{"gene":"PITPNC1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2012,"finding":"PITPNC1 (RdgBβ) binds and transfers phosphatidic acid (PA) in addition to phosphatidylinositol (PI), but unlike Class I PITPs does not bind phosphatidylcholine. When purified from E. coli, PITPNC1 is preloaded with PA and phosphatidylglycerol. In permeabilized HL60 cells, PITPNC1 exchanges phosphatidylglycerol for PA and PI. Activation of phospholipase D increases PA binding to PITPNC1 at the expense of PI binding.","method":"In vitro lipid binding and transfer assays, permeabilized cell reconstitution, lipid mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal lipid binding/transfer assays and cell-based validation","pmids":["22822086"],"is_preprint":false},{"year":2011,"finding":"PITPNC1 C-terminus contains two tandem phosphorylated serine residues (Ser274 and Ser299) that bind 14-3-3 proteins. 14-3-3 binding shields PEST sequences in the C-terminus and protects PITPNC1 from ubiquitin-proteasome-mediated degradation (half-life ~4 h wild-type vs ~2 h for 14-3-3 binding mutant). Upon PMA treatment, the PITP domain of PITPNC1 interacts with the integral membrane protein ATRAP (angiotensin II type I receptor-associated protein), causing membrane recruitment.","method":"Co-immunoprecipitation, mutagenesis, pulse-chase degradation assay, proteasome inhibitor treatment, PMA stimulation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with binding assays and degradation kinetics in a single study","pmids":["21728994"],"is_preprint":false},{"year":2016,"finding":"PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi recruits GOLPH3, which facilitates Golgi extension and enhanced vesicular release, driving secretion of pro-invasive and pro-angiogenic mediators (HTRA1, MMP1, FAM3C, PDGFA, ADAM10).","method":"Biochemical lipid-binding assays, Co-IP, subcellular fractionation/localization, loss-of-function knockdown, epistasis experiments, mass spectrometry","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including PI4P-binding assay, Co-IP of RAB1B/GOLPH3, subcellular localization, and functional secretion readouts","pmids":["26977884"],"is_preprint":false},{"year":2011,"finding":"PITPNC1 is a target of miR-126 in metastatic breast cancer cells. Loss-of-function and epistasis experiments establish that PITPNC1, together with IGFBP2 and MERTK, mediates miR-126-regulated endothelial recruitment, metastatic angiogenesis, and metastatic colonization.","method":"miRNA overexpression, loss-of-function knockdown, epistasis rescue experiments, in vitro endothelial recruitment assay, in vivo metastasis assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal loss-of-function and epistasis experiments in vitro and in vivo, highly cited foundational study","pmids":["22170610"],"is_preprint":false},{"year":2018,"finding":"PITPNC1 promotes anoikis resistance in gastric cancer through enhancement of fatty acid oxidation (FAO), upregulating CD36 and CPT1B expression. PITPNC1 expression is induced by co-culture with omental adipocytes, linking the adipocyte microenvironment to PITPNC1-mediated metabolic reprogramming and metastasis.","method":"siRNA knockdown, overexpression, co-culture systems, in vitro anoikis assays, in vivo metastasis models, FAO inhibitor treatment","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/KD with defined cellular phenotype but single lab; pathway placement via FAO inhibitor rescue","pmids":["30555557"],"is_preprint":false},{"year":2023,"finding":"PITPNC1 is regulated by KRAS via MEK1/2 and JNK1/2 signaling. PITPNC1 controls mTOR localization through enhanced MYC protein stability, thereby preventing autophagy in lung and pancreatic cancer cells. PITPNC1 loss-of-function impairs cell proliferation, cell cycle progression, and tumor growth.","method":"Genetic KRAS modulation, pharmacological MEK/JNK inhibition, RNA sequencing, protein localization assays, in vitro and in vivo loss-of-function models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple epistasis and biochemical approaches in single lab with in vivo validation","pmids":["37210549"],"is_preprint":false},{"year":2022,"finding":"PITPNC1 knockout mice develop hypothermia under acute cold exposure due to defective β-oxidation in brown adipocytes. Pitpnc1-/- brown adipocytes show excessive accumulation of phosphatidylcholine and reduction of phosphatidic acid, linking PITPNC1-mediated phospholipid homeostasis to mitochondrial thermogenesis.","method":"Pitpnc1 knockout mice, cold exposure phenotyping, lipidomics, metabolic assays, mitochondrial function analysis","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with