{"gene":"KREMEN2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2003,"finding":"Kremen2 (Krm2) functions as a switch that converts Dkk2 from an activator into an inhibitor of Wnt/LRP6 signaling: in 293 fibroblasts, transfected Dkk2 activates LRP6 signaling, but co-transfection of Krm2 blocks this activation and enhances Wnt/Frizzled inhibition. Krm2 also cooperates with Dkk4 (but not Dkk3) to inhibit Wnt signaling. The interaction between Krm2 and Dkks is mediated by the second cysteine-rich domain of Dkks. In Xenopus embryos, Dkk2 and Krm2 cooperate to inhibit Wnt signaling and cause anteriorization.","method":"Transfection/co-transfection in human 293 fibroblasts, Xenopus embryo overexpression, domain-mapping experiments","journal":"Gene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell-based signaling assays, in vivo Xenopus embryo, domain mapping), replicated across two experimental systems","pmids":["12527209"],"is_preprint":false},{"year":2010,"finding":"Osteoblast-specific overexpression of Krm2 in transgenic mice (Col1a1-Krm2) results in severe osteoporosis with impaired osteoblast maturation, decreased canonical Wnt signaling, and decreased OPG production in primary osteoblasts (cell-autonomous differentiation defect). Conversely, Krm2-deficient mice exhibit high bone mass with more than three-fold increase in bone formation, establishing Krm2 as a negative regulator of bone formation through the Dkk1/Krm1/2-LRP5/6 ternary complex mechanism.","method":"Transgenic mouse overexpression (Col1a1-Krm2), Krm2-knockout mice, histomorphometry, primary osteoblast culture with Wnt signaling assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary gain-of-function and loss-of-function mouse models with defined cellular phenotypes and Wnt signaling readouts","pmids":["20436912"],"is_preprint":false},{"year":2014,"finding":"Osteoblast-specific Krm2 overexpression (Col1a1-Krm2) impairs fracture healing more severely than Lrp5 deficiency, with greater reduction in bone formation and decreased active β-catenin in fracture callus. Microarray analysis identified reduced expression of osteogenesis genes (including Smpd3) in Col1a1-Krm2 callus, suggesting Krm2 regulates Wnt/β-catenin-dependent osteogenesis during repair.","method":"Transgenic mouse fracture model (flexible and semi-rigid fixation), histomorphometry, microarray gene expression, immunohistochemistry for active β-catenin","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function/gain-of-function comparison with multiple readouts, single lab","pmids":["25061805"],"is_preprint":false},{"year":2021,"finding":"Knockdown of Krm2 in gastric cancer cells suppresses the PI3K/Akt signaling pathway, inhibits cell survival in vitro, and reduces tumorigenesis in vivo in xenograft models, with induction of apoptosis and G2/M cell cycle arrest.","method":"siRNA knockdown in gastric cancer cell lines, xenograft mouse model, Western blot for PI3K/Akt pathway components","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo knockdown with defined signaling readout, single lab, no rescue or domain experiments","pmids":["33489867"],"is_preprint":false},{"year":2023,"finding":"Kremen2 interacts with SOCS3 (suppressor of cytokine signaling 3) to prevent SOCS3-mediated ubiquitination and proteasomal degradation of EGFR, thereby maintaining EGFR protein levels and promoting downstream PI3K-AKT and JAK2-STAT3 signaling in NSCLC cells.","method":"Co-immunoprecipitation, immunofluorescence, Western blot (ubiquitination assay), KREMEN2 knockout/knockdown, in vivo xenograft and metastasis models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-immunoprecipitation combined with ubiquitination assay, in vitro and in vivo models, multiple orthogonal methods in one study","pmids":["37270563"],"is_preprint":false},{"year":2024,"finding":"In SMARCB1-deficient cancers, loss of SMARCB1-containing SWI/SNF complexes (which normally co-localize with H3K27me3 and EZH2 at the KREMEN2 locus to repress transcription) leads to recruitment of CBP and p300 and H3K27ac accumulation at the KREMEN2 locus, causing transcriptional upregulation of KREMEN2. Simultaneous CBP/p300 inhibition suppresses KREMEN2 transcription, leading to KREMEN1 monomerization (failure to interact with KREMEN2) and induction of apoptosis.","method":"Dual siRNA synthetic lethality screen, ChIP for H3K27me3/H3K27ac/EZH2/CBP/p300, CBP/p300 dual inhibitor treatment, xenograft models, co-IP for KREMEN1-KREMEN2 interaction","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, co-IP, genetic screen, in vitro and in vivo models) in a single rigorous study with mechanistic validation","pmids":["38839769"],"is_preprint":false},{"year":2024,"finding":"KREMEN2 mRNA