{"gene":"CLPTM1L","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"CRR9 (CLPTM1L) encodes a novel transmembrane protein with multiple transmembrane-like domains, conserved at the C-terminus with human CLPTM1 and homologs in Drosophila and C. elegans. Transfection of CRR9 into cisplatin-sensitive 2008 cells increased sensitivity to cisplatin, indicating CRR9 is associated with cisplatin-induced apoptosis rather than cisplatin resistance per se.","method":"Full-length cDNA cloning by 5'RACE, Northern blot, transfection assay with cisplatin sensitivity readout","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transfection functional assay with defined phenotypic readout, single lab, two methods (cloning + functional assay)","pmids":["11162647"],"is_preprint":false},{"year":2012,"finding":"CLPTM1L knockdown in lung tumor cells increased cisplatin- and camptothecin-induced apoptosis proportional to knockdown level, and significantly decreased Bcl-xL protein accumulation. Exogenous Bcl-xL expression rescued sensitization to apoptosis upon CLPTM1L knockdown, placing CLPTM1L upstream of Bcl-xL in the anti-apoptotic pathway.","method":"RNAi knockdown, apoptosis assays (cisplatin/camptothecin), Western blot for Bcl-xL, rescue experiment with exogenous Bcl-xL","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined phenotype + epistasis rescue experiment, single lab, multiple orthogonal methods","pmids":["22675468"],"is_preprint":false},{"year":2012,"finding":"CLPTM1L protein localizes to mitochondria, as demonstrated by co-localization of CLPTM1L-EGFP with the mitochondrial marker MitoTracker and enrichment in mitochondrial versus plasma membrane protein fractions. Knockdown increased cisplatin sensitivity and activated caspase-9 and caspase-3/7.","method":"Subcellular fractionation, CLPTM1L-EGFP fluorescence imaging with MitoTracker co-staining, immunohistochemistry, RNAi knockdown, caspase activity assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with two orthogonal methods (fractionation + live imaging), single lab","pmids":["23300716"],"is_preprint":false},{"year":2013,"finding":"CLPTM1L is required for Ras-induced lung tumorigenesis: RNAi depletion of CLPTM1L inhibited morphological transformation by H-RasV12 or K-RasV12, anchorage-independent growth, and anoikis resistance. Mechanistically, CLPTM1L physically interacts with phosphoinositide 3-kinase (PI3K) and is essential for Ras-induced AKT phosphorylation. Bcl-xL is regulated by CLPTM1L independently of AKT. Constitutively active AKT or Bcl-xL rescued the transformed phenotype in CLPTM1L-depleted cells.","method":"RNAi knockdown, transformation assays (morphology, soft-agar colony formation, anoikis), co-immunoprecipitation (CLPTM1L–PI3K interaction), Western blot for pAKT and Bcl-xL, rescue experiments with constitutively active AKT and Bcl-xL","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for PI3K interaction, clean KO phenotype, epistasis rescue with multiple orthogonal methods, single lab but comprehensive mechanistic dissection","pmids":["24366883"],"is_preprint":false},{"year":2014,"finding":"CLPTM1L localizes to the endoplasmic reticulum membrane (consistent with multiple predicted transmembrane domains) as shown by immunofluorescence. Overexpression promoted pancreatic cancer cell growth in vitro and in vivo, and this was abrogated by deletion of two hydrophilic domains. Affinity purification/mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II); the two proteins co-localized in the cytoplasm and, after DNA damage, at centrosomes. Overexpression of CLPTM1L and depletion of NMM-II both induced aneuploidy, suggesting CLPTM1L interferes with NMM-II function in cytokinesis.","method":"Immunofluorescence localization, overexpression growth assays (in vitro and xenograft), domain deletion mutagenesis, affinity purification + mass spectrometry, co-localization imaging, aneuploidy assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS interaction plus domain mutagenesis plus functional phenotype, single lab, multiple orthogonal methods","pmids":["24648346"],"is_preprint":false},{"year":2016,"finding":"CLPTM1L is exposed at the tumor cell surface and can be targeted there. Anti-CLPTM1L monoclonal antibodies inhibited surface accumulation of CLPTM1L, reduced Akt phosphorylation, inhibited anchorage-independent growth, and decreased chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and PI3K p110α in pancreatic cells, which was blocked by anti-CLPTM1L antibodies. In vivo, anti-CLPTM1L treatment inhibited growth of lung and pancreatic adenocarcinoma xenografts.","method":"Monoclonal antibody development, flow cytometry for surface CLPTM1L, co-immunoprecipitation (CLPTM1L–p110α), Akt phosphorylation Western blot, anchorage-independent growth assay, xenograft in vivo treatment","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, functional antibody inhibition with multiple phenotypic readouts, in vivo validation, single lab","pmids":["26939707"],"is_preprint":false},{"year":2019,"finding":"Under ER stress (including gemcitabine treatment), CLPTM1L relocalizes to the cell surface and interacts with GRP78/BiP and PI3K-alpha (p110α). This interaction and surface relocalization is induced by ER stress. The extracellular loop of CLPTM1L is required for gemcitabine resistance and for interaction with GRP78. Inhibition of CLPTM1L with antibodies abrogated GRP78-mediated chemoresistance, anchorage-independent growth, and Akt phosphorylation.","method":"Co-immunoprecipitation (CLPTM1L–GRP78 and CLPTM1L–PI3Kα), surface relocalization imaging, extracellular loop deletion/mutagenesis, anti-CLPTM1L antibody functional inhibition, anchorage-independent growth assay, Akt phosphorylation Western blot","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interactions, domain mutagenesis defining extracellular loop requirement, functional antibody assays, single lab","pmids":["30468251"],"is_preprint":false},{"year":2019,"finding":"miR-182 directly targets CRR9 (CLPTM1L) mRNA in laryngeal squamous cell carcinoma cells. Luciferase reporter assay confirmed CRR9 as a direct downstream target of miR-182. Reintroduction of CRR9 reversed miR-182-induced growth inhibition and apoptosis, placing CRR9 downstream of miR-182 in cell survival regulation.","method":"Luciferase reporter assay (miR-182 target validation), RT-qPCR and Western blot for CRR9, MTT proliferation assay, Annexin V apoptosis assay, rescue experiment with CRR9 re-expression, in vivo mouse tumor model","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase reporter validation of miRNA target site plus epistasis rescue, single lab","pmids":["31519771"],"is_preprint":false},{"year":2020,"finding":"CLPTM1L acts as a transcriptional co-activator of estrogen receptor β (ERβ) in NSCLC cells by directly interacting with ERβ through an LXXLL nuclear receptor-binding motif. Irradiation induced translocation of CLPTM1L from the cytoplasm into the nucleus. CLPTM1L co-activated ERβ target genes CDC25A, c-Jun, and BCL2. ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance, and CLPTM1L shRNA combined with irradiation inhibited xenograft tumor growth.","method":"Chromatin immunoprecipitation, luciferase reporter gene assay, co-immunoprecipitation, GST pull-down assay (direct interaction via LXXLL motif), immunofluorescence/confocal microscopy (nuclear translocation), iTRAQ proteomics, cDNA microarray, shRNA knockdown, xenograft in vivo model","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding confirmed by GST pull-down + Co-IP, LXXLL motif identified, ChIP for target gene transcription, nuclear translocation by imaging, in vivo validation, multiple orthogonal methods in single study","pmids":["32943060"],"is_preprint":false},{"year":2021,"finding":"Extracellular vesicle (exosomal) CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines confers cisplatin resistance in trans to drug-sensitive parental cell lines in an ectodomain-dependent fashion. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patient serum, increasing upon chemotherapy treatment. Anti-CLPTM1L biologics inhibited both cell-autonomous and intercellular (exosomal) chemoresistance, and re-sensitized resistant cells in orthotopic isograft and patient-derived xenograft models.","method":"Exosome isolation and functional transfer assay, anti-CLPTM1L monoclonal antibody inhibition, orthotopic isograft and patient-derived xenograft in vivo models, serum detection of extracellular CLPTM1L","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional exosome transfer experiment with ectodomain dependence, in vivo validation, single lab","pmids":["33654182"],"is_preprint":false},{"year":2022,"finding":"CLPTM1L is the major lipid scramblase required for efficient glycosylphosphatidylinositol (GPI) biosynthesis in the ER membrane. A genome-wide CRISPR screen identified CLPTM1L as required for GPI biosynthesis. CLPTM1L is an integral membrane protein with eight putative transmembrane domains that facilitates cytosol-to-lumen lipid translocation across the ER membrane, enabling efficient GPI-anchored protein biosynthesis.","method":"Genome-wide CRISPR screen, functional GPI biosynthesis assays, characterization of transmembrane topology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — unbiased genome-wide CRISPR screen identifying CLPTM1L, validated with functional GPI biosynthesis assays, mechanistic model of scramblase activity established","pmids":["35344438"],"is_preprint":false},{"year":2023,"finding":"CLPTM1L is a component of a non-canonical GPI-anchoring pathway. CLPTM1L is required for surface expression of specific GPI-anchored proteins (CD109, CD59, MELTF, MICA*008) but not others (ULBP2, ULBP3). CLPTM1L's function depends on its interaction with a free form of PIG-T (normally part of the GPI transamidase complex). The HCMV protein US9 inhibits CLPTM1L–PIG-T interaction, thereby downregulating CLPTM1L-dependent GPI-anchored proteins including MICA*008 and MELTF during infection.","method":"CRISPR/KO cell lines, flow cytometry for GPI-anchored protein surface expression, co-immunoprecipitation (CLPTM1L–PIG-T interaction), viral infection assays with HCMV US9","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR KO with defined protein-specific phenotype, Co-IP identifying PIG-T as binding partner, mechanistic dissection of US9 inhibition of CLPTM1L–PIG-T interaction, multiple orthogonal methods","pmids":["37389656"],"is_preprint":false},{"year":2025,"finding":"CLPTM1L interacts with the lipid raft-associated protein ERLIN2 to cooperatively stabilize SREBP1 protein by inhibiting its ubiquitination, thereby upregulating intracellular free fatty acid levels in NPC cells. The transcription factor KLF1 directly binds the CLPTM1L promoter and drives its transcriptional activation. Knockdown of ERLIN2 or SREBP1 inhibited NPC proliferation and migration synergistically with CLPTM1L depletion; SREBP1 overexpression rescued the inhibitory effects of CLPTM1L and ERLIN2 knockdown.","method":"Co-immunoprecipitation (CLPTM1L–ERLIN2 interaction), ubiquitination assay, ChIP assay (KLF1 binding to CLPTM1L promoter), transcriptome analysis, siRNA knockdown, rescue overexpression experiments, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, ubiquitination assay, ChIP for transcriptional regulation, epistasis rescue experiments, single lab with multiple orthogonal methods","pmids":["40550808"],"is_preprint":false},{"year":2026,"finding":"In microglia, Clptm1l functions as a lipid scramblase involved in ferroptosis downstream of the ERK5–NFATC4 signaling axis. ERK5-mediated phosphorylation of NFATC4 activates Clptm1l transcription, promoting microglial ferroptosis (oxidative stress and lipid peroxidation) that drives ischemic white matter damage. Pharmacological and genetic inhibition of ERK5 reduced Clptm1l-dependent ferroptosis and improved cognitive outcomes.","method":"Animal models of white matter damage, genetic and pharmacological ERK5 inhibition, NFATC4 phosphorylation analysis, Clptm1l expression measurement, ferroptosis assays (lipid peroxidation, oxidative stress), cognitive behavioral testing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic + pharmacological epistasis in animal models, defined pathway (ERK5→NFATC4→Clptm1l→ferroptosis), multiple methods, single lab","pmids":["41512030"],"is_preprint":false}],"current_model":"CLPTM1L is an integral ER membrane protein with multiple transmembrane domains that functions as a major lipid scramblase required for GPI-anchored protein biosynthesis (via interaction with a free form of PIG-T), promotes tumor cell survival by interacting with PI3K/p110α to sustain AKT phosphorylation and Bcl-xL expression, relocalizes to the cell surface under ER stress where it engages GRP78 to drive chemoresistance, can act as a nuclear co-activator of estrogen receptor β through an LXXLL motif to confer radioresistance, and in NPC interacts with ERLIN2 to stabilize SREBP1 by blocking its ubiquitination; in microglia it functions as a ferroptosis-promoting lipid scramblase downstream of the ERK5–NFATC4 axis."