defined physiological phenotype and lipidomics; single lab","pmids":["36166181"],"is_preprint":false},{"year":2024,"finding":"PITPNC1 regulates CD155 expression on the surface of radioresistant colorectal cancer cells through FASN (fatty acid synthase). This PITPNC1/FASN/CD155 axis inhibits CD8+ T cell immune function and promotes radioresistance. Immunoprecipitation confirmed interaction between these proteins; silencing PITPNC1 restored CD8+ T cell-mediated tumor killing.","method":"Immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, lentiviral overexpression, co-culture with PBMCs/CD8+ T cells, in vivo tumor-bearing models, flow cytometry","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and co-localization support protein interaction; functional rescue validates pathway placement; single lab","pmids":["38291470"],"is_preprint":false},{"year":2017,"finding":"PITPNC1 expression is upregulated during differentiation of H9c2 cells toward cardiomyocytes. PITPNC1 binds PA/PI in mitochondria-associated contexts; its expression correlates with increased mitochondrial biogenesis markers. However, the mitochondrial CDP-diacylglycerol synthase activity was attributed to TAMM41, not PITPNC1.","method":"Western blotting, cell fractionation, immunoreactivity profiling during cardiomyocyte differentiation","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Low","confidence_rationale":"Tier 3 — expression correlation during differentiation; PITPNC1 not the primary subject of functional experiments in this study","pmids":["29253589"],"is_preprint":false}],"current_model":"PITPNC1 is a soluble Class II phosphatidylinositol transfer protein that binds and transfers both phosphatidylinositol and phosphatidic acid (but not phosphatidylcholine); its stability is regulated by 14-3-3 binding to phosphorylated C-terminal PEST sequences, and its activity is coupled to PI4P at the Golgi where it recruits RAB1B to drive GOLPH3-mediated Golgi extension and enhanced vesicular secretion of pro-invasive and pro-angiogenic factors, while also functioning downstream of KRAS (via MEK/JNK) to stabilize MYC, control mTOR localization, and suppress autophagy, and playing roles in mitochondrial phospholipid homeostasis and brown adipose tissue thermogenesis."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing how PITPNC1 protein turnover is controlled resolved the previously unknown regulatory logic of a Class II PITP: 14-3-3 binding to dual phosphoserine sites shields C-terminal PEST sequences from ubiquitin–proteasome degradation, and the PITP domain can be membrane-recruited through interaction with the integral membrane protein ATRAP.","evidence":"Co-immunoprecipitation, phosphosite mutagenesis, pulse-chase degradation kinetics, and proteasome-inhibitor rescue in cultured cells","pmids":["21728994"],"confidence":"High","gaps":["Kinases responsible for Ser274/Ser299 phosphorylation are unidentified","Physiological contexts that trigger ATRAP–PITPNC1 interaction are unexplored","Whether 14-3-3 binding alters lipid transfer activity is untested"]},{"year":2011,"claim":"Identifying PITPNC1 as a functional target of miR-126 in metastatic breast cancer established it as a mediator of metastatic angiogenesis and colonization, positioning it within the broader miR-126/IGFBP2/MERTK network.","evidence":"miRNA overexpression, PITPNC1 knockdown, epistasis rescue, in vitro endothelial recruitment and in vivo metastasis assays","pmids":["22170610"],"confidence":"High","gaps":["Direct transcriptional versus post-transcriptional regulation by miR-126 on PITPNC1 mRNA not dissected at the binding-site level","Relative contribution of PITPNC1 versus IGFBP2 and MERTK to metastatic phenotype is not quantitatively resolved"]},{"year":2012,"claim":"Defining the lipid specificity of PITPNC1 answered whether Class II PITPs share the phosphatidylcholine-transfer capacity of Class I PITPs: PITPNC1 transfers PA and PI but not PC, and phospholipase D activation shifts the cargo equilibrium from PI toward PA.","evidence":"Purified recombinant protein from E. coli, in vitro lipid transfer assays, permeabilized HL60 cell reconstitution, lipid mass spectrometry","pmids":["22822086"],"confidence":"High","gaps":["Structural basis for PA selectivity over PC is unknown","In vivo lipid cargo under physiological conditions has not been validated","Whether PA transfer has a dedicated cellular function distinct from PI transfer is unresolved"]},{"year":2016,"claim":"Connecting PITPNC1's lipid-binding activity to a specific organelle-level output resolved how it drives malignant secretion: PITPNC1 binds