is subject to m6A modification; the m6A demethylase FTO reduces m6A at the 3' and 5' UTRs of KREMEN2 mRNA and decreases its expression. The m6A reader IGF2BP1 (but not IGF2BP2 or IGF2BP3) recognizes and stabilizes m6A-modified KREMEN2 mRNA, thereby regulating KREMEN2 protein levels in high-grade serous ovarian cancer.","method":"Methylated RNA immunoprecipitation (MeRIP)-qPCR, RNA immunoprecipitation (RIP), FTO overexpression, IGF2BP1/2/3 knockdown, in vitro and in vivo growth assays","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-qPCR and RIP assays identify m6A writer/eraser/reader, functional consequence shown, single lab","pmids":["38615731"],"is_preprint":false},{"year":2025,"finding":"In cBAF-deficient cancers (SMARCA4/SMARCA2-deficient and SS18-SSX fusion cancers), KREMEN2 is transcriptionally upregulated and cancer cells depend on this upregulation. CBP/p300 dual inhibition represses KREMEN2 expression, induces apoptosis via KREMEN1, and suppresses xenograft growth, extending the KREMEN2-KREMEN1 apoptotic mechanism to the broader cBAF-deficient cancer context.","method":"CBP/p300 dual inhibitor treatment, xenograft models, gene expression analysis, apoptosis assays","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo models with defined mechanistic readout (KREMEN2 repression → KREMEN1-mediated apoptosis), single lab, partial mechanistic detail in abstract","pmids":["39625239"],"is_preprint":false},{"year":2025,"finding":"KRM2 interacts with ATF2 protein (verified by co-immunoprecipitation and cycloheximide pulse-chase assay), positively regulates ATF2 expression, and promotes RCC progression and inhibition of ferroptosis through this downstream target; ATF2 knockdown reverses the cancer-promoting and ferroptosis-inhibiting effects of KRM2.","method":"Co-immunoprecipitation, cycloheximide pulse-chase assay, gene expression microarray, lentiviral KRM2 knockdown/overexpression, ATF2 knockdown, xenograft models, ferroptosis assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and pulse-chase validate physical interaction and protein stability regulation, functional epistasis via ATF2 knockdown rescue, single lab","pmids":["40057259"],"is_preprint":false},{"year":2025,"finding":"KREMEN2 activates the PI3K/AKT/mTOR signaling pathway in NSCLC cells; KREMEN2 knockdown represses this pathway and inhibits proliferation, migration, invasion, and EMT, while PI3K activator treatment or PI3K overexpression reverses the inhibitory effects of KREMEN2 knockdown.","method":"siRNA knockdown, overexpression, PI3K activator (740Y-P) rescue, xenograft mouse model, Western blot for PI3K/AKT/mTOR pathway components","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via PI3K activator/overexpression rescue, multiple functional readouts, single lab","pmids":["40638942"],"is_preprint":false},{"year":2026,"finding":"Knockdown of Kremen2 in colorectal cancer cells (HCT116) downregulates the EGFR/JAK2/STAT3 signaling pathway and reduces cell viability and migration.","method":"siRNA knockdown in CRC cell lines, cell viability and migration assays, Western blot for EGFR/JAK2/STAT3 pathway","journal":"Iranian journal of biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (knockdown + pathway Western blot), no mechanistic detail on how KREMEN2 connects to EGFR/JAK2/STAT3, single lab","pmids":["41472941"],"is_preprint":false}],"current_model":"KREMEN2 is a transmembrane receptor that acts as a high-affinity co-receptor for Dickkopf proteins (Dkk1, Dkk2, Dkk4), functioning as a molecular switch that converts Dkk2 from a Wnt/LRP6 activator into an inhibitor; in cancer contexts, KREMEN2 suppresses SOCS3-mediated EGFR ubiquitination/degradation to sustain PI3K-AKT and JAK2-STAT3 signaling, interacts with ATF2 to inhibit ferroptosis, and—when upregulated in SWI/SNF-deficient tumors through CBP/p300-mediated H3K27 acetylation—forms a complex with KREMEN1 that suppresses apoptosis, while its mRNA stability is post-transcriptionally regulated by FTO-mediated m6A demethylation and IGF2BP1-mediated recognition."