},"narrative":{"mechanistic_narrative":"CLPTM1L (CRR9) is a multipass integral endoplasmic reticulum membrane protein whose core biochemical activity is lipid scramblase: a genome-wide CRISPR screen identified it as the major scramblase required for efficient GPI-anchored protein biosynthesis, facilitating cytosol-to-lumen lipid translocation across the ER membrane [PMID:35344438], and it participates in a non-canonical GPI-anchoring route that selectively controls surface display of specific GPI-anchored proteins (CD109, CD59, MELTF, MICA*008) through interaction with a free form of PIG-T, an interaction that HCMV US9 antagonizes during infection [PMID:37389656]. Beyond this membrane-biogenesis role, CLPTM1L is a determinant of tumor cell survival and chemoresistance: it physically interacts with PI3K and is essential for Ras-induced AKT phosphorylation and anchorage-independent growth, while regulating Bcl-xL through an AKT-independent route [PMID:22675468, PMID:24366883]. Under ER stress, including gemcitabine treatment, CLPTM1L relocalizes to the cell surface where its extracellular loop engages GRP78/BiP and p110α to sustain AKT signaling and drive chemoresistance, a node that anti-CLPTM1L antibodies can block [PMID:26939707, PMID:30468251]. CLPTM1L can also translocate to the nucleus after irradiation and act as a transcriptional co-activator of estrogen receptor β via an LXXLL motif, inducing CDC25A, c-Jun and BCL2 to confer radioresistance [PMID:32943060], and in nasopharyngeal carcinoma it interacts with ERLIN2 to stabilize SREBP1 against ubiquitination and elevate fatty acid levels [PMID:40550808]. In microglia, its scramblase activity drives ferroptosis downstream of an ERK5–NFATC4 transcriptional axis, contributing to ischemic white matter damage [PMID:41512030]. Earlier reports placed CLPTM1L at mitochondria and at centrosomes via non-muscle myosin II, where its dysregulation induced aneuploidy [PMID:23300716, PMID:24648346].","teleology":[{"year":2001,"claim":"Establishing that CRR9/CLPTM1L is a novel conserved multi-transmembrane protein and linking it to cisplatin-induced apoptosis defined the gene as a modulator of drug-induced cell death.","evidence":"5'RACE cDNA cloning, Northern blot, and transfection with cisplatin sensitivity readout in 2008 ovarian cells","pmids":["11162647"],"confidence":"Medium","gaps":["No molecular mechanism for the apoptosis link","Subcellular localization not yet defined","Transfection-overexpression phenotype only"]},{"year":2012,"claim":"Loss-of-function and rescue experiments showed CLPTM1L acts upstream of Bcl-xL to restrain apoptosis, converting an associative drug-sensitivity link into a defined anti-apoptotic pathway.","evidence":"RNAi knockdown with cisplatin/camptothecin apoptosis assays, Bcl-xL Western blot, and exogenous Bcl-xL rescue in lung tumor cells; separate work localized CLPTM1L-EGFP to mitochondria by fractionation and MitoTracker co-staining with caspase-9/3-7 activation","pmids":["22675468","23300716"],"confidence":"Medium","gaps":["How CLPTM1L controls Bcl-xL levels is unresolved","Mitochondrial localization later contrasted with ER findings","Single lab"]},{"year":2013,"claim":"Mechanistic dissection of Ras-driven transformation placed CLPTM1L on the PI3K–AKT survival axis, showing it physically binds PI3K and is required for Ras-induced AKT phosphorylation.","evidence":"RNAi knockdown, transformation/anoikis assays, CLPTM1L–PI3K co-immunoprecipitation, pAKT Western blot, and rescue with constitutively active AKT or Bcl-xL","pmids":["24366883"],"confidence":"High","gaps":["Direct vs indirect nature of the PI3K interaction not structurally defined","Bcl-xL regulation shown AKT-independent but its route unknown"]},{"year":2014,"claim":"ER localization plus an AP-MS interaction with non-muscle myosin II implicated CLPTM1L in cytokinesis and genome stability, broadening its role beyond survival signaling.","evidence":"Immunofluorescence, overexpression growth assays in vitro and xenograft, domain-deletion mutagenesis, affinity purification/mass spectrometry, and aneuploidy assays in pancreatic cancer cells","pmids":["24648346"],"confidence":"Medium","gaps":["NMM-II interaction not reciprocally validated beyond AP-MS","Centrosomal function not linked to scramblase activity","Reconciliation with mitochondrial localization absent"]},{"year":2016,"claim":"Demonstrating cell-surface exposure of CLPTM1L and its gemcitabine-induced binding to p110α revealed a targetable surface node sustaining AKT and chemoresistance.","evidence":"Monoclonal antibody development, flow cytometry for surface CLPTM1L, CLPTM1L–p110α co-IP, pAKT Western blot, anchorage-independent growth, and lung/pancreatic xenograft antibody treatment","pmids":["26939707"],"confidence":"Medium","gaps":["Mechanism of ER-to-surface trafficking not defined here","Single lab antibody reagents"]},{"year":2019,"claim":"ER stress was identified as the trigger for surface relocalization, where the CLPTM1L extracellular loop engages GRP78 to drive chemoresistance, and CLPTM1L was placed downstream of miR-182 in survival control.","evidence":"CLPTM1L–GRP78 and CLPTM1L–PI3Kα co-IP, surface relocalization imaging, extracellular-loop mutagenesis, antibody inhibition; separately, luciferase reporter validation of miR-182 targeting CRR9 with re-expression rescue in laryngeal carcinoma","pmids":["30468251","31519771"],"confidence":"Medium","gaps":["Structural basis of extracellular-loop–GRP78 binding unknown","How ER stress drives trafficking mechanistically unresolved"]},{"year":2020,"claim":"Identification of an LXXLL motif and irradiation-induced nuclear translocation established a transcriptional co-activator function for CLPTM1L on ERβ target