Golgi PI4P, recruits RAB1B, which localizes GOLPH3 to extend Golgi membranes and enhance vesicular secretion of pro-invasive/pro-angiogenic cargo.","evidence":"PI4P-binding assays, Co-IP of RAB1B and GOLPH3, subcellular fractionation, knockdown epistasis, secreted-proteome mass spectrometry in cancer cells","pmids":["26977884"],"confidence":"High","gaps":["Whether PITPNC1 directly presents PI4P to RAB1B or acts via an intermediate is unknown","Contribution of PA transfer versus PI4P sensing to Golgi phenotype is not separated","Regulation of PITPNC1 Golgi targeting is not defined"]},{"year":2018,"claim":"Demonstrating that PITPNC1 promotes anoikis resistance through fatty acid oxidation expanded its role beyond lipid transfer to metabolic reprogramming, linking the omental adipocyte microenvironment to PITPNC1-mediated upregulation of CD36 and CPT1B in gastric cancer.","evidence":"siRNA/overexpression, co-culture with adipocytes, FAO inhibitor rescue, in vivo metastasis models in gastric cancer","pmids":["30555557"],"confidence":"Medium","gaps":["Mechanism by which PITPNC1 upregulates CD36/CPT1B transcription is not defined","Whether lipid transfer activity is required for FAO enhancement is untested","Single-lab finding without independent replication"]},{"year":2022,"claim":"Knockout mouse phenotyping revealed a physiological requirement for PITPNC1 in brown adipose tissue thermogenesis, linking its phospholipid homeostasis function to mitochondrial β-oxidation in vivo: Pitpnc1−/− mice accumulate PC and lose PA in brown adipocytes, causing cold intolerance.","evidence":"Pitpnc1 global knockout mice, acute cold exposure, lipidomics, mitochondrial function assays","pmids":["36166181"],"confidence":"Medium","gaps":["Whether the phenotype is cell-autonomous to brown adipocytes versus systemic is not resolved","Molecular mechanism connecting PA depletion to defective β-oxidation is uncharacterized","Single-lab study"]},{"year":2023,"claim":"Placing PITPNC1 downstream of KRAS via MEK/JNK signaling and upstream of MYC stabilization and mTOR localization unified its oncogenic functions: PITPNC1 acts as a KRAS effector that suppresses autophagy and promotes proliferation in lung and pancreatic cancers.","evidence":"Genetic KRAS modulation, pharmacological MEK/JNK inhibition, RNA-seq, protein localization, in vivo tumor models","pmids":["37210549"],"confidence":"Medium","gaps":["Direct biochemical mechanism by which PITPNC1 stabilizes MYC protein is unknown","Whether lipid transfer activity is required for MYC/mTOR axis is untested","Relationship between Golgi secretion function and KRAS/MYC/mTOR axis is not integrated"]},{"year":2024,"claim":"Identifying a PITPNC1/FASN/CD155 axis in radioresistant colorectal cancer showed that PITPNC1 can modulate immune evasion by regulating surface checkpoint ligand expression, with functional consequences for CD8+ T cell cytotoxicity.","evidence":"Co-IP and co-localization of PITPNC1–FASN–CD155, siRNA knockdown, co-culture with CD8+ T cells, in vivo tumor models","pmids":["38291470"],"confidence":"Medium","gaps":["Mechanism linking PITPNC1 to FASN-dependent CD155 surface expression is indirect","Whether lipid transfer or scaffolding mediates the interaction is unknown","Single-lab finding"]},{"year":null,"claim":"A unifying structural and biochemical model explaining how PITPNC1 lipid transfer specificity (PA vs PI vs PI4P) is coupled to its diverse downstream outputs — Golgi secretion, metabolic reprogramming, MYC stabilization, and immune modulation — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of PITPNC1 with bound lipid cargo exists","Whether distinct lipid cargoes mediate distinct cellular functions is untested","Integration of PITPNC1 phospholipid homeostasis role with its oncogenic signaling role has not been attempted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,6]}],"complexes":[],"partners":["RAB1B","GOLPH3","YWHAZ","ATRAP","FASN"],"other_free_text":[]},"mechanistic_narrative":"PITPNC1 is a Class II phosphatidylinositol transfer protein that couples lipid sensing to vesicular secretion, metabolic reprogramming, and signaling in both normal physiology and cancer. It selectively binds and transfers phosphatidylinositol (PI) and phosphatidic acid (PA) but not phosphatidylcholine, and its lipid cargo is influenced by phospholipase D activity [PMID:22822086]. At the Golgi, PITPNC1 engages PI4P and recruits RAB1B, which in turn localizes GOLPH3 to drive Golgi extension and enhanced vesicular secretion of pro-invasive and pro-angiogenic mediators such as MMP1 and PDGFA [PMID:26977884]. PITPNC1 protein stability is controlled by 14-3-3 binding to phosphorylated C-terminal PEST motifs that shield it from proteasomal degradation [PMID:21728994], and in KRAS-driven cancers it is transcriptionally upregulated via MEK/JNK signaling to stabilize MYC, direct mTOR localization, and suppress autophagy [PMID:37210549]."