},"narrative":{"mechanistic_narrative":"KREMEN2 is a transmembrane co-receptor that functions as a molecular switch in Wnt signaling, converting the Dickkopf protein Dkk2 from an activator into an inhibitor of Wnt/LRP6 signaling and cooperating with Dkk4 to suppress Wnt output, an interaction mediated by the second cysteine-rich domain of the Dkk partners [PMID:12527209]. Through this Dkk/Krm/LRP5-6 ternary mechanism, KREMEN2 acts as a cell-autonomous negative regulator of canonical Wnt/β-catenin signaling and bone formation: its overexpression in osteoblasts causes severe osteoporosis with impaired osteoblast maturation and reduced β-catenin activity, whereas its loss yields high bone mass [PMID:20436912, PMID:25061805]. In cancer, KREMEN2 is repurposed as a pro-survival, signaling-sustaining factor. It binds SOCS3 to block SOCS3-mediated ubiquitination and proteasomal degradation of EGFR, thereby maintaining EGFR levels and driving downstream PI3K-AKT and JAK2-STAT3 signaling [PMID:37270563], and it activates a PI3K/AKT/mTOR axis that promotes proliferation, migration, invasion, and EMT [PMID:40638942, PMID:33489867]. KREMEN2 also interacts with and stabilizes ATF2 to inhibit ferroptosis and promote tumor progression [PMID:40057259]. KREMEN2 expression is itself controlled at two levels: transcriptionally, loss of SWI/SNF (SMARCB1/cBAF) complexes permits CBP/p300-mediated H3K27 acetylation and upregulation at the KREMEN2 locus, after which KREMEN2 heterodimerizes with KREMEN1 to suppress apoptosis [PMID:38839769, PMID:39625239]; post-transcriptionally, FTO-mediated m6A demethylation and IGF2BP1-mediated m6A reading set KREMEN2 mRNA stability and protein levels [PMID:38615731].","teleology":[{"year":2003,"claim":"Established the founding molecular function of KREMEN2: it is the cofactor that switches Dkk2 between Wnt activation and inhibition, defining its place in the Wnt/LRP6 axis.","evidence":"Co-transfection signaling assays in human 293 fibroblasts, Xenopus embryo overexpression, and Dkk domain-mapping","pmids":["12527209"],"confidence":"High","gaps":["No structural model of the Krm2-Dkk-LRP6 complex","Endogenous receptor function not tested, only overexpression"]},{"year":2010,"claim":"Demonstrated the physiological consequence of KREMEN2 Wnt inhibition in vivo, identifying it as a cell-autonomous negative regulator of osteoblast differentiation and bone formation.","evidence":"Complementary gain- and loss-of-function mouse models (Col1a1-Krm2 transgenic, Krm2-knockout) with histomorphometry and Wnt readouts","pmids":["20436912"],"confidence":"High","gaps":["Mechanism of OPG regulation not detailed","Did not resolve relative contributions of Krm1 vs Krm2"]},{"year":2014,"claim":"Extended the bone phenotype to tissue repair, showing KREMEN2 suppresses Wnt/β-catenin-dependent osteogenesis during fracture healing more potently than LRP5 loss.","evidence":"Transgenic mouse fracture model with histomorphometry, microarray, and active β-catenin immunohistochemistry","pmids":["25061805"],"confidence":"Medium","gaps":["Downstream targets (e.g., Smpd3) not functionally validated","Single lab"]},{"year":2021,"claim":"Opened the oncogenic chapter by linking KREMEN2 to pro-survival PI3K/Akt signaling in gastric cancer, contrasting with its tumor-suppressive Wnt-inhibitory role in bone.","evidence":"siRNA knockdown in gastric cancer lines with xenografts and pathway Western blots","pmids":["33489867"],"confidence":"Medium","gaps":["No molecular mechanism connecting KREMEN2 to PI3K/Akt","No rescue experiments"]},{"year":2023,"claim":"Provided the first molecular mechanism for KREMEN2's oncogenic signaling: it protects EGFR from SOCS3-mediated degradation, sustaining PI3K-AKT and JAK2-STAT3 activity.","evidence":"Reciprocal co-IP, ubiquitination assay, KREMEN2 knockout/knockdown, and in vivo xenograft/metastasis models in NSCLC","pmids":["37270563"],"confidence":"High","gaps":["Whether KREMEN2-SOCS3 binding is direct not resolved","Relationship to Dkk/Wnt co-receptor function unaddressed"]},{"year":2024,"claim":"Revealed how KREMEN2 is transcriptionally controlled in SWI/SNF-deficient cancers and identified a KREMEN2-KREMEN1 heterodimer as an anti-apoptotic module exploitable by CBP/p300 inhibition.","evidence":"Dual siRNA synthetic lethality screen, ChIP for chromatin marks/EZH2/CBP/p300, CBP/p300 inhibitor, co-IP, and xenografts in SMARCB1-deficient cancers","pmids":["38839769"],"confidence":"High","gaps":["Mechanism by which KREMEN1-KREMEN2 dimer suppresses apoptosis not defined","Membrane topology of the heterodimer unresolved"]},{"year":2024,"claim":"Defined post-transcriptional control of KREMEN2 via m6A, showing FTO demethylation and IGF2BP1 reading set its mRNA stability and protein abundance.","evidence":"MeRIP-qPCR, RIP, FTO overexpression, IGF2BP1/2/3 knockdown, and growth assays in high-grade serous ovarian cancer","pmids":["38615731"],"confidence":"Medium","gaps":["m6A site mapping at single-nucleotide resolution not shown","Single lab"]},{"year":2025,"claim":"Identified ATF2 as a KREMEN2 interaction partner whose stabilization mediates ferroptosis inhibition and tumor progression, adding a cell-death-resistance arm to KREMEN2 function.","evidence":"Co-IP, cycloheximide pulse-chase, ATF2-knockdown epistasis, and xenograft/ferroptosis assays in RCC","pmids":["40057259"],"confidence":"Medium","gaps":["Whether KREMEN2-ATF2 