genes, explaining radioresistance.","evidence":"GST pull-down and co-IP (direct ERβ binding via LXXLL), ChIP, luciferase reporters, confocal imaging of nuclear translocation, iTRAQ/microarray, shRNA, and xenograft irradiation models in NSCLC","pmids":["32943060"],"confidence":"High","gaps":["How a multipass ER membrane protein accesses the nucleus is unexplained","Relationship between nuclear and scramblase roles unknown"]},{"year":2021,"claim":"Extracellular vesicle transfer experiments showed CLPTM1L confers chemoresistance in trans via its ectodomain, extending its role to intercellular communication and serum biomarker potential.","evidence":"Exosome isolation and functional transfer, anti-CLPTM1L antibody inhibition, orthotopic isograft and patient-derived xenograft models, and serum detection in ovarian carcinoma","pmids":["33654182"],"confidence":"Medium","gaps":["Mechanism by which exosomal CLPTM1L acts on recipient cells undefined","Single lab"]},{"year":2022,"claim":"An unbiased genome-wide CRISPR screen defined the long-sought core biochemical activity of CLPTM1L: a lipid scramblase facilitating cytosol-to-lumen translocation required for GPI biosynthesis.","evidence":"Genome-wide CRISPR screen, functional GPI biosynthesis assays, and transmembrane topology characterization (eight putative TM domains)","pmids":["35344438"],"confidence":"High","gaps":["Lipid substrate specificity not fully defined","Link between scramblase activity and cancer survival functions not bridged","No high-resolution structure"]},{"year":2023,"claim":"Defining a non-canonical GPI-anchoring pathway through a free form of PIG-T explained how CLPTM1L selectively controls a subset of GPI-anchored proteins and how a viral protein hijacks this for immune evasion.","evidence":"CRISPR KO cell lines, flow cytometry of GPI-anchored protein surface expression, CLPTM1L–PIG-T co-IP, and HCMV US9 infection assays","pmids":["37389656"],"confidence":"High","gaps":["Why only specific GPI-anchored proteins depend on CLPTM1L unknown","Structural basis of CLPTM1L–PIG-T interaction undefined"]},{"year":2025,"claim":"In nasopharyngeal carcinoma, CLPTM1L was shown to control lipid metabolism by stabilizing SREBP1 via ERLIN2, with KLF1 driving its transcription, connecting CLPTM1L to fatty acid metabolism.","evidence":"CLPTM1L–ERLIN2 co-IP, ubiquitination assay, KLF1 ChIP on the CLPTM1L promoter, siRNA knockdown, SREBP1 rescue, and in vivo tumor models","pmids":["40550808"],"confidence":"Medium","gaps":["Whether SREBP1 stabilization depends on scramblase activity unknown","Direct vs indirect block of SREBP1 ubiquitination unresolved"]},{"year":2026,"claim":"Linking Clptm1l scramblase activity to ferroptosis downstream of ERK5–NFATC4 in microglia connected its lipid-handling function to a pathological cell-death program in ischemic white matter damage.","evidence":"Animal white-matter-damage models, genetic and pharmacological ERK5 inhibition, NFATC4 phosphorylation analysis, ferroptosis assays, and cognitive testing","pmids":["41512030"],"confidence":"Medium","gaps":["Lipid species scrambled to promote ferroptosis not identified","Generalizability beyond microglia unknown"]},{"year":null,"claim":"How CLPTM1L's single ER-membrane scramblase activity mechanistically gives rise to its diverse PI3K/AKT survival, surface GRP78, nuclear ERβ co-activator, and SREBP1-stabilizing roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the channel or its substrate-binding pockets","No unifying model linking scramblase activity to signaling/nuclear functions","Conflicting localizations (mitochondria, ER, surface, nucleus, centrosome) not reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]}],"pathway":[],"complexes":[],"partners":["PIK3CA","GRP78","PIG-T","ERLIN2","ESR2","MYH9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96KA5","full_name":"Lipid scramblase CLPTM1L","aliases":["Cisplatin resistance-related protein 9","CRR9p","Cleft lip and palate transmembrane protein 1-like protein","CLPTM1-like protein"],"length_aa":538,"mass_kda":62.2,"function":"Scramblase that mediates the translocation of glucosaminylphosphatidylinositol (alpha-D-GlcN-(1-6)-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to the luminal leaflet of the ER membrane, where it participates in the biosynthesis of glycosylphosphatidylinositol (GPI) (PubMed:35344438). GPI is a lipid glycoconjugate involved in post-translational modification of proteins (PubMed:35344438). Can also translocate 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) (phosphatidylinositol or PI), as well as several other phospholipids (1,2-diacyl-sn-glycero-3-phosphocholine, 1,2-diacyl-sn-glycero-3-phosphoethanolamine), and N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI) in vitro (PubMed:35344438)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96KA5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLPTM1L","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CLPTM1L","total_profiled":1310},"omim":[{"mim_id":"614210","title":"LUNG CANCER SUSCEPTIBILITY 5; LNCR5","url":"https://www.omim.org/entry/614210"},{"mim_id":"613059","title":"BASAL CELL CARCINOMA, SUSCEPTIBILITY TO, 3; BCC3","url":"https://www.omim.org/entry/613059"},{"mim_id":"612585","title":"CLPTM1-LIKE PROTEIN; CLPTM1L","url":"https://www.omim.org/entry/612585"},{"mim_id":"612571","title":"LUNG CANCER SUSCEPTIBILITY 3; LNCR3","url":"https://www.omim.org/entry/612571"},{"mim_id":"605462","title":"BASAL CELL CARCINOMA, SUSCEPTIBILITY TO, 1; BCC1","url":"https://www.omim.org/entry/605462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CLPTM1L"},"hgnc":{"alias_symbol":["FLJ14400","CRR9"],"prev_symbol":[]},"alphafold":{"accession":"Q96KA5","domains":[{"cath_id":"-","chopping":"43-144_165-282","consensus_level":"high","plddt":85.6267,"start":43,"end":282},{"cath_id":"-","chopping":"291-517","consensus_level":"medium","plddt":77.2216,"start":291,"end":517}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96KA5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96KA5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96KA5-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLPTM1L","jax_strain_url":"https://www.jax.org/strain/search?query=CLPTM1L"},"sequence":{"accession":"Q96KA5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96KA5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96KA5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96KA5"}},"corpus_meta":[{"pmid":"19151717","id":"PMC_19151717","title":"Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19151717","citation_count":516,"is_preprint":false},{"pmid":"22037553","id":"PMC_22037553","title":"A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22037553","citation_count":262,"is_preprint":false},{"pmid":"11162647","id":"PMC_11162647","title":"A novel gene, CRR9, which was up-regulated in CDDP-resistant ovarian tumor cell line, was associated with apoptosis.