":"Chemical crosslinking, co-immunoprecipitation, luciferase reporter assays in HepG2 and 293T cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple binding and functional assays, replicated across cell lines","pmids":["12682303"],"is_preprint":false},{"year":2003,"finding":"Cripto directly binds Activin B via its CFC domain, and overexpression blocks Activin B-induced growth suppression of breast cancer cells; anti-CFC domain antibody disrupts both Cripto-Nodal and Cripto-Activin B interactions by blocking CFC domain association with ALK4 or Activin B.","method":"Binding assays, cell proliferation assays, antibody blocking experiments, xenograft tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated plus functional growth inhibition assays with antibody blockade","pmids":["12925698"],"is_preprint":false},{"year":2003,"finding":"Cripto-dependent Nodal/Cripto/Alk4 (ActRIB) signaling activates the Smad2 pathway and is required for cardiomyogenesis in embryonic stem cells; constitutively active ActRIB compensates for lack of Cripto, placing Cripto upstream of Alk4 in this pathway.","method":"ES cell differentiation assays, Smad2 activation assays, genetic rescue with constitutively active ActRIB, Nodal antagonist treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — epistasis demonstrated by genetic rescue, multiple orthogonal methods","pmids":["14581455"],"is_preprint":false},{"year":2006,"finding":"Cripto binds TGF-β1 directly and reduces association of TGF-β with its type I receptor TβRI, thereby suppressing TGF-β signaling and its cytostatic effects in mammary epithelial cells; siRNA knockdown of Cripto enhances TGF-β signaling, confirming endogenous Cripto restrains TGF-β responses.","method":"Binding assays, Smad phosphorylation assays, siRNA knockdown, cell proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — direct binding plus loss-of-function (siRNA) with defined signaling readouts","pmids":["17030617"],"is_preprint":false},{"year":2007,"finding":"GPI anchorage of Cripto-1 is required for its paracrine (trans) activity as a Nodal co-receptor; soluble truncated forms and transmembrane forms show significantly reduced ability to induce Nodal signaling compared to GPI-anchored Cripto; PI-PLC treatment removes cell-surface Cripto and renders cells refractory to Nodal stimulation.","method":"Fluorescent cell-labeling, immunofluorescence, PI-PLC treatment, luciferase reporter assay with truncation mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution-like assays with multiple mutant constructs and enzymatic removal","pmids":["17925387"],"is_preprint":false},{"year":2008,"finding":"Cripto binds the proprotein convertases Furin and PACE4 and localizes Nodal precursor 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 Flotillin, coupling Nodal processing and endocytosis.","method":"Co-immunoprecipitation, density gradient fractionation, antibody uptake experiments, brefeldin A treatment, confocal microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal binding and trafficking assays in a single study","pmids":["18772886"],"is_preprint":false},{"year":1999,"finding":"Cripto-1 does not bind directly to ErbB receptors but indirectly induces tyrosine phosphorylation of ErbB-4; chemical crosslinking identifies two specific Cripto-1 binding bands of 130 kDa and 60 kDa on mammary epithelial cell membranes, suggesting a novel receptor; functional ErbB-4 is required for Cripto-1-induced MAPK activation.","method":"Chemical crosslinking with 125I-Cripto-1, anti-ErbB-4 blocking antibody, hammerhead ribozyme knockdown of ErbB-4, tyrosine phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — chemical crosslinking identifies receptor; functional epistasis via ribozyme knockdown","pmids":["10085099"],"is_preprint":false},{"year":2005,"finding":"Cripto-1 activates c-Src/PI3K/Akt and Ras/MAPK intracellular pathways through a Nodal/Alk4-independent mechanism that involves binding to the cell surface heparan sulfate proteoglycan glypican-1.","method":"Cell signaling assays, pathway inhibitor studies (review summarizing experimental findings)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — review citing experimental work; binding to glypican-1 and pathway activation established by cited studies","pmids":["16123806"],"is_preprint":false},{"year":2011,"finding":"Cripto signals through cell surface receptor GRP78 to regulate hematopoietic stem cell quiescence in the hypoxic bone marrow niche; Cripto/GRP78 signaling induces higher glycolytic activity and lower mitochondrial potential in HSCs; HIF-1α regulates Cripto expression in the endosteal niche.","method":"Flow cytometry, transplantation assays, in vitro HSC culture with Cripto, HIF-1α knockout mice, GRP78 blocking antibody","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function (GRP78 blocking, HIF-1α KO) with defined functional readouts, multiple orthogonal methods","pmids":["21982233"],"is_preprint":false},{"year":2004,"finding":"Cripto-1 overexpression promotes epithelial-mesenchymal transition, decreasing E-cadherin and increasing N-cadherin, vimentin, Snail, cyclin-D1, and activating c-Src, FAK, Akt, GSK-3β, and β-catenin; c-Src inhibitor PP2 reduces phosphorylation of these downstream mediators and impairs CR-1-enhanced cell migration.","method":"Western blot, immunohistochemistry, Src inhibitor (PP2) treatment, wound-healing/Boyden chamber migration assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway inhibitor defines c-Src as mediator; multiple markers of EMT measured","pmids":["15334661"],"is_preprint":false},{"year":2014,"finding":"CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo; surface GRP78 marks CRIPTO-responsive stem cell-enriched populations; deletion of GRP78 from mammary epithelial cells blocks their mammary gland reconstitution potential.","method":"Mammary gland reconstitution assay, GRP78 conditional knockout, CRIPTO antagonist treatment, ex vivo culture","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout with functional reconstitution assay, CRIPTO antagonist orthogonal approach","pmids":["24749068"],"is_preprint":false},{"year":2012,"finding":"Cripto regulates skeletal muscle regeneration and satellite cell determination by antagonizing the TGF-β ligand myostatin; conditional inactivation of Cripto in adult satellite cells compromises regeneration, while gain-of-function accelerates regeneration and leads to muscle hypertrophy.","method":"Conditional knockout (satellite cell-specific Cripto deletion), gain-of-function overexpression, muscle injury models, myostatin antagonism assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — conditional KO and gain-of-function with defined phenotypic readouts and pathway identification","pmids":["23129614"],"is_preprint":false},{"year":2007,"finding":"Expression of the short form of human Cripto-1 is directly