},"prefetch_data":{"uniprot":{"accession":"Q9UKF7","full_name":"Cytoplasmic phosphatidylinositol transfer protein 1","aliases":["Mammalian rdgB homolog beta","M-rdgB beta","MrdgBbeta","Retinal degeneration B homolog beta","RdgBbeta"],"length_aa":332,"mass_kda":38.4,"function":"Catalyzes the transfer of phosphatidylinositol (PI) and phosphatidic acid (PA) between membranes (PubMed:10531358, PubMed:22822086). Binds PA derived from the phospholipase D signaling pathway and among the cellular PA species, preferably binds to the C16:0/16:1 and C16:1/18:1 PA species (PubMed:22822086) Catalyzes the transfer of phosphatidylinositol between membranes","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UKF7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PITPNC1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PITPNC1","total_profiled":1310},"omim":[{"mim_id":"611767","title":"MICRO RNA 126; MIR126","url":"https://www.omim.org/entry/611767"},{"mim_id":"605134","title":"PHOSPHATIDYLINOSITOL TRANSFER PROTEIN, CYTOPLASMIC, 1; PITPNC1","url":"https://www.omim.org/entry/605134"},{"mim_id":"604705","title":"MER TYROSINE KINASE PROTOONCOGENE; MERTK","url":"https://www.omim.org/entry/604705"},{"mim_id":"146731","title":"INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN 2; IGFBP2","url":"https://www.omim.org/entry/146731"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":24.4}],"url":"https://www.proteinatlas.org/search/PITPNC1"},"hgnc":{"alias_symbol":["RDGBB1","RDGBB","RDGB-BETA"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKF7","domains":[{"cath_id":"3.30.530.20","chopping":"1-245","consensus_level":"medium","plddt":94.8655,"start":1,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKF7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKF7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKF7-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PITPNC1","jax_strain_url":"https://www.jax.org/strain/search?query=PITPNC1"},"sequence":{"accession":"Q9UKF7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKF7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKF7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKF7"}},"corpus_meta":[{"pmid":"22170610","id":"PMC_22170610","title":"A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22170610","citation_count":437,"is_preprint":false},{"pmid":"26977884","id":"PMC_26977884","title":"PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion.","date":"2016","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/26977884","citation_count":115,"is_preprint":false},{"pmid":"30555557","id":"PMC_30555557","title":"Adipocytes fuel gastric cancer omental metastasis via PITPNC1-mediated fatty acid metabolic reprogramming.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30555557","citation_count":98,"is_preprint":false},{"pmid":"22822086","id":"PMC_22822086","title":"Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) binds and transfers phosphatidic acid.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22822086","citation_count":78,"is_preprint":false},{"pmid":"31462439","id":"PMC_31462439","title":"The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer).","date":"2019","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/31462439","citation_count":59,"is_preprint":false},{"pmid":"25918132","id":"PMC_25918132","title":"Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.","date":"2015","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/25918132","citation_count":45,"is_preprint":false},{"pmid":"29253589","id":"PMC_29253589","title":"Mitochondrial CDP-diacylglycerol synthase activity is due to the peripheral protein, TAMM41 and not due to the integral membrane protein, CDP-diacylglycerol synthase 1.","date":"2017","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/29253589","citation_count":39,"is_preprint":false},{"pmid":"23086419","id":"PMC_23086419","title":"The diverse functions of phosphatidylinositol transfer proteins.","date":"2012","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23086419","citation_count":35,"is_preprint":false},{"pmid":"34111527","id":"PMC_34111527","title":"Courier service for phosphatidylinositol: PITPs deliver on demand.","date":"2021","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/34111527","citation_count":32,"is_preprint":false},{"pmid":"21728994","id":"PMC_21728994","title":"The