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11162647","citation_count":127,"is_preprint":false},{"pmid":"23555636","id":"PMC_23555636","title":"Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23555636","citation_count":106,"is_preprint":false},{"pmid":"22675468","id":"PMC_22675468","title":"Functional characterization of CLPTM1L as a lung cancer risk candidate gene in the 5p15.33 locus.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22675468","citation_count":92,"is_preprint":false},{"pmid":"19465454","id":"PMC_19465454","title":"The TERT-CLPTM1L lung cancer susceptibility variant associates with higher DNA adduct formation in the lung.","date":"2009","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/19465454","citation_count":91,"is_preprint":false},{"pmid":"25027329","id":"PMC_25027329","title":"Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.","date":"2014","source":"Human 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novel transmembrane protein with multiple transmembrane-like domains, conserved at the C-terminus with human CLPTM1 and homologs in Drosophila and C. elegans. Transfection of CRR9 into cisplatin-sensitive 2008 cells increased sensitivity to cisplatin, indicating CRR9 is associated with cisplatin-induced apoptosis rather than cisplatin resistance per se.\",\n      \"method\": \"Full-length cDNA cloning by 5'RACE, Northern blot, transfection assay with cisplatin sensitivity readout\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transfection functional assay with defined phenotypic readout, single lab, two methods (cloning + functional assay)\",\n      \"pmids\": [\"11162647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLPTM1L knockdown in lung tumor cells increased cisplatin- and camptothecin-induced apoptosis proportional to knockdown level, and significantly decreased Bcl-xL protein accumulation. Exogenous Bcl-xL expression rescued sensitization to apoptosis upon CLPTM1L knockdown, placing CLPTM1L upstream of Bcl-xL in the anti-apoptotic pathway.\",\n      \"method\": \"RNAi knockdown, apoptosis assays (cisplatin/camptothecin), Western blot for Bcl-xL, rescue experiment with exogenous Bcl-xL\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined phenotype + epistasis rescue experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22675468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CLPTM1L protein localizes to mitochondria, as demonstrated by co-localization of CLPTM1L-EGFP with the mitochondrial marker MitoTracker and enrichment in mitochondrial versus plasma membrane protein fractions. Knockdown increased cisplatin sensitivity and activated caspase-9 and caspase-3/7.\",\n      \"method\": \"Subcellular fractionation, CLPTM1L-EGFP fluorescence imaging with MitoTracker co-staining, immunohistochemistry, RNAi knockdown, caspase activity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with two orthogonal methods (fractionation + live imaging), single lab\",\n      \"pmids\": [\"23300716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CLPTM1L is required for Ras-induced lung tumorigenesis: RNAi depletion of CLPTM1L inhibited morphological transformation by H-RasV12 or K-RasV12, anchorage-independent growth, and anoikis resistance. Mechanistically, CLPTM1L physically interacts with phosphoinositide 3-kinase (PI3K) and is essential for Ras-induced AKT phosphorylation. Bcl-xL is regulated by CLPTM1L independently of AKT. Constitutively active AKT or Bcl-xL rescued the transformed phenotype in CLPTM1L-depleted cells.\",\n      \"method\": \"RNAi knockdown, transformation assays (morphology, soft-agar colony formation, anoikis), co-immunoprecipitation (CLPTM1L–PI3K interaction), Western blot for pAKT and Bcl-xL, rescue experiments with constitutively active AKT and Bcl-xL\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for PI3K interaction, clean KO phenotype, epistasis rescue with multiple orthogonal methods, single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"24366883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CLPTM1L localizes to the endoplasmic reticulum membrane (consistent with multiple predicted transmembrane domains) as shown by immunofluorescence. Overexpression promoted pancreatic cancer cell growth in vitro and in vivo, and this was abrogated by deletion of two hydrophilic domains. Affinity purification/mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II); the two proteins co-localized in the cytoplasm and, after DNA damage, at centrosomes. Overexpression of CLPTM1L and depletion of NMM-II both induced aneuploidy, suggesting CLPTM1L interferes with NMM-II function in cytokinesis.\",\n      \"method\": \"Immunofluorescence localization, overexpression growth assays (in vitro and xenograft), domain deletion mutagenesis, affinity purification + mass spectrometry, co-localization imaging, aneuploidy assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS interaction plus domain mutagenesis plus functional phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24648346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CLPTM1L is exposed at the tumor cell surface and can be targeted there. Anti-CLPTM1L monoclonal antibodies inhibited surface accumulation of CLPTM1L, reduced Akt phosphorylation, inhibited anchorage-independent growth, and decreased chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and PI3K p110α in pancreatic cells, which was blocked by anti-CLPTM1L antibodies. In vivo, anti-CLPTM1L treatment inhibited growth of lung and pancreatic adenocarcinoma xenografts.