regulated at the transcriptional level by the canonical Wnt/β-catenin/TCF signaling pathway through an intronic-exonic enhancer element containing three tandem TCF/LEF binding sites.","method":"Luciferase reporter assay with TCF/LEF binding site mutations, chromatin-based analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay with defined binding sites identifies transcriptional mechanism","pmids":["17291450"],"is_preprint":false},{"year":2009,"finding":"The CFC domain of human Cripto interacts with the ALK4 receptor with a KD in the micromolar range; NMR analysis shows the CFC domain topology is determined by three disulfide bridges, and residues H120 and W124 are externally exposed and contribute to ALK4 binding as identified by molecular docking consistent with prior mutagenesis data.","method":"NMR spectroscopy, surface plasmon resonance (SPR), molecular docking","journal":"Journal of peptide science","confidence":"Medium","confidence_rationale":"Tier 1 — NMR structure with SPR binding validation; single lab study","pmids":["19035567"],"is_preprint":false},{"year":2016,"finding":"MEF2C directly regulates transcription of Tdgf1 (Cripto) in the anterior second heart field via an AHF-restricted Tdgf1 enhancer; loss of Mef2c in the AHF leads to outflow tract alignment defects and reduced Cripto expression.","method":"Conditional knockout of Mef2c in AHF, Tdgf1 enhancer reporter assay, ChIP-like enhancer analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined transcriptional target via enhancer reporter","pmids":["26811383"],"is_preprint":false},{"year":2010,"finding":"Cripto-1 expression in NTERA2/D1 embryonal carcinoma cells is regulated by a Smad2/3-dependent autocrine loop, by Oct4/Nanog transcription factors, and partially by DNA methylation status of the promoter region.","method":"siRNA knockdown of Smad2/3, Oct4, Nanog; promoter methylation analysis; luciferase reporter assay","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple loss-of-function approaches identifying upstream regulators of Cripto expression","pmids":["20549704"],"is_preprint":false},{"year":2020,"finding":"Cripto in muscle-infiltrating macrophages is required for anti-inflammatory CD206+ macrophage expansion during regeneration; conditional deletion of Cripto in the myeloid lineage causes aberrant TGFβ/Smad signaling activation in macrophages, impairs macrophage plasticity, increases Endothelial-to-Mesenchymal Transition (EndMT), and exacerbates muscular dystrophy.","method":"Conditional myeloid-specific Cripto knockout (CriptoMy-LOF), mdx model, TGFβ/Smad signaling assays, vascular remodeling analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined molecular mechanism (TGFβ/Smad) and multiple phenotypic readouts","pmids":["32107853"],"is_preprint":false},{"year":2016,"finding":"Cripto-1 activates NF-κB signaling in macrophages by inducing IκB kinase phosphorylation and p65 nuclear translocation, enhancing cytokine secretion and phagocytic activity; NF-κB inhibitor blocks these Cripto-1-induced effects.","method":"Stable Cripto-1 overexpressing cell line, macrophage conditioning assays, NF-κB inhibitor (PDTC) treatment, Western blot for IκB kinase and p65","journal":"Immunologic research","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway inhibitor and signaling markers define NF-κB as mediator; single lab","pmids":["26476731"],"is_preprint":false},{"year":2013,"finding":"Conditional inactivation of Cripto during gastrulation results in accumulation of mesenchymal cells around the primitive streak and defects in mesoderm and definitive endoderm formation; both the Fgf8-Fgfr1 pathway and p38 MAP kinase activation are partially affected by loss of Cripto.","method":"Conditional Cripto knockout during gastrulation, embryo phenotyping, pathway analysis (Fgf8-Fgfr1, p38 MAPK)","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with pathway analysis; single lab","pmids":["23747598"],"is_preprint":false},{"year":2022,"finding":"CRIPTO is present on both small and large extracellular vesicles (EVs) released by teratocarcinoma cells; large EVs containing CRIPTO specifically impair migration of glioblastoma recipient cells without affecting proliferation or drug sensitivity.","method":"Differential centrifugation EV isolation, Western blot, nanoparticle tracking analysis, cell migration assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization to EVs with functional migration assay; single lab","pmids":["35954365"],"is_preprint":false},{"year":2018,"finding":"Cripto enhances proliferation and survival of mesenchymal stem cells by activating the JAK2/STAT3 pathway in a GRP78-dependent manner; anti-GRP78 antibody blocks Cripto-induced p-JAK2, p-STAT3, c-Myc, cyclin D1, and BCL3 upregulation.","method":"Anti-GRP78 blocking antibody, STAT3 siRNA, BCL3 siRNA, Western blot for pathway components, proliferation/apoptosis assays","journal":"Biomolecules & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — receptor blocking antibody and siRNA define GRP78/JAK2/STAT3 pathway; single lab","pmids":["28835002"],"is_preprint":false}],"current_model":"CRIPTO (TDGF1) is a GPI-anchored, O-fucosylated EGF-CFC cell-surface glycoprotein that acts as an obligate co-receptor for TGF-β family ligands Nodal, GDF1, and GDF3 by binding them and ALK4 (via its CFC domain) to assemble productive ALK4/ActRIIB signaling complexes that activate Smad2/3; it also recruits Furin/PACE4 to couple Nodal precursor processing with endocytosis in Flotillin-marked microdomains, inhibits signaling by activin-A/B and TGF-β1 by blocking receptor complex assembly, and in a GRP78-dependent Nodal/ALK4-independent manner activates Src/MAPK/PI3K-Akt and JAK2/STAT3 pathways, collectively promoting EMT, stem cell maintenance, and tumorigenesis while antagonizing myostatin during muscle regeneration and regulating macrophage plasticity via TGFβ/Smad signaling."