interaction is direct not established","Mechanism of ATF2 stabilization not defined"]},{"year":2025,"claim":"Consolidated the PI3K/AKT/mTOR effector axis of KREMEN2 with genetic epistasis and broadened the KREMEN2-KREMEN1 apoptotic dependency to the wider cBAF-deficient cancer class.","evidence":"siRNA/overexpression with PI3K activator rescue in NSCLC, and CBP/p300 inhibition with apoptosis assays/xenografts in SMARCA4/SMARCA2-deficient and SS18-SSX cancers","pmids":["40638942","39625239"],"confidence":"Medium","gaps":["How KREMEN2 couples to PI3K upstream not mechanistically resolved","Single lab for each context"]},{"year":2026,"claim":"Recapitulated EGFR/JAK2/STAT3 dependence in colorectal cancer, supporting generality of the KREMEN2-EGFR signaling link across tumor types.","evidence":"siRNA knockdown in HCT116 with viability/migration assays and pathway Western blots","pmids":["41472941"],"confidence":"Low","gaps":["Single method without mechanistic linkage to EGFR/JAK2/STAT3","No rescue or in vivo validation"]},{"year":null,"claim":"It remains unresolved how KREMEN2's canonical role as a Dkk/Wnt co-receptor mechanistically connects to its tumor context-specific functions in EGFR stabilization, PI3K signaling, and ferroptosis suppression.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data integrating Wnt co-receptor and oncogenic interaction modes","Whether SOCS3, ATF2, and KREMEN1 binding occur through shared or distinct domains is unknown","Direct vs indirect nature of several reported interactions undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,7,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]}],"complexes":["KREMEN1-KREMEN2 heterodimer","Dkk/Kremen/LRP5-6 ternary complex"],"partners":["DKK2","DKK4","SOCS3","EGFR","KREMEN1","ATF2","IGF2BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NCW0","full_name":"Kremen protein 2","aliases":["Dickkopf receptor 2","Kringle domain-containing transmembrane protein 2","Kringle-containing protein marking the eye and the nose"],"length_aa":462,"mass_kda":48.8,"function":"Receptor for Dickkopf proteins. Cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt receptors LRP5 and LRP6. Plays a role in limb development; attenuates Wnt signaling in the developing limb to allow normal limb patterning and can also negatively regulate bone formation","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8NCW0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KREMEN2","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KREMEN2","total_profiled":1310},"omim":[{"mim_id":"609899","title":"KRINGLE DOMAIN-CONTAINING TRANSMEMBRANE PROTEIN 2; KREMEN2","url":"https://www.omim.org/entry/609899"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"retina","ntpm":3.8},{"tissue":"skin 1","ntpm":7.5}],"url":"https://www.proteinatlas.org/search/KREMEN2"},"hgnc":{"alias_symbol":["MGC10791","KRM2"],"prev_symbol":[]},"alphafold":{"accession":"Q8NCW0","domains":[{"cath_id":"2.40.20.10","chopping":"46-119","consensus_level":"medium","plddt":93.8389,"start":46,"end":119},{"cath_id":"-","chopping":"125-214","consensus_level":"high","plddt":94.2994,"start":125,"end":214},{"cath_id":"2.60.120.290","chopping":"221-327","consensus_level":"high","plddt":94.7375,"start":221,"end":327}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NCW0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NCW0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NCW0-F1-predicted_aligned_error_v6.png","plddt_mean":76.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KREMEN2","jax_strain_url":"https://www.jax.org/strain/search?query=KREMEN2"},"sequence":{"accession":"Q8NCW0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NCW0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NCW0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NCW0"}},"corpus_meta":[{"pmid":"12527209","id":"PMC_12527209","title":"Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12527209","citation_count":266,"is_preprint":false},{"pmid":"20436912","id":"PMC_20436912","title":"Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20436912","citation_count":52,"is_preprint":false},{"pmid":"25061805","id":"PMC_25061805","title":"Osteoblast-specific Krm2 overexpression and Lrp5 deficiency have different effects on fracture healing in mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25061805","citation_count":19,"is_preprint":false},{"pmid":"37270563","id":"PMC_37270563","title":"Kremen2 drives the progression of non-small cell lung cancer by preventing SOCS3-mediated degradation of EGFR.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37270563","citation_count":16,"is_preprint":false},{"pmid":"38839769","id":"PMC_38839769","title":"Targeting dependency on a paralog pair of CBP/p300 against de-repression of KREMEN2 in SMARCB1-deficient cancers.