phosphatidylinositol transfer protein RdgBβ binds 14-3-3 via its unstructured C-terminus, whereas its lipid-binding domain interacts with the integral membrane protein ATRAP (angiotensin II type I receptor-associated protein).","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21728994","citation_count":27,"is_preprint":false},{"pmid":"24153013","id":"PMC_24153013","title":"Altered expression of miR-24, miR-126 and miR-365 does not affect viability of childhood TCF3-rearranged leukemia cells.","date":"2013","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/24153013","citation_count":23,"is_preprint":false},{"pmid":"34634522","id":"PMC_34634522","title":"Plasma triacylglycerols are biomarkers of β-cell function in mice and humans.","date":"2021","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34634522","citation_count":22,"is_preprint":false},{"pmid":"34439480","id":"PMC_34439480","title":"Pterostilbene Changes Epigenetic Marks at Enhancer Regions of Oncogenes in Breast Cancer Cells.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34439480","citation_count":18,"is_preprint":false},{"pmid":"32175419","id":"PMC_32175419","title":"PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production.","date":"2020","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32175419","citation_count":17,"is_preprint":false},{"pmid":"37210549","id":"PMC_37210549","title":"The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer.","date":"2023","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37210549","citation_count":16,"is_preprint":false},{"pmid":"35292404","id":"PMC_35292404","title":"Aberrant overexpression of HOTAIR inhibits abdominal adipogenesis through remodelling of genome-wide DNA methylation and transcription.","date":"2022","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35292404","citation_count":16,"is_preprint":false},{"pmid":"38291470","id":"PMC_38291470","title":"PITPNC1 Suppress CD8+ T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38291470","citation_count":15,"is_preprint":false},{"pmid":"36166181","id":"PMC_36166181","title":"PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure.","date":"2022","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36166181","citation_count":14,"is_preprint":false},{"pmid":"39406587","id":"PMC_39406587","title":"Expanding functions of the phosphatidylinositol/phosphatidate lipid transporter, PITPNC1 in physiology and in pathology.","date":"2024","source":"Advances in biological regulation","url":"https://pubmed.ncbi.nlm.nih.gov/39406587","citation_count":7,"is_preprint":false},{"pmid":"38371897","id":"PMC_38371897","title":"Genome-wide association study of blood lipid levels in Southern Han Chinese adults with prediabetes.","date":"2024","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/38371897","citation_count":5,"is_preprint":false},{"pmid":"22010007","id":"PMC_22010007","title":"Profiling CCK-mediated pancreatic growth: the dynamic genetic program and the role of STATs as potential regulators.","date":"2011","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22010007","citation_count":4,"is_preprint":false},{"pmid":"35454363","id":"PMC_35454363","title":"Identification of a De Novo Deletion by Using A-CGH Involving PLNAX2: An Interesting Candidate Gene in Psychomotor Developmental Delay.","date":"2022","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/35454363","citation_count":4,"is_preprint":false},{"pmid":"39324181","id":"PMC_39324181","title":"Identification of fatty acid metabolism signature genes in patients with pulmonary arterial hypertension using WGCNA and machine learning.","date":"2024","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/39324181","citation_count":1,"is_preprint":false},{"pmid":"34459411","id":"PMC_34459411","title":"Early Changes in Skeletal Muscle of Young C22 Mice, A Model of Charcot-Marie-Tooth 1A.","date":"2021","source":"Journal of neuromuscular diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34459411","citation_count":1,"is_preprint":false},{"pmid":"41492412","id":"PMC_41492412","title":"Decoding ulcerative colitis pathogenesis through transcriptomics: from dysregulated gene networks to targeted intervention strategies.","date":"2025","source":"Journal of translational autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/41492412","citation_count":0,"is_preprint":false},{"pmid":"41674976","id":"PMC_41674976","title":"Key genes and pathway differences between serrated polyps and conventional adenomas: insights from multi-omics.