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that CRIPTO signals through a novel, non-ErbB receptor to activate MAPK resolved the paradox of CRIPTO-induced ErbB-4 phosphorylation without direct ErbB binding, pointing to an unidentified receptor intermediate.","evidence":"Chemical crosslinking with radiolabeled CRIPTO and ErbB-4 blocking antibody/ribozyme knockdown in mammary epithelial cells","pmids":["10085099"],"confidence":"Medium","gaps":["The 130 kDa and 60 kDa binding species were not molecularly identified","Mechanism by which ErbB-4 is indirectly activated remains unclear"]},{"year":2000,"claim":"Demonstrating GPI anchorage of CRIPTO established its membrane-tethered topology, explaining how a protein lacking a transmembrane domain operates as a cell-surface co-receptor.","evidence":"PI-PLC treatment, immunofluorescence, and biochemical fractionation","pmids":["10640699"],"confidence":"High","gaps":["Whether GPI anchorage is required for signaling activity was not tested"]},{"year":2001,"claim":"Identification of the CFC domain as the interface for ALK4 binding, and demonstration that this interaction is required for Nodal to engage the ALK4/ActRIIB complex and activate Smad2, defined CRIPTO's core co-receptor mechanism.","evidence":"Reciprocal co-immunoprecipitation, receptor binding assays, and Smad2 phosphorylation assays","pmids":["11389842"],"confidence":"High","gaps":["Structural basis of CFC–ALK4 interaction not resolved at atomic level","Whether CRIPTO contacts Nodal and ALK4 simultaneously was not demonstrated"]},{"year":2002,"claim":"Showing that O-linked fucosylation is essential for Nodal binding and signaling revealed a post-translational modification requirement that gates CRIPTO co-receptor competence.","evidence":"Glycosylation site mutants tested in luciferase reporter and cell co-culture signaling assays","pmids":["12052855"],"confidence":"High","gaps":["The fucosyltransferase responsible was not identified in this study","Whether fucosylation affects other CRIPTO ligand interactions was untested"]},{"year":2003,"claim":"Discovery that CRIPTO simultaneously promotes Nodal signaling and antagonizes activin signaling—by binding activin and blocking its ALK4/ActRII assembly—revealed a dual agonist/antagonist logic governing TGF-β pathway selectivity.","evidence":"Chemical crosslinking, co-immunoprecipitation, and luciferase reporter assays across HepG2 and 293T cells; antibody blocking of CFC domain","pmids":["12682303","12925698"],"confidence":"High","gaps":["Stoichiometry and competitive binding kinetics between Nodal and activin for CRIPTO were not quantified"]},{"year":2003,"claim":"Epistasis experiments placing CRIPTO upstream of ALK4 in cardiomyogenesis established its role as an obligate Nodal pathway component during lineage commitment.","evidence":"Rescue of Cripto-null ES cell differentiation defect by constitutively active ALK4","pmids":["14581455"],"confidence":"High","gaps":["Whether CRIPTO has ALK4-independent roles in cardiac specification was not addressed"]},{"year":2004,"claim":"Linking CRIPTO overexpression to a full EMT program (E-cadherin loss, N-cadherin/vimentin/Snail gain) through c-Src identified CRIPTO as a driver of mesenchymal conversion independent of canonical TGF-β/Smad signaling.","evidence":"Src inhibitor PP2, migration assays, and EMT marker profiling by Western blot","pmids":["15334661"],"confidence":"Medium","gaps":["The receptor mediating c-Src activation was not identified","In vivo relevance of CRIPTO-driven EMT not demonstrated in this study"]},{"year":2006,"claim":"Demonstrating that CRIPTO directly binds TGF-β1 and blocks its engagement with TβRI extended the antagonism model beyond activins, establishing CRIPTO as a broad suppressor of growth-inhibitory TGF-β superfamily signaling.","evidence":"Binding assays, Smad phosphorylation, siRNA knockdown of endogenous CRIPTO in mammary epithelial cells","pmids":["17030617"],"confidence":"High","gaps":["Whether CRIPTO antagonizes other TGF-β isoforms (TGF-β2, TGF-β3) was not tested"]},{"year":2007,"claim":"Proving that GPI anchorage is required for trans (paracrine) Nodal co-receptor activity resolved how a GPI-linked protein without a cytoplasmic domain organizes signaling complexes on opposing cells.","evidence":"Truncation mutants, transmembrane chimeras, and PI-PLC treatment with luciferase reporter readout","pmids":["17925387"],"confidence":"High","gaps":["Mechanism of trans-signaling across cell membranes by a GPI-linked protein remains structurally unresolved"]},{"year":2008,"claim":"Showing that CRIPTO recruits Furin/PACE4 and couples Nodal precursor processing to endocytosis in Flotillin-positive membrane microdomains revealed a trafficking-dependent mechanism that integrates ligand maturation with receptor activation.","evidence":"Co-immunoprecipitation with Furin/PACE4, density gradient fractionation, confocal microscopy of Flotillin compartments, brefeldin A block","pmids":["18772886"],"confidence":"High","gaps":["Whether endocytosis is strictly required for signaling output was not tested by endocytosis-blocking mutants"]},{"year":2009,"claim":"NMR determination of CFC domain topology and SPR measurement of micromolar-affinity ALK4 binding provided the first structural framework for the CRIPTO co-receptor interface.","evidence":"NMR spectroscopy, surface plasmon resonance, molecular docking validated against prior mutagenesis","pmids":["19035567"],"confidence":"Medium","gaps":["No co-crystal structure of CFC–ALK4 complex exists","Full-length CRIPTO structure remains undetermined"]},{"year":2011,"claim":"Identification of GRP78 as a cell-surface CRIPTO receptor on hematopoietic stem cells, mediating quiescence via metabolic reprogramming under hypoxia, established a Nodal/ALK4-independent signaling axis in the bone marrow niche.","evidence":"GRP78 blocking antibody, HIF-1α knockout mice, HSC transplantation and metabolic assays","pmids":["21982233"],"confidence":"High","gaps":["How CRIPTO–GRP78 engagement is transduced to intracellular kinases was not fully defined","Whether this pathway operates in non-hematopoietic stem niches was unknown"]},{"year":2012,"claim":"Demonstrating that CRIPTO antagonizes myostatin in satellite cells to promote muscle regeneration established an adult tissue-repair function and expanded the range of TGF-β ligands controlled by CRIPTO.","evidence":"Satellite cell-specific conditional knockout and gain-of-function in muscle injury models","pmids":["23129614"],"confidence":"High","gaps":["Whether CRIPTO binds myostatin directly or acts indirectly through shared receptors was not resolved"]},{"year":2014,"claim":"Showing that CRIPTO/GRP78 maintains both fetal and adult mammary stem cells, with GRP78 conditional deletion abolishing reconstitution potential, validated the GRP78 axis as a general stem cell maintenance pathway.","evidence":"Mammary gland reconstitution assay, GRP78 conditional knockout, CRIPTO antagonist treatment","pmids":["24749068"],"confidence":"High","gaps":["Downstream effectors of GRP78 in mammary stem cells were not fully mapped"]},{"year":2018,"claim":"Defining JAK2/STAT3 as the intracellular cascade downstream of CRIPTO–GRP78 in mesenchymal stem cells provided a specific signaling pathway linking this receptor pair to proliferation and survival.","evidence":"Anti-GRP78 blocking antibody, STAT3 and BCL3 siRNA, Western blot for pathway components","pmids":["28835002"],"confidence":"Medium","gaps":["How GRP78 activates JAK2 mechanistically is unknown","Whether JAK2/STAT3 mediates all GRP78-dependent CRIPTO functions is untested"]},{"year":2020,"claim":"Myeloid-specific Cripto deletion revealed that CRIPTO restrains TGFβ/Smad signaling in macrophages to enable anti-inflammatory polarization, linking CRIPTO to immune cell plasticity and dystrophic muscle pathology.","evidence":"Conditional