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38839769","citation_count":13,"is_preprint":false},{"pmid":"33489867","id":"PMC_33489867","title":"Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33489867","citation_count":10,"is_preprint":false},{"pmid":"28487939","id":"PMC_28487939","title":"Identification of novel genes associated with fracture healing in osteoporosis induced by Krm2 overexpression or Lrp5 deficiency.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28487939","citation_count":8,"is_preprint":false},{"pmid":"38615731","id":"PMC_38615731","title":"N6-Methyladenosine-Modified KREMEN2 Promotes Tumorigenesis and Malignant Progression of High-Grade Serous Ovarian Cancer.","date":"2024","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38615731","citation_count":7,"is_preprint":false},{"pmid":"40057259","id":"PMC_40057259","title":"KRM2 promotes renal cell carcinoma progression and inhibits ferroptosis by interacting with ATF2.","date":"2025","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40057259","citation_count":2,"is_preprint":false},{"pmid":"39625239","id":"PMC_39625239","title":"Efficacy of CBP/p300 Dual Inhibitors against Derepression of KREMEN2 in cBAF-Deficient Cancers.","date":"2025","source":"Cancer research communications","url":"https://pubmed.ncbi.nlm.nih.gov/39625239","citation_count":1,"is_preprint":false},{"pmid":"40638942","id":"PMC_40638942","title":"KREMEN2 promotes the proliferation and the metastasis through activating PI3K/AKT/mTOR signaling pathway in non-small cell lung cancer.","date":"2025","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/40638942","citation_count":0,"is_preprint":false},{"pmid":"41472941","id":"PMC_41472941","title":"Kremen2 Promotes Colorectal Cancer Progression by Activating the EGFR/JAK2/STAT3 Signaling Pathway.","date":"2026","source":"Iranian journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41472941","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8822,"output_tokens":3270,"usd":0.037758,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10694,"output_tokens":3695,"usd":0.072923,"stage2_stop_reason":"end_turn"},"total_usd":0.110681,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Kremen2 (Krm2) functions as a switch that converts Dkk2 from an activator into an inhibitor of Wnt/LRP6 signaling: in 293 fibroblasts, transfected Dkk2 activates LRP6 signaling, but co-transfection of Krm2 blocks this activation and enhances Wnt/Frizzled inhibition. Krm2 also cooperates with Dkk4 (but not Dkk3) to inhibit Wnt signaling. The interaction between Krm2 and Dkks is mediated by the second cysteine-rich domain of Dkks. In Xenopus embryos, Dkk2 and Krm2 cooperate to inhibit Wnt signaling and cause anteriorization.\",\n      \"method\": \"Transfection/co-transfection in human 293 fibroblasts, Xenopus embryo overexpression, domain-mapping experiments\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell-based signaling assays, in vivo Xenopus embryo, domain mapping), replicated across two experimental systems\",\n      \"pmids\": [\"12527209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Osteoblast-specific overexpression of Krm2 in transgenic mice (Col1a1-Krm2) results in severe osteoporosis with impaired osteoblast maturation, decreased canonical Wnt signaling, and decreased OPG production in primary osteoblasts (cell-autonomous differentiation defect). Conversely, Krm2-deficient mice exhibit high bone mass with more than three-fold increase in bone formation, establishing Krm2 as a negative regulator of bone formation through the Dkk1/Krm1/2-LRP5/6 ternary complex mechanism.\",\n      \"method\": \"Transgenic mouse overexpression (Col1a1-Krm2), Krm2-knockout mice, histomorphometry, primary osteoblast culture with Wnt signaling assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary gain-of-function and loss-of-function mouse models with defined cellular phenotypes and Wnt signaling readouts\",\n      \"pmids\": [\"20436912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Osteoblast-specific Krm2 overexpression (Col1a1-Krm2) impairs fracture healing more severely than Lrp5 deficiency, with greater reduction in bone formation and decreased active β-catenin in fracture callus. Microarray analysis identified reduced expression of osteogenesis genes (including Smpd3) in Col1a1-Krm2 callus, suggesting Krm2 regulates Wnt/β-catenin-dependent osteogenesis during repair.