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41674976","citation_count":0,"is_preprint":false},{"pmid":"39843866","id":"PMC_39843866","title":"Genetic insights into CRP levels in Indian adolescents: confirming adult genetic associations.","date":"2025","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/39843866","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15975,"output_tokens":2487,"usd":0.042615},"stage2":{"model":"claude-opus-4-6","input_tokens":5785,"output_tokens":2592,"usd":0.140588},"total_usd":0.183203,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"PITPNC1 (RdgBβ) binds and transfers phosphatidic acid (PA) in addition to phosphatidylinositol (PI), but unlike Class I PITPs does not bind phosphatidylcholine. When purified from E. coli, PITPNC1 is preloaded with PA and phosphatidylglycerol. In permeabilized HL60 cells, PITPNC1 exchanges phosphatidylglycerol for PA and PI. Activation of phospholipase D increases PA binding to PITPNC1 at the expense of PI binding.\",\n      \"method\": \"In vitro lipid binding and transfer assays, permeabilized cell reconstitution, lipid mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal lipid binding/transfer assays and cell-based validation\",\n      \"pmids\": [\"22822086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PITPNC1 C-terminus contains two tandem phosphorylated serine residues (Ser274 and Ser299) that bind 14-3-3 proteins. 14-3-3 binding shields PEST sequences in the C-terminus and protects PITPNC1 from ubiquitin-proteasome-mediated degradation (half-life ~4 h wild-type vs ~2 h for 14-3-3 binding mutant). Upon PMA treatment, the PITP domain of PITPNC1 interacts with the integral membrane protein ATRAP (angiotensin II type I receptor-associated protein), causing membrane recruitment.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, pulse-chase degradation assay, proteasome inhibitor treatment, PMA stimulation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with binding assays and degradation kinetics in a single study\",\n      \"pmids\": [\"21728994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi recruits GOLPH3, which facilitates Golgi extension and enhanced vesicular release, driving secretion of pro-invasive and pro-angiogenic mediators (HTRA1, MMP1, FAM3C, PDGFA, ADAM10).\",\n      \"method\": \"Biochemical lipid-binding assays, Co-IP, subcellular fractionation/localization, loss-of-function knockdown, epistasis experiments, mass spectrometry\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including PI4P-binding assay, Co-IP of RAB1B/GOLPH3, subcellular localization, and functional secretion readouts\",\n      \"pmids\": [\"26977884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PITPNC1 is a target of miR-126 in metastatic breast cancer cells. Loss-of-function and epistasis experiments establish that PITPNC1, together with IGFBP2 and MERTK, mediates miR-126-regulated endothelial recruitment, metastatic angiogenesis, and metastatic colonization.\",\n      \"method\": \"miRNA overexpression, loss-of-function knockdown, epistasis rescue experiments, in vitro endothelial recruitment assay, in vivo metastasis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal loss-of-function and epistasis experiments in vitro and in vivo, highly cited foundational study\",\n      \"pmids\": [\"22170610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PITPNC1 promotes anoikis resistance in gastric cancer through enhancement of fatty acid oxidation (FAO), upregulating CD36 and CPT1B expression. PITPNC1 expression is induced by co-culture with omental adipocytes, linking the adipocyte microenvironment to PITPNC1-mediated metabolic reprogramming and metastasis.\",\n      \"method\": \"siRNA knockdown, overexpression, co-culture systems, in vitro anoikis assays, in vivo metastasis models, FAO inhibitor treatment\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotype but single lab; pathway placement via FAO inhibitor rescue\",\n      \"pmids\": [\"30555557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PITPNC1 is regulated by KRAS via MEK1/2 and JNK1/2 signaling. PITPNC1 controls mTOR localization through enhanced MYC protein stability, thereby preventing autophagy in lung and pancreatic cancer cells. PITPNC1 loss-of-function impairs cell proliferation, cell cycle progression, and tumor growth.\",\n      \"method\": \"Genetic KRAS modulation, pharmacological MEK/JNK inhibition, RNA sequencing, protein localization assays, in vitro and in vivo loss-of-function models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple epistasis and biochemical approaches in single lab with in vivo validation\",\n      \"pmids\": [\"37210549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PITPNC1 knockout mice develop hypothermia under acute cold exposure due to defective β-oxidation in brown adipocytes. Pitpnc1-/- brown adipocytes show excessive accumulation of phosphatidylcholine and reduction of phosphatidic acid, linking PITPNC1-mediated phospholipid homeostasis to mitochondrial thermogenesis.