myeloid-specific Cripto knockout in mdx dystrophy model, TGFβ/Smad signaling and vascular remodeling analysis","pmids":["32107853"],"confidence":"High","gaps":["Whether CRIPTO acts on macrophages via GRP78 or another receptor in this context is unknown","Relevance to non-dystrophic inflammatory conditions untested"]},{"year":null,"claim":"The structural basis of CRIPTO's simultaneous engagement with multiple TGF-β ligands and receptors, the precise mechanism coupling GRP78 binding to intracellular kinase activation, and whether extracellular vesicle-associated CRIPTO constitutes a physiologically significant signaling mode remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure of any CRIPTO–ligand–receptor ternary complex","GRP78-to-JAK2 signal transduction mechanism undefined","EV-associated CRIPTO function demonstrated only in one in vitro system"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,6,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,7,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5,6,10,11,12,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,17,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,20]}],"complexes":["Nodal/CRIPTO/ALK4/ActRIIB signaling complex"],"partners":["ALK4","GRP78","NODAL","FURIN","PACE4","ACVR2B","TGFB1"],"other_free_text":[]},"mechanistic_narrative":"CRIPTO (TDGF1) is a GPI-anchored, O-fucosylated EGF-CFC family glycoprotein that serves as a multifunctional co-receptor integrating TGF-β superfamily signaling at the cell surface to control embryonic patterning, stem cell maintenance, tissue regeneration, and tumorigenesis. Through its CFC domain, CRIPTO binds the type I receptor ALK4 and is required for Nodal to assemble productive ALK4/ActRIIB complexes that activate Smad2/3 signaling [PMID:11389842, PMID:14581455]; it simultaneously antagonizes activin-A/B and TGF-β1 signaling by sequestering these ligands away from their cognate receptor complexes, thereby relieving cytostatic constraints on cell proliferation [PMID:12682303, PMID:17030617]. Independent of Nodal/ALK4, CRIPTO engages cell-surface GRP78 to activate c-Src/MAPK/PI3K-Akt and JAK2/STAT3 pathways, promoting epithelial–mesenchymal transition, hematopoietic and mammary stem cell maintenance, and mesenchymal stem cell survival [PMID:21982233, PMID:24749068, PMID:28835002, PMID:15334661]. In adult tissues, CRIPTO antagonizes myostatin in satellite cells to drive skeletal muscle regeneration and modulates macrophage plasticity by restraining TGFβ/Smad signaling, with myeloid-specific deletion exacerbating muscular dystrophy [PMID:23129614, PMID:32107853]."},"prefetch_data":{"uniprot":{"accession":"P13385","full_name":"Protein Cripto","aliases":["Cripto, EGF-CFC family member","Cripto-1 growth factor","CRGF","Epidermal growth factor-like cripto protein CR1","Teratocarcinoma-derived growth factor 1"],"length_aa":188,"mass_kda":21.2,"function":"GPI-anchored cell membrane protein involved in Nodal signaling. Cell-associated CRIPTO acts as a Nodal coreceptor in cis. Shedding of CRIPTO by TMEM8A modulates Nodal signaling by allowing soluble CRIPTO to act as a Nodal coreceptor on other cells (PubMed:27881714). Could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm (PubMed:11909953)","subcellular_location":"Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P13385/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CRIPTO","classification":"Common Essential","n_dependent_lines":780,"n_total_lines":1208,"dependency_fraction":0.6456953642384106},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CRIPTO","total_profiled":1310},"omim":[{"mim_id":"619342","title":"POST-GPI ATTACHMENT TO PROTEINS 6; PGAP6","url":"https://www.omim.org/entry/619342"},{"mim_id":"608981","title":"ACTIVIN A RECEPTOR, TYPE IC; ACVR1C","url":"https://www.omim.org/entry/608981"},{"mim_id":"607491","title":"PROTEIN O-FUCOSYLTRANSFERASE 1; POFUT1","url":"https://www.omim.org/entry/607491"},{"mim_id":"606522","title":"GROWTH/DIFFERENTIATION FACTOR 3; GDF3","url":"https://www.omim.org/entry/606522"},{"mim_id":"605194","title":"CRYPTIC, EGF-CFC FAMILY MEMBER 1; CFC1","url":"https://www.omim.org/entry/605194"}],"hpa":{"profiled":true,"resolved_as":"TDGF1","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":18.8},{"tissue":"lymphoid tissue","ntpm":19.7},{"tissue":"ovary","ntpm":9.4}],"url":"https://www.proteinatlas.org/search/TDGF1"},"hgnc":{"alias_symbol":["CR","Cripto-1","CR-1"],"prev_symbol":["TDGF1"]},"alphafold":{"accession":"P13385","domains":[{"cath_id":"2.10.25.10","chopping":"75-112","consensus_level":"medium","plddt":89.1624,"start":75,"end":112},{"cath_id":"-","chopping":"115-149","consensus_level":"medium","plddt":92.0117,"start":115,"end":149}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13385","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13385-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13385-F1-predicted_aligned_error_v6.png","plddt_mean":68.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRIPTO","jax_strain_url":"https://www.jax.org/strain/search?query=CRIPTO"},"sequence":{"accession":"P13385","fasta_url":"https://rest.uniprot.org/uniprotkb/P13385.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13385/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13385"}},"corpus_meta":[{"pmid":"11389842","id":"PMC_11389842","title":"Nodal 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gracilis.","date":"2010","source":"Aquatic toxicology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/20851473","citation_count":16,"is_preprint":false},{"pmid":"23747598","id":"PMC_23747598","title":"Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation.","date":"2013","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/23747598","citation_count":15,"is_preprint":false},{"pmid":"33321321","id":"PMC_33321321","title":"Efficient reduction of reactive black 5 and Cr(Ⅵ) by a newly isolated bacterium of Ochrobactrum anthropi.","date":"2020","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/33321321","citation_count":15,"is_preprint":false},{"pmid":"34502188","id":"PMC_34502188","title":"Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34502188","citation_count":14,"is_preprint":false},{"pmid":"25228630","id":"PMC_25228630","title":"Expression of Nodal, Cripto, SMAD3, phosphorylated SMAD3, and SMAD4 in the proliferative endometrium of women with endometriosis.","date":"2014","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/25228630","citation_count":14,"is_preprint":false},{"pmid":"22182448","id":"PMC_22182448","title":"Human recombinant Cripto-1 increases doubling time and reduces proliferation of HeLa cells independent of pro-proliferation pathways.","date":"2011","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/22182448","citation_count":14,"is_preprint":false},{"pmid":"35954365","id":"PMC_35954365","title":"A Novel Localization in Human Large Extracellular Vesicles for the EGF-CFC Founder Member CRIPTO and Its Biological and Therapeutic Implications.