\",\n      \"method\": \"Transgenic mouse fracture model (flexible and semi-rigid fixation), histomorphometry, microarray gene expression, immunohistochemistry for active β-catenin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function/gain-of-function comparison with multiple readouts, single lab\",\n      \"pmids\": [\"25061805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of Krm2 in gastric cancer cells suppresses the PI3K/Akt signaling pathway, inhibits cell survival in vitro, and reduces tumorigenesis in vivo in xenograft models, with induction of apoptosis and G2/M cell cycle arrest.\",\n      \"method\": \"siRNA knockdown in gastric cancer cell lines, xenograft mouse model, Western blot for PI3K/Akt pathway components\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo knockdown with defined signaling readout, single lab, no rescue or domain experiments\",\n      \"pmids\": [\"33489867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kremen2 interacts with SOCS3 (suppressor of cytokine signaling 3) to prevent SOCS3-mediated ubiquitination and proteasomal degradation of EGFR, thereby maintaining EGFR protein levels and promoting downstream PI3K-AKT and JAK2-STAT3 signaling in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Western blot (ubiquitination assay), KREMEN2 knockout/knockdown, in vivo xenograft and metastasis models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-immunoprecipitation combined with ubiquitination assay, in vitro and in vivo models, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37270563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In SMARCB1-deficient cancers, loss of SMARCB1-containing SWI/SNF complexes (which normally co-localize with H3K27me3 and EZH2 at the KREMEN2 locus to repress transcription) leads to recruitment of CBP and p300 and H3K27ac accumulation at the KREMEN2 locus, causing transcriptional upregulation of KREMEN2. Simultaneous CBP/p300 inhibition suppresses KREMEN2 transcription, leading to KREMEN1 monomerization (failure to interact with KREMEN2) and induction of apoptosis.\",\n      \"method\": \"Dual siRNA synthetic lethality screen, ChIP for H3K27me3/H3K27ac/EZH2/CBP/p300, CBP/p300 dual inhibitor treatment, xenograft models, co-IP for KREMEN1-KREMEN2 interaction\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, co-IP, genetic screen, in vitro and in vivo models) in a single rigorous study with mechanistic validation\",\n      \"pmids\": [\"38839769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KREMEN2 mRNA is subject to m6A modification; the m6A demethylase FTO reduces m6A at the 3' and 5' UTRs of KREMEN2 mRNA and decreases its expression. The m6A reader IGF2BP1 (but not IGF2BP2 or IGF2BP3) recognizes and stabilizes m6A-modified KREMEN2 mRNA, thereby regulating KREMEN2 protein levels in high-grade serous ovarian cancer.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP)-qPCR, RNA immunoprecipitation (RIP), FTO overexpression, IGF2BP1/2/3 knockdown, in vitro and in vivo growth assays\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-qPCR and RIP assays identify m6A writer/eraser/reader, functional consequence shown, single lab\",\n      \"pmids\": [\"38615731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cBAF-deficient cancers (SMARCA4/SMARCA2-deficient and SS18-SSX fusion cancers), KREMEN2 is transcriptionally upregulated and cancer cells depend on this upregulation. CBP/p300 dual inhibition represses KREMEN2 expression, induces apoptosis via KREMEN1, and suppresses xenograft growth, extending the KREMEN2-KREMEN1 apoptotic mechanism to the broader cBAF-deficient cancer context.\",\n      \"method\": \"CBP/p300 dual inhibitor treatment, xenograft models, gene expression analysis, apoptosis assays\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo models with defined mechanistic readout (KREMEN2 repression → KREMEN1-mediated apoptosis), single lab, partial mechanistic detail in abstract\",\n      \"pmids\": [\"39625239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRM2 interacts with ATF2 protein (verified by co-immunoprecipitation and cycloheximide pulse-chase assay), positively regulates ATF2 expression, and promotes RCC progression and inhibition of ferroptosis through this downstream target; ATF2 knockdown reverses the cancer-promoting and ferroptosis-inhibiting effects of KRM2.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide pulse-chase assay, gene expression microarray, lentiviral KRM2 knockdown/overexpression, ATF2 knockdown, xenograft models, ferroptosis assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and pulse-chase validate physical interaction and protein stability regulation, functional epistasis via ATF2 knockdown rescue, single lab\",\n      \"pmids\": [\"40057259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KREMEN2 activates the PI3K/AKT/mTOR signaling pathway in NSCLC cells; KREMEN2 knockdown represses this pathway and inhibits proliferation, migration, invasion, and EMT, while PI3K activator treatment or PI3K overexpression reverses the inhibitory effects of KREMEN2 knockdown.