\",\n      \"method\": \"Monoclonal antibody development, flow cytometry for surface CLPTM1L, co-immunoprecipitation (CLPTM1L–p110α), Akt phosphorylation Western blot, anchorage-independent growth assay, xenograft in vivo treatment\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, functional antibody inhibition with multiple phenotypic readouts, in vivo validation, single lab\",\n      \"pmids\": [\"26939707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under ER stress (including gemcitabine treatment), CLPTM1L relocalizes to the cell surface and interacts with GRP78/BiP and PI3K-alpha (p110α). This interaction and surface relocalization is induced by ER stress. The extracellular loop of CLPTM1L is required for gemcitabine resistance and for interaction with GRP78. Inhibition of CLPTM1L with antibodies abrogated GRP78-mediated chemoresistance, anchorage-independent growth, and Akt phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (CLPTM1L–GRP78 and CLPTM1L–PI3Kα), surface relocalization imaging, extracellular loop deletion/mutagenesis, anti-CLPTM1L antibody functional inhibition, anchorage-independent growth assay, Akt phosphorylation Western blot\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interactions, domain mutagenesis defining extracellular loop requirement, functional antibody assays, single lab\",\n      \"pmids\": [\"30468251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-182 directly targets CRR9 (CLPTM1L) mRNA in laryngeal squamous cell carcinoma cells. Luciferase reporter assay confirmed CRR9 as a direct downstream target of miR-182. Reintroduction of CRR9 reversed miR-182-induced growth inhibition and apoptosis, placing CRR9 downstream of miR-182 in cell survival regulation.\",\n      \"method\": \"Luciferase reporter assay (miR-182 target validation), RT-qPCR and Western blot for CRR9, MTT proliferation assay, Annexin V apoptosis assay, rescue experiment with CRR9 re-expression, in vivo mouse tumor model\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase reporter validation of miRNA target site plus epistasis rescue, single lab\",\n      \"pmids\": [\"31519771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CLPTM1L acts as a transcriptional co-activator of estrogen receptor β (ERβ) in NSCLC cells by directly interacting with ERβ through an LXXLL nuclear receptor-binding motif. Irradiation induced translocation of CLPTM1L from the cytoplasm into the nucleus. CLPTM1L co-activated ERβ target genes CDC25A, c-Jun, and BCL2. ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance, and CLPTM1L shRNA combined with irradiation inhibited xenograft tumor growth.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter gene assay, co-immunoprecipitation, GST pull-down assay (direct interaction via LXXLL motif), immunofluorescence/confocal microscopy (nuclear translocation), iTRAQ proteomics, cDNA microarray, shRNA knockdown, xenograft in vivo model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding confirmed by GST pull-down + Co-IP, LXXLL motif identified, ChIP for target gene transcription, nuclear translocation by imaging, in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32943060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Extracellular vesicle (exosomal) CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines confers cisplatin resistance in trans to drug-sensitive parental cell lines in an ectodomain-dependent fashion. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patient serum, increasing upon chemotherapy treatment. Anti-CLPTM1L biologics inhibited both cell-autonomous and intercellular (exosomal) chemoresistance, and re-sensitized resistant cells in orthotopic isograft and patient-derived xenograft models.\",\n      \"method\": \"Exosome isolation and functional transfer assay, anti-CLPTM1L monoclonal antibody inhibition, orthotopic isograft and patient-derived xenograft in vivo models, serum detection of extracellular CLPTM1L\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional exosome transfer experiment with ectodomain dependence, in vivo validation, single lab\",\n      \"pmids\": [\"33654182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CLPTM1L is the major lipid scramblase required for efficient glycosylphosphatidylinositol (GPI) biosynthesis in the ER membrane. A genome-wide CRISPR screen identified CLPTM1L as required for GPI biosynthesis. CLPTM1L is an integral membrane protein with eight putative transmembrane domains that facilitates cytosol-to-lumen lipid translocation across the ER membrane, enabling efficient GPI-anchored protein biosynthesis.\",\n      \"method\": \"Genome-wide CRISPR screen, functional GPI biosynthesis assays, characterization of transmembrane topology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — unbiased genome-wide CRISPR screen identifying CLPTM1L, validated with functional GPI biosynthesis assays, mechanistic model of scramblase activity established\",\n      \"pmids\": [\"35344438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLPTM1L is a component of a non-canonical GPI-anchoring pathway. CLPTM1L is required for surface expression of specific GPI-anchored proteins (CD109, CD59, MELTF, MICA*008) but not others (ULBP2, ULBP3). CLPTM1L's function depends on its interaction with a free form of PIG-T (normally part of the GPI transamidase complex). The HCMV protein US9 inhibits CLPTM1L–PIG-T interaction, thereby downregulating CLPTM1L-dependent GPI-anchored proteins including MICA*008 and MELTF during infection.\",\n      \"method\": \"CRISPR/KO cell lines, flow cytometry for GPI-anchored protein surface expression, co-immunoprecipitation (CLPTM1L–PIG-T interaction), viral infection assays with HCMV US9\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR KO with defined protein-specific phenotype, Co-IP identifying PIG-T as binding partner, mechanistic dissection of US9 inhibition of CLPTM1L–PIG-T interaction, multiple orthogonal methods\",\n      \"pmids\": [\"37389656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLPTM1L interacts with the lipid raft-associated protein ERLIN2 to cooperatively stabilize SREBP1 protein by inhibiting its ubiquitination, thereby upregulating intracellular free fatty acid levels in NPC cells. The transcription factor KLF1 directly binds the CLPTM1L promoter and drives its transcriptional activation. Knockdown of ERLIN2 or SREBP1 inhibited NPC proliferation and migration synergistically with CLPTM1L depletion; SREBP1 overexpression rescued the inhibitory effects of CLPTM1L and ERLIN2 knockdown.