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35954365","citation_count":14,"is_preprint":false},{"pmid":"23500129","id":"PMC_23500129","title":"Quantitative proteome analysis of overexpressed Cripto-1 tumor cell reveals 14-3-3γ as a novel biomarker in nasopharyngeal carcinoma.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23500129","citation_count":14,"is_preprint":false},{"pmid":"19035567","id":"PMC_19035567","title":"Structural insights into the interaction between the Cripto CFC domain and the ALK4 receptor.","date":"2009","source":"Journal of peptide science : an official publication of the European Peptide Society","url":"https://pubmed.ncbi.nlm.nih.gov/19035567","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46246,"output_tokens":5310,"usd":0.109194},"stage2":{"model":"claude-opus-4-6","input_tokens":8966,"output_tokens":3665,"usd":0.204682},"total_usd":0.313876,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Cripto interacts with the type I receptor ALK4 via its conserved CFC motif, and this interaction is necessary for Nodal binding to the ALK4/ActR-IIB receptor complex and for Smad2 activation by Nodal.\",\n      \"method\": \"Co-immunoprecipitation, receptor binding assays, Smad2 phosphorylation assays in cell culture\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional signaling assays, widely replicated across multiple labs\",\n      \"pmids\": [\"11389842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cripto functions as both a coreceptor and a coligand (secreted signaling factor) for Nodal, and its ability to bind Nodal and mediate Nodal signaling requires O-linked fucosylation at a conserved site within EGF-CFC proteins.\",\n      \"method\": \"Luciferase reporter assay, cell coculture assays, glycosylation mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional assays with glycosylation mutants and cell-based signaling readouts, replicated\",\n      \"pmids\": [\"12052855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Cripto protein is anchored to the plasma membrane via a glycosylphosphatidylinositol (GPI) moiety, as demonstrated by immunofluorescence and biochemical characterization.\",\n      \"method\": \"Immunofluorescence, biochemical fractionation, PI-PLC treatment\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical characterization with multiple orthogonal methods\",\n      \"pmids\": [\"10640699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cripto can form a complex with activin and ActRII/IIB receptors, and inhibits activin signaling by blocking the association of ALK4 with ActRII/IIB; Cripto can simultaneously facilitate Nodal signaling while antagonizing activin signaling.\",\n      \"method\": \"Chemical crosslinking, co-immunoprecipitation, luciferase reporter assays in HepG2 and 293T cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding and functional assays, replicated across cell lines\",\n      \"pmids\": [\"12682303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cripto directly binds Activin B via its CFC domain, and overexpression blocks Activin B-induced growth suppression of breast cancer cells; anti-CFC domain antibody disrupts both Cripto-Nodal and Cripto-Activin B interactions by blocking CFC domain association with ALK4 or Activin B.\",\n      \"method\": \"Binding assays, cell proliferation assays, antibody blocking experiments, xenograft tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated plus functional growth inhibition assays with antibody blockade\",\n      \"pmids\": [\"12925698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cripto-dependent Nodal/Cripto/Alk4 (ActRIB) signaling activates the Smad2 pathway and is required for cardiomyogenesis in embryonic stem cells; constitutively active ActRIB compensates for lack of Cripto, placing Cripto upstream of Alk4 in this pathway.\",\n      \"method\": \"ES cell differentiation assays, Smad2 activation assays, genetic rescue with constitutively active ActRIB, Nodal antagonist treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis demonstrated by genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"14581455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cripto binds TGF-β1 directly and reduces association of TGF-β with its type I receptor TβRI, thereby suppressing TGF-β signaling and its cytostatic effects in mammary epithelial cells; siRNA knockdown of Cripto enhances TGF-β signaling, confirming endogenous Cripto restrains TGF-β responses.\",\n      \"method\": \"Binding assays, Smad phosphorylation assays, siRNA knockdown, cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding plus loss-of-function (siRNA) with defined signaling readouts\",\n      \"pmids\": [\"17030617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GPI anchorage of Cripto-1 is required for its paracrine (trans) activity as a Nodal co-receptor; soluble truncated forms and transmembrane forms show significantly reduced ability to induce Nodal signaling compared to GPI-anchored Cripto; PI-PLC treatment removes cell-surface Cripto and renders cells refractory to Nodal stimulation.\",\n      \"method\": \"Fluorescent cell-labeling, immunofluorescence, PI-PLC treatment, luciferase reporter assay with truncation mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution-like assays with multiple mutant constructs and enzymatic removal\",\n      \"pmids\": [\"17925387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cripto binds the proprotein convertases Furin and PACE4 and localizes Nodal precursor 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 Flotillin, coupling Nodal processing and endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, density gradient fractionation, antibody uptake experiments, brefeldin A treatment, confocal microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal binding and trafficking assays in a single study\",\n      \"pmids\": [\"18772886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Cripto-1 does not bind directly to ErbB receptors but indirectly induces tyrosine phosphorylation of ErbB-4; chemical crosslinking identifies two specific Cripto-1 binding bands of 130 kDa and 60 kDa on mammary epithelial cell membranes, suggesting a novel receptor; functional ErbB-4 is required for Cripto-1-induced MAPK activation.\",\n      \"method\": \"Chemical crosslinking with 125I-Cripto-1, anti-ErbB-4 blocking antibody, hammerhead ribozyme knockdown of ErbB-4, tyrosine phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical crosslinking identifies receptor; functional epistasis via ribozyme knockdown\",\n      \"pmids\": [\"10085099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cripto-1 activates c-Src/PI3K/Akt and Ras/MAPK intracellular pathways through a Nodal/Alk4-independent mechanism that involves binding to the cell surface heparan sulfate proteoglycan glypican-1.