\",\n      \"method\": \"siRNA knockdown, overexpression, PI3K activator (740Y-P) rescue, xenograft mouse model, Western blot for PI3K/AKT/mTOR pathway components\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via PI3K activator/overexpression rescue, multiple functional readouts, single lab\",\n      \"pmids\": [\"40638942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of Kremen2 in colorectal cancer cells (HCT116) downregulates the EGFR/JAK2/STAT3 signaling pathway and reduces cell viability and migration.\",\n      \"method\": \"siRNA knockdown in CRC cell lines, cell viability and migration assays, Western blot for EGFR/JAK2/STAT3 pathway\",\n      \"journal\": \"Iranian journal of biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (knockdown + pathway Western blot), no mechanistic detail on how KREMEN2 connects to EGFR/JAK2/STAT3, single lab\",\n      \"pmids\": [\"41472941\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KREMEN2 is a transmembrane receptor that acts as a high-affinity co-receptor for Dickkopf proteins (Dkk1, Dkk2, Dkk4), functioning as a molecular switch that converts Dkk2 from a Wnt/LRP6 activator into an inhibitor; in cancer contexts, KREMEN2 suppresses SOCS3-mediated EGFR ubiquitination/degradation to sustain PI3K-AKT and JAK2-STAT3 signaling, interacts with ATF2 to inhibit ferroptosis, and—when upregulated in SWI/SNF-deficient tumors through CBP/p300-mediated H3K27 acetylation—forms a complex with KREMEN1 that suppresses apoptosis, while its mRNA stability is post-transcriptionally regulated by FTO-mediated m6A demethylation and IGF2BP1-mediated recognition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KREMEN2 is a transmembrane co-receptor that functions as a molecular switch in Wnt signaling, converting the Dickkopf protein Dkk2 from an activator into an inhibitor of Wnt/LRP6 signaling and cooperating with Dkk4 to suppress Wnt output, an interaction mediated by the second cysteine-rich domain of the Dkk partners [#0]. Through this Dkk/Krm/LRP5-6 ternary mechanism, KREMEN2 acts as a cell-autonomous negative regulator of canonical Wnt/\\u03b2-catenin signaling and bone formation: its overexpression in osteoblasts causes severe osteoporosis with impaired osteoblast maturation and reduced \\u03b2-catenin activity, whereas its loss yields high bone mass [#1, #2]. In cancer, KREMEN2 is repurposed as a pro-survival, signaling-sustaining factor. It binds SOCS3 to block SOCS3-mediated ubiquitination and proteasomal degradation of EGFR, thereby maintaining EGFR levels and driving downstream PI3K-AKT and JAK2-STAT3 signaling [#4], and it activates a PI3K/AKT/mTOR axis that promotes proliferation, migration, invasion, and EMT [#9, #3]. KREMEN2 also interacts with and stabilizes ATF2 to inhibit ferroptosis and promote tumor progression [#8]. KREMEN2 expression is itself controlled at two levels: transcriptionally, loss of SWI/SNF (SMARCB1/cBAF) complexes permits CBP/p300-mediated H3K27 acetylation and upregulation at the KREMEN2 locus, after which KREMEN2 heterodimerizes with KREMEN1 to suppress apoptosis [#5, #7]; post-transcriptionally, FTO-mediated m6A demethylation and IGF2BP1-mediated m6A reading set KREMEN2 mRNA stability and protein levels [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the founding molecular function of KREMEN2: it is the cofactor that switches Dkk2 between Wnt activation and inhibition, defining its place in the Wnt/LRP6 axis.\",\n      \"evidence\": \"Co-transfection signaling assays in human 293 fibroblasts, Xenopus embryo overexpression, and Dkk domain-mapping\",\n      \"pmids\": [\"12527209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the Krm2-Dkk-LRP6 complex\", \"Endogenous receptor function not tested, only overexpression\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated the physiological consequence of KREMEN2 Wnt inhibition in vivo, identifying it as a cell-autonomous negative regulator of osteoblast differentiation and bone formation.\",\n      \"evidence\": \"Complementary gain- and loss-of-function mouse models (Col1a1-Krm2 transgenic, Krm2-knockout) with histomorphometry and Wnt readouts\",\n      \"pmids\": [\"20436912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of OPG regulation not detailed\", \"Did not resolve relative contributions of Krm1 vs Krm2\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the bone phenotype to tissue repair, showing KREMEN2 suppresses Wnt/\\u03b2-catenin-dependent osteogenesis during fracture healing more potently than LRP5 loss.