\",\n      \"method\": \"Pitpnc1 knockout mice, cold exposure phenotyping, lipidomics, metabolic assays, mitochondrial function analysis\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined physiological phenotype and lipidomics; single lab\",\n      \"pmids\": [\"36166181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PITPNC1 regulates CD155 expression on the surface of radioresistant colorectal cancer cells through FASN (fatty acid synthase). This PITPNC1/FASN/CD155 axis inhibits CD8+ T cell immune function and promotes radioresistance. Immunoprecipitation confirmed interaction between these proteins; silencing PITPNC1 restored CD8+ T cell-mediated tumor killing.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, lentiviral overexpression, co-culture with PBMCs/CD8+ T cells, in vivo tumor-bearing models, flow cytometry\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and co-localization support protein interaction; functional rescue validates pathway placement; single lab\",\n      \"pmids\": [\"38291470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PITPNC1 expression is upregulated during differentiation of H9c2 cells toward cardiomyocytes. PITPNC1 binds PA/PI in mitochondria-associated contexts; its expression correlates with increased mitochondrial biogenesis markers. However, the mitochondrial CDP-diacylglycerol synthase activity was attributed to TAMM41, not PITPNC1.\",\n      \"method\": \"Western blotting, cell fractionation, immunoreactivity profiling during cardiomyocyte differentiation\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression correlation during differentiation; PITPNC1 not the primary subject of functional experiments in this study\",\n      \"pmids\": [\"29253589\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PITPNC1 is a soluble Class II phosphatidylinositol transfer protein that binds and transfers both phosphatidylinositol and phosphatidic acid (but not phosphatidylcholine); its stability is regulated by 14-3-3 binding to phosphorylated C-terminal PEST sequences, and its activity is coupled to PI4P at the Golgi where it recruits RAB1B to drive GOLPH3-mediated Golgi extension and enhanced vesicular secretion of pro-invasive and pro-angiogenic factors, while also functioning downstream of KRAS (via MEK/JNK) to stabilize MYC, control mTOR localization, and suppress autophagy, and playing roles in mitochondrial phospholipid homeostasis and brown adipose tissue thermogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PITPNC1 is a Class II phosphatidylinositol transfer protein that couples lipid sensing to vesicular secretion, metabolic reprogramming, and signaling in both normal physiology and cancer. It selectively binds and transfers phosphatidylinositol (PI) and phosphatidic acid (PA) but not phosphatidylcholine, and its lipid cargo is influenced by phospholipase D activity [PMID:22822086]. At the Golgi, PITPNC1 engages PI4P and recruits RAB1B, which in turn localizes GOLPH3 to drive Golgi extension and enhanced vesicular secretion of pro-invasive and pro-angiogenic mediators such as MMP1 and PDGFA [PMID:26977884]. PITPNC1 protein stability is controlled by 14-3-3 binding to phosphorylated C-terminal PEST motifs that shield it from proteasomal degradation [PMID:21728994], and in KRAS-driven cancers it is transcriptionally upregulated via MEK/JNK signaling to stabilize MYC, direct mTOR localization, and suppress autophagy [PMID:37210549].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing how PITPNC1 protein turnover is controlled resolved the previously unknown regulatory logic of a Class II PITP: 14-3-3 binding to dual phosphoserine sites shields C-terminal PEST sequences from ubiquitin–proteasome degradation, and the PITP domain can be membrane-recruited through interaction with the integral membrane protein ATRAP.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphosite mutagenesis, pulse-chase degradation kinetics, and proteasome-inhibitor rescue in cultured cells\",\n      \"pmids\": [\"21728994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases responsible for Ser274/Ser299 phosphorylation are unidentified\", \"Physiological contexts that trigger ATRAP–PITPNC1 interaction are unexplored\", \"Whether 14-3-3 binding alters lipid transfer activity is