\",\n      \"method\": \"Cell signaling assays, pathway inhibitor studies (review summarizing experimental findings)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review citing experimental work; binding to glypican-1 and pathway activation established by cited studies\",\n      \"pmids\": [\"16123806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cripto signals through cell surface receptor GRP78 to regulate hematopoietic stem cell quiescence in the hypoxic bone marrow niche; Cripto/GRP78 signaling induces higher glycolytic activity and lower mitochondrial potential in HSCs; HIF-1α regulates Cripto expression in the endosteal niche.\",\n      \"method\": \"Flow cytometry, transplantation assays, in vitro HSC culture with Cripto, HIF-1α knockout mice, GRP78 blocking antibody\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (GRP78 blocking, HIF-1α KO) with defined functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"21982233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cripto-1 overexpression promotes epithelial-mesenchymal transition, decreasing E-cadherin and increasing N-cadherin, vimentin, Snail, cyclin-D1, and activating c-Src, FAK, Akt, GSK-3β, and β-catenin; c-Src inhibitor PP2 reduces phosphorylation of these downstream mediators and impairs CR-1-enhanced cell migration.\",\n      \"method\": \"Western blot, immunohistochemistry, Src inhibitor (PP2) treatment, wound-healing/Boyden chamber migration assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway inhibitor defines c-Src as mediator; multiple markers of EMT measured\",\n      \"pmids\": [\"15334661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo; surface GRP78 marks CRIPTO-responsive stem cell-enriched populations; deletion of GRP78 from mammary epithelial cells blocks their mammary gland reconstitution potential.\",\n      \"method\": \"Mammary gland reconstitution assay, GRP78 conditional knockout, CRIPTO antagonist treatment, ex vivo culture\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with functional reconstitution assay, CRIPTO antagonist orthogonal approach\",\n      \"pmids\": [\"24749068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cripto regulates skeletal muscle regeneration and satellite cell determination by antagonizing the TGF-β ligand myostatin; conditional inactivation of Cripto in adult satellite cells compromises regeneration, while gain-of-function accelerates regeneration and leads to muscle hypertrophy.\",\n      \"method\": \"Conditional knockout (satellite cell-specific Cripto deletion), gain-of-function overexpression, muscle injury models, myostatin antagonism assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and gain-of-function with defined phenotypic readouts and pathway identification\",\n      \"pmids\": [\"23129614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Expression of the short form of human Cripto-1 is directly regulated at the transcriptional level by the canonical Wnt/β-catenin/TCF signaling pathway through an intronic-exonic enhancer element containing three tandem TCF/LEF binding sites.\",\n      \"method\": \"Luciferase reporter assay with TCF/LEF binding site mutations, chromatin-based analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with defined binding sites identifies transcriptional mechanism\",\n      \"pmids\": [\"17291450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The CFC domain of human Cripto interacts with the ALK4 receptor with a KD in the micromolar range; NMR analysis shows the CFC domain topology is determined by three disulfide bridges, and residues H120 and W124 are externally exposed and contribute to ALK4 binding as identified by molecular docking consistent with prior mutagenesis data.\",\n      \"method\": \"NMR spectroscopy, surface plasmon resonance (SPR), molecular docking\",\n      \"journal\": \"Journal of peptide science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with SPR binding validation; single lab study\",\n      \"pmids\": [\"19035567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MEF2C directly regulates transcription of Tdgf1 (Cripto) in the anterior second heart field via an AHF-restricted Tdgf1 enhancer; loss of Mef2c in the AHF leads to outflow tract alignment defects and reduced Cripto expression.\",\n      \"method\": \"Conditional knockout of Mef2c in AHF, Tdgf1 enhancer reporter assay, ChIP-like enhancer analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined transcriptional target via enhancer reporter\",\n      \"pmids\": [\"26811383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cripto-1 expression in NTERA2/D1 embryonal carcinoma cells is regulated by a Smad2/3-dependent autocrine loop, by Oct4/Nanog transcription factors, and partially by DNA methylation status of the promoter region.\",\n      \"method\": \"siRNA knockdown of Smad2/3, Oct4, Nanog; promoter methylation analysis; luciferase reporter assay\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple loss-of-function approaches identifying upstream regulators of Cripto expression\",\n      \"pmids\": [\"20549704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cripto in muscle-infiltrating macrophages is required for anti-inflammatory CD206+ macrophage expansion during regeneration; conditional deletion of Cripto in the myeloid lineage causes aberrant TGFβ/Smad signaling activation in macrophages, impairs macrophage plasticity, increases Endothelial-to-Mesenchymal Transition (EndMT), and exacerbates muscular dystrophy.\",\n      \"method\": \"Conditional myeloid-specific Cripto knockout (CriptoMy-LOF), mdx model, TGFβ/Smad signaling assays, vascular remodeling analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular mechanism (TGFβ/Smad) and multiple phenotypic readouts\",\n      \"pmids\": [\"32107853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cripto-1 activates NF-κB signaling in macrophages by inducing IκB kinase phosphorylation and p65 nuclear translocation, enhancing cytokine secretion and phagocytic activity; NF-κB inhibitor blocks these Cripto-1-induced effects.\",\n      \"method\": \"Stable Cripto-1 overexpressing cell line, macrophage conditioning assays, NF-κB inhibitor (PDTC) treatment, Western blot for IκB kinase and p65\",\n      \"journal\": \"Immunologic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway inhibitor and signaling markers define NF-κB as mediator; single lab\",\n      \"pmids\": [\"26476731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Conditional inactivation of Cripto during gastrulation results in accumulation of mesenchymal cells around the primitive streak and defects in mesoderm and definitive endoderm formation; both the Fgf8-Fgfr1 pathway and p38 MAP kinase activation are partially affected by loss of Cripto.