\",\n      \"evidence\": \"Transgenic mouse fracture model with histomorphometry, microarray, and active \\u03b2-catenin immunohistochemistry\",\n      \"pmids\": [\"25061805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream targets (e.g., Smpd3) not functionally validated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Opened the oncogenic chapter by linking KREMEN2 to pro-survival PI3K/Akt signaling in gastric cancer, contrasting with its tumor-suppressive Wnt-inhibitory role in bone.\",\n      \"evidence\": \"siRNA knockdown in gastric cancer lines with xenografts and pathway Western blots\",\n      \"pmids\": [\"33489867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism connecting KREMEN2 to PI3K/Akt\", \"No rescue experiments\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the first molecular mechanism for KREMEN2's oncogenic signaling: it protects EGFR from SOCS3-mediated degradation, sustaining PI3K-AKT and JAK2-STAT3 activity.\",\n      \"evidence\": \"Reciprocal co-IP, ubiquitination assay, KREMEN2 knockout/knockdown, and in vivo xenograft/metastasis models in NSCLC\",\n      \"pmids\": [\"37270563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KREMEN2-SOCS3 binding is direct not resolved\", \"Relationship to Dkk/Wnt co-receptor function unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed how KREMEN2 is transcriptionally controlled in SWI/SNF-deficient cancers and identified a KREMEN2-KREMEN1 heterodimer as an anti-apoptotic module exploitable by CBP/p300 inhibition.\",\n      \"evidence\": \"Dual siRNA synthetic lethality screen, ChIP for chromatin marks/EZH2/CBP/p300, CBP/p300 inhibitor, co-IP, and xenografts in SMARCB1-deficient cancers\",\n      \"pmids\": [\"38839769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which KREMEN1-KREMEN2 dimer suppresses apoptosis not defined\", \"Membrane topology of the heterodimer unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-transcriptional control of KREMEN2 via m6A, showing FTO demethylation and IGF2BP1 reading set its mRNA stability and protein abundance.\",\n      \"evidence\": \"MeRIP-qPCR, RIP, FTO overexpression, IGF2BP1/2/3 knockdown, and growth assays in high-grade serous ovarian cancer\",\n      \"pmids\": [\"38615731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A site mapping at single-nucleotide resolution not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ATF2 as a KREMEN2 interaction partner whose stabilization mediates ferroptosis inhibition and tumor progression, adding a cell-death-resistance arm to KREMEN2 function.\",\n      \"evidence\": \"Co-IP, cycloheximide pulse-chase, ATF2-knockdown epistasis, and xenograft/ferroptosis assays in RCC\",\n      \"pmids\": [\"40057259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KREMEN2-ATF2 interaction is direct not established\", \"Mechanism of ATF2 stabilization not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated the PI3K/AKT/mTOR effector axis of KREMEN2 with genetic epistasis and broadened the KREMEN2-KREMEN1 apoptotic dependency to the wider cBAF-deficient cancer class.\",\n      \"evidence\": \"siRNA/overexpression with PI3K activator rescue in NSCLC, and CBP/p300 inhibition with apoptosis assays/xenografts in SMARCA4/SMARCA2-deficient and SS18-SSX cancers\",\n      \"pmids\": [\"40638942\", \"39625239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How KREMEN2 couples to PI3K upstream not mechanistically resolved\", \"Single lab for each context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Recapitulated EGFR/JAK2/STAT3 dependence in colorectal cancer, supporting generality of the KREMEN2-EGFR signaling link across tumor types.\",\n      \"evidence\": \"siRNA knockdown in HCT116 with viability/migration assays and pathway Western blots\",\n      \"pmids\": [\"41472941\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method without mechanistic linkage to EGFR/JAK2/STAT3\", \"No rescue or in vivo validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how KREMEN2's canonical role as a Dkk/Wnt co-receptor mechanistically connects to its tumor context-specific functions in EGFR stabilization, PI3K signaling, and ferroptosis suppression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data integrating Wnt co-receptor and oncogenic interaction modes\", \"Whether SOCS3, ATF2, and KREMEN1 binding occur through shared or distinct domains is unknown\", \"Direct vs indirect nature of several reported interactions undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"KREMEN1-KREMEN2 heterodimer\", \"Dkk/Kremen/LRP5-6 ternary complex\"],\n    \"partners\": [\"DKK2\", \"DKK4\", \"SOCS3\", \"EGFR\", \"KREMEN1\", \"ATF2\", \"IGF2BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}