\",\n      \"method\": \"Co-immunoprecipitation (CLPTM1L–ERLIN2 interaction), ubiquitination assay, ChIP assay (KLF1 binding to CLPTM1L promoter), transcriptome analysis, siRNA knockdown, rescue overexpression experiments, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, ubiquitination assay, ChIP for transcriptional regulation, epistasis rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40550808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In microglia, Clptm1l functions as a lipid scramblase involved in ferroptosis downstream of the ERK5–NFATC4 signaling axis. ERK5-mediated phosphorylation of NFATC4 activates Clptm1l transcription, promoting microglial ferroptosis (oxidative stress and lipid peroxidation) that drives ischemic white matter damage. Pharmacological and genetic inhibition of ERK5 reduced Clptm1l-dependent ferroptosis and improved cognitive outcomes.\",\n      \"method\": \"Animal models of white matter damage, genetic and pharmacological ERK5 inhibition, NFATC4 phosphorylation analysis, Clptm1l expression measurement, ferroptosis assays (lipid peroxidation, oxidative stress), cognitive behavioral testing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic + pharmacological epistasis in animal models, defined pathway (ERK5→NFATC4→Clptm1l→ferroptosis), multiple methods, single lab\",\n      \"pmids\": [\"41512030\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLPTM1L is an integral ER membrane protein with multiple transmembrane domains that functions as a major lipid scramblase required for GPI-anchored protein biosynthesis (via interaction with a free form of PIG-T), promotes tumor cell survival by interacting with PI3K/p110α to sustain AKT phosphorylation and Bcl-xL expression, relocalizes to the cell surface under ER stress where it engages GRP78 to drive chemoresistance, can act as a nuclear co-activator of estrogen receptor β through an LXXLL motif to confer radioresistance, and in NPC interacts with ERLIN2 to stabilize SREBP1 by blocking its ubiquitination; in microglia it functions as a ferroptosis-promoting lipid scramblase downstream of the ERK5–NFATC4 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLPTM1L (CRR9) is a multipass integral endoplasmic reticulum membrane protein whose core biochemical activity is lipid scramblase: a genome-wide CRISPR screen identified it as the major scramblase required for efficient GPI-anchored protein biosynthesis, facilitating cytosol-to-lumen lipid translocation across the ER membrane [#10], and it participates in a non-canonical GPI-anchoring route that selectively controls surface display of specific GPI-anchored proteins (CD109, CD59, MELTF, MICA*008) through interaction with a free form of PIG-T, an interaction that HCMV US9 antagonizes during infection [#11]. Beyond this membrane-biogenesis role, CLPTM1L is a determinant of tumor cell survival and chemoresistance: it physically interacts with PI3K and is essential for Ras-induced AKT phosphorylation and anchorage-independent growth, while regulating Bcl-xL through an AKT-independent route [#1, #3]. Under ER stress, including gemcitabine treatment, CLPTM1L relocalizes to the cell surface where its extracellular loop engages GRP78/BiP and p110\\u03b1 to sustain AKT signaling and drive chemoresistance, a node that anti-CLPTM1L antibodies can block [#5, #6]. CLPTM1L can also translocate to the nucleus after irradiation and act as a transcriptional co-activator of estrogen receptor \\u03b2 via an LXXLL motif, inducing CDC25A, c-Jun and BCL2 to confer radioresistance [#8], and in nasopharyngeal carcinoma it interacts with ERLIN2 to stabilize SREBP1 against ubiquitination and elevate fatty acid levels [#12]. In microglia, its scramblase activity drives ferroptosis downstream of an ERK5\\u2013NFATC4 transcriptional axis, contributing to ischemic white matter damage [#13]. Earlier reports placed CLPTM1L at mitochondria and at centrosomes via non-muscle myosin II, where its dysregulation induced aneuploidy [#2, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that CRR9/CLPTM1L is a novel conserved multi-transmembrane protein and linking it to cisplatin-induced apoptosis defined the gene as a modulator of drug-induced cell death.\",\n      \"evidence\": \"5'RACE cDNA cloning, Northern blot, and transfection with cisplatin sensitivity readout in 2008 ovarian cells\",\n      \"pmids\": [\"11162647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the apoptosis link\", \"Subcellular localization not yet defined\", \"Transfection-overexpression phenotype only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Loss-of-function and rescue experiments showed CLPTM1L acts upstream of Bcl-xL to restrain apoptosis, converting an associative drug-sensitivity link into a defined anti-apoptotic pathway.\",\n      \"evidence\": \"RNAi knockdown with cisplatin/camptothecin apoptosis assays, Bcl-xL Western blot, and exogenous Bcl-xL rescue in lung tumor cells; separate work localized CLPTM1L-EGFP to mitochondria by fractionation and MitoTracker co-staining with caspase-9/3-7 activation\",\n      \"pmids\": [\"22675468\", \"23300716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CLPTM1L controls Bcl-xL levels is unresolved\", \"Mitochondrial localization later contrasted with ER findings\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mechanistic dissection of Ras-driven transformation placed CLPTM1L on the PI3K\\u2013AKT survival axis, showing it physically binds PI3K and is required for Ras-induced AKT phosphorylation.\",\n      \"evidence\": \"RNAi knockdown, transformation/anoikis assays, CLPTM1L\\u2013PI3K co-immunoprecipitation, pAKT Western blot, and rescue with constitutively active AKT or Bcl-xL\",\n      \"pmids\": [\"24366883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of the PI3K interaction not structurally defined\", \"Bcl-xL regulation shown AKT-independent but its route unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ER localization plus an AP-MS interaction with non-muscle myosin II implicated CLPTM1L in cytokinesis and genome stability, broadening its role beyond survival signaling.