\",\n      \"method\": \"Conditional Cripto knockout during gastrulation, embryo phenotyping, pathway analysis (Fgf8-Fgfr1, p38 MAPK)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with pathway analysis; single lab\",\n      \"pmids\": [\"23747598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRIPTO is present on both small and large extracellular vesicles (EVs) released by teratocarcinoma cells; large EVs containing CRIPTO specifically impair migration of glioblastoma recipient cells without affecting proliferation or drug sensitivity.\",\n      \"method\": \"Differential centrifugation EV isolation, Western blot, nanoparticle tracking analysis, cell migration assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization to EVs with functional migration assay; single lab\",\n      \"pmids\": [\"35954365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cripto enhances proliferation and survival of mesenchymal stem cells by activating the JAK2/STAT3 pathway in a GRP78-dependent manner; anti-GRP78 antibody blocks Cripto-induced p-JAK2, p-STAT3, c-Myc, cyclin D1, and BCL3 upregulation.\",\n      \"method\": \"Anti-GRP78 blocking antibody, STAT3 siRNA, BCL3 siRNA, Western blot for pathway components, proliferation/apoptosis assays\",\n      \"journal\": \"Biomolecules & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor blocking antibody and siRNA define GRP78/JAK2/STAT3 pathway; single lab\",\n      \"pmids\": [\"28835002\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRIPTO (TDGF1) is a GPI-anchored, O-fucosylated EGF-CFC cell-surface glycoprotein that acts as an obligate co-receptor for TGF-β family ligands Nodal, GDF1, and GDF3 by binding them and ALK4 (via its CFC domain) to assemble productive ALK4/ActRIIB signaling complexes that activate Smad2/3; it also recruits Furin/PACE4 to couple Nodal precursor processing with endocytosis in Flotillin-marked microdomains, inhibits signaling by activin-A/B and TGF-β1 by blocking receptor complex assembly, and in a GRP78-dependent Nodal/ALK4-independent manner activates Src/MAPK/PI3K-Akt and JAK2/STAT3 pathways, collectively promoting EMT, stem cell maintenance, and tumorigenesis while antagonizing myostatin during muscle regeneration and regulating macrophage plasticity via TGFβ/Smad signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CRIPTO (TDGF1) is a GPI-anchored, O-fucosylated EGF-CFC family glycoprotein that serves as a multifunctional co-receptor integrating TGF-β superfamily signaling at the cell surface to control embryonic patterning, stem cell maintenance, tissue regeneration, and tumorigenesis. Through its CFC domain, CRIPTO binds the type I receptor ALK4 and is required for Nodal to assemble productive ALK4/ActRIIB complexes that activate Smad2/3 signaling [PMID:11389842, PMID:14581455]; it simultaneously antagonizes activin-A/B and TGF-β1 signaling by sequestering these ligands away from their cognate receptor complexes, thereby relieving cytostatic constraints on cell proliferation [PMID:12682303, PMID:17030617]. Independent of Nodal/ALK4, CRIPTO engages cell-surface GRP78 to activate c-Src/MAPK/PI3K-Akt and JAK2/STAT3 pathways, promoting epithelial–mesenchymal transition, hematopoietic and mammary stem cell maintenance, and mesenchymal stem cell survival [PMID:21982233, PMID:24749068, PMID:28835002, PMID:15334661]. In adult tissues, CRIPTO antagonizes myostatin in satellite cells to drive skeletal muscle regeneration and modulates macrophage plasticity by restraining TGFβ/Smad signaling, with myeloid-specific deletion exacerbating muscular dystrophy [PMID:23129614, PMID:32107853].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that CRIPTO signals through a novel, non-ErbB receptor to activate MAPK resolved the paradox of CRIPTO-induced ErbB-4 phosphorylation without direct ErbB binding, pointing to an unidentified receptor intermediate.\",\n      \"evidence\": \"Chemical crosslinking with radiolabeled CRIPTO and ErbB-4 blocking antibody/ribozyme knockdown in mammary epithelial cells\",\n      \"pmids\": [\"10085099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The 130 kDa and 60 kDa binding species were not molecularly identified\", \"Mechanism by which ErbB-4 is indirectly activated remains unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating GPI anchorage of CRIPTO established its membrane-tethered topology, explaining how a protein lacking a transmembrane domain operates as a cell-surface co-receptor.\",\n      \"evidence\": \"PI-PLC treatment, immunofluorescence, and biochemical fractionation\",\n      \"pmids\": [\"10640699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPI anchorage is required for signaling activity was not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of the CFC domain as the interface for ALK4 binding, and demonstration that this interaction is required for Nodal to engage the ALK4/ActRIIB complex and activate Smad2, defined CRIPTO's core co-receptor mechanism.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, receptor binding assays, and Smad2 phosphorylation assays\",\n      \"pmids\": [\"11389842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CFC–ALK4 interaction not resolved at atomic level\", \"Whether CRIPTO contacts Nodal and ALK4 simultaneously was not demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that O-linked fucosylation is essential for Nodal binding and signaling revealed a post-translational modification requirement that gates CRIPTO co-receptor competence.\",\n      \"evidence\": \"Glycosylation site mutants tested in luciferase reporter and cell co-culture signaling assays\",\n      \"pmids\": [\"12052855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The fucosyltransferase responsible was not identified in this study\", \"Whether fucosylation affects other CRIPTO ligand interactions was untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that CRIPTO simultaneously promotes Nodal signaling and antagonizes activin signaling—by binding activin and blocking its ALK4/ActRII assembly—revealed a dual agonist/antagonist logic governing TGF-β pathway selectivity.\",\n      \"evidence\": \"Chemical crosslinking, co-immunoprecipitation, and luciferase reporter assays across HepG2 and 293T cells; antibody blocking of CFC domain\",\n      \"pmids\": [\"12682303\", \"12925698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and competitive binding kinetics between Nodal and activin for CRIPTO were not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Epistasis experiments placing CRIPTO upstream of ALK4 in cardiomyogenesis established its role as an obligate Nodal pathway component during lineage commitment.