\",\n      \"evidence\": \"Immunofluorescence, overexpression growth assays in vitro and xenograft, domain-deletion mutagenesis, affinity purification/mass spectrometry, and aneuploidy assays in pancreatic cancer cells\",\n      \"pmids\": [\"24648346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NMM-II interaction not reciprocally validated beyond AP-MS\", \"Centrosomal function not linked to scramblase activity\", \"Reconciliation with mitochondrial localization absent\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating cell-surface exposure of CLPTM1L and its gemcitabine-induced binding to p110\\u03b1 revealed a targetable surface node sustaining AKT and chemoresistance.\",\n      \"evidence\": \"Monoclonal antibody development, flow cytometry for surface CLPTM1L, CLPTM1L\\u2013p110\\u03b1 co-IP, pAKT Western blot, anchorage-independent growth, and lung/pancreatic xenograft antibody treatment\",\n      \"pmids\": [\"26939707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ER-to-surface trafficking not defined here\", \"Single lab antibody reagents\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ER stress was identified as the trigger for surface relocalization, where the CLPTM1L extracellular loop engages GRP78 to drive chemoresistance, and CLPTM1L was placed downstream of miR-182 in survival control.\",\n      \"evidence\": \"CLPTM1L\\u2013GRP78 and CLPTM1L\\u2013PI3K\\u03b1 co-IP, surface relocalization imaging, extracellular-loop mutagenesis, antibody inhibition; separately, luciferase reporter validation of miR-182 targeting CRR9 with re-expression rescue in laryngeal carcinoma\",\n      \"pmids\": [\"30468251\", \"31519771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of extracellular-loop\\u2013GRP78 binding unknown\", \"How ER stress drives trafficking mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of an LXXLL motif and irradiation-induced nuclear translocation established a transcriptional co-activator function for CLPTM1L on ER\\u03b2 target genes, explaining radioresistance.\",\n      \"evidence\": \"GST pull-down and co-IP (direct ER\\u03b2 binding via LXXLL), ChIP, luciferase reporters, confocal imaging of nuclear translocation, iTRAQ/microarray, shRNA, and xenograft irradiation models in NSCLC\",\n      \"pmids\": [\"32943060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a multipass ER membrane protein accesses the nucleus is unexplained\", \"Relationship between nuclear and scramblase roles unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extracellular vesicle transfer experiments showed CLPTM1L confers chemoresistance in trans via its ectodomain, extending its role to intercellular communication and serum biomarker potential.\",\n      \"evidence\": \"Exosome isolation and functional transfer, anti-CLPTM1L antibody inhibition, orthotopic isograft and patient-derived xenograft models, and serum detection in ovarian carcinoma\",\n      \"pmids\": [\"33654182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which exosomal CLPTM1L acts on recipient cells undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An unbiased genome-wide CRISPR screen defined the long-sought core biochemical activity of CLPTM1L: a lipid scramblase facilitating cytosol-to-lumen translocation required for GPI biosynthesis.\",\n      \"evidence\": \"Genome-wide CRISPR screen, functional GPI biosynthesis assays, and transmembrane topology characterization (eight putative TM domains)\",\n      \"pmids\": [\"35344438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid substrate specificity not fully defined\", \"Link between scramblase activity and cancer survival functions not bridged\", \"No high-resolution structure\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining a non-canonical GPI-anchoring pathway through a free form of PIG-T explained how CLPTM1L selectively controls a subset of GPI-anchored proteins and how a viral protein hijacks this for immune evasion.\",\n      \"evidence\": \"CRISPR KO cell lines, flow cytometry of GPI-anchored protein surface expression, CLPTM1L\\u2013PIG-T co-IP, and HCMV US9 infection assays\",\n      \"pmids\": [\"37389656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only specific GPI-anchored proteins depend on CLPTM1L unknown\", \"Structural basis of CLPTM1L\\u2013PIG-T interaction undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In nasopharyngeal carcinoma, CLPTM1L was shown to control lipid metabolism by stabilizing SREBP1 via ERLIN2, with KLF1 driving its transcription, connecting CLPTM1L to fatty acid metabolism.\",\n      \"evidence\": \"CLPTM1L\\u2013ERLIN2 co-IP, ubiquitination assay, KLF1 ChIP on the CLPTM1L promoter, siRNA knockdown, SREBP1 rescue, and in vivo tumor models\",\n      \"pmids\": [\"40550808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SREBP1 stabilization depends on scramblase activity unknown\", \"Direct vs indirect block of SREBP1 ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linking Clptm1l scramblase activity to ferroptosis downstream of ERK5\\u2013NFATC4 in microglia connected its lipid-handling function to a pathological cell-death program in ischemic white matter damage.\",\n      \"evidence\": \"Animal white-matter-damage models, genetic and pharmacological ERK5 inhibition, NFATC4 phosphorylation analysis, ferroptosis assays, and cognitive testing\",\n      \"pmids\": [\"41512030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipid species scrambled to promote ferroptosis not identified\", \"Generalizability beyond microglia unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CLPTM1L's single ER-membrane scramblase activity mechanistically gives rise to its diverse PI3K/AKT survival, surface GRP78, nuclear ER\\u03b2 co-activator, and SREBP1-stabilizing roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the channel or its substrate-binding pockets\", \"No unifying model linking scramblase activity to signaling/nuclear functions\", \"Conflicting localizations (mitochondria, ER, surface, nucleus, centrosome) not reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0392499\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PIK3CA\", \"GRP78\", \"PIG-T\", \"ERLIN2\", \"ESR2\", \"MYH9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}