\",\n      \"evidence\": \"Rescue of Cripto-null ES cell differentiation defect by constitutively active ALK4\",\n      \"pmids\": [\"14581455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRIPTO has ALK4-independent roles in cardiac specification was not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking CRIPTO overexpression to a full EMT program (E-cadherin loss, N-cadherin/vimentin/Snail gain) through c-Src identified CRIPTO as a driver of mesenchymal conversion independent of canonical TGF-β/Smad signaling.\",\n      \"evidence\": \"Src inhibitor PP2, migration assays, and EMT marker profiling by Western blot\",\n      \"pmids\": [\"15334661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The receptor mediating c-Src activation was not identified\", \"In vivo relevance of CRIPTO-driven EMT not demonstrated in this study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that CRIPTO directly binds TGF-β1 and blocks its engagement with TβRI extended the antagonism model beyond activins, establishing CRIPTO as a broad suppressor of growth-inhibitory TGF-β superfamily signaling.\",\n      \"evidence\": \"Binding assays, Smad phosphorylation, siRNA knockdown of endogenous CRIPTO in mammary epithelial cells\",\n      \"pmids\": [\"17030617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRIPTO antagonizes other TGF-β isoforms (TGF-β2, TGF-β3) was not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Proving that GPI anchorage is required for trans (paracrine) Nodal co-receptor activity resolved how a GPI-linked protein without a cytoplasmic domain organizes signaling complexes on opposing cells.\",\n      \"evidence\": \"Truncation mutants, transmembrane chimeras, and PI-PLC treatment with luciferase reporter readout\",\n      \"pmids\": [\"17925387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of trans-signaling across cell membranes by a GPI-linked protein remains structurally unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that CRIPTO recruits Furin/PACE4 and couples Nodal precursor processing to endocytosis in Flotillin-positive membrane microdomains revealed a trafficking-dependent mechanism that integrates ligand maturation with receptor activation.\",\n      \"evidence\": \"Co-immunoprecipitation with Furin/PACE4, density gradient fractionation, confocal microscopy of Flotillin compartments, brefeldin A block\",\n      \"pmids\": [\"18772886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endocytosis is strictly required for signaling output was not tested by endocytosis-blocking mutants\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"NMR determination of CFC domain topology and SPR measurement of micromolar-affinity ALK4 binding provided the first structural framework for the CRIPTO co-receptor interface.\",\n      \"evidence\": \"NMR spectroscopy, surface plasmon resonance, molecular docking validated against prior mutagenesis\",\n      \"pmids\": [\"19035567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-crystal structure of CFC–ALK4 complex exists\", \"Full-length CRIPTO structure remains undetermined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of GRP78 as a cell-surface CRIPTO receptor on hematopoietic stem cells, mediating quiescence via metabolic reprogramming under hypoxia, established a Nodal/ALK4-independent signaling axis in the bone marrow niche.\",\n      \"evidence\": \"GRP78 blocking antibody, HIF-1α knockout mice, HSC transplantation and metabolic assays\",\n      \"pmids\": [\"21982233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CRIPTO–GRP78 engagement is transduced to intracellular kinases was not fully defined\", \"Whether this pathway operates in non-hematopoietic stem niches was unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that CRIPTO antagonizes myostatin in satellite cells to promote muscle regeneration established an adult tissue-repair function and expanded the range of TGF-β ligands controlled by CRIPTO.\",\n      \"evidence\": \"Satellite cell-specific conditional knockout and gain-of-function in muscle injury models\",\n      \"pmids\": [\"23129614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRIPTO binds myostatin directly or acts indirectly through shared receptors was not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that CRIPTO/GRP78 maintains both fetal and adult mammary stem cells, with GRP78 conditional deletion abolishing reconstitution potential, validated the GRP78 axis as a general stem cell maintenance pathway.\",\n      \"evidence\": \"Mammary gland reconstitution assay, GRP78 conditional knockout, CRIPTO antagonist treatment\",\n      \"pmids\": [\"24749068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of GRP78 in mammary stem cells were not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining JAK2/STAT3 as the intracellular cascade downstream of CRIPTO–GRP78 in mesenchymal stem cells provided a specific signaling pathway linking this receptor pair to proliferation and survival.\",\n      \"evidence\": \"Anti-GRP78 blocking antibody, STAT3 and BCL3 siRNA, Western blot for pathway components\",\n      \"pmids\": [\"28835002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GRP78 activates JAK2 mechanistically is unknown\", \"Whether JAK2/STAT3 mediates all GRP78-dependent CRIPTO functions is untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Myeloid-specific Cripto deletion revealed that CRIPTO restrains TGFβ/Smad signaling in macrophages to enable anti-inflammatory polarization, linking CRIPTO to immune cell plasticity and dystrophic muscle pathology.\",\n      \"evidence\": \"Conditional myeloid-specific Cripto knockout in mdx dystrophy model, TGFβ/Smad signaling and vascular remodeling analysis\",\n      \"pmids\": [\"32107853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRIPTO acts on macrophages via GRP78 or another receptor in this context is unknown\", \"Relevance to non-dystrophic inflammatory conditions untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CRIPTO's simultaneous engagement with multiple TGF-β ligands and receptors, the precise mechanism coupling GRP78 binding to intracellular kinase activation, and whether extracellular vesicle-associated CRIPTO constitutes a physiologically significant signaling mode remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure of any CRIPTO–ligand–receptor ternary complex\", \"GRP78-to-JAK2 signal transduction mechanism undefined\", \"EV-associated CRIPTO function demonstrated only in one in vitro system\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 6, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5, 6, 10, 11, 12, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 17, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"complexes\": [\n      \"Nodal/CRIPTO/ALK4/ActRIIB signaling complex\"\n    ],\n    \"partners\": [\n      \"ALK4\",\n      \"GRP78\",\n      \"NODAL\",\n      \"FURIN\",\n      \"PACE4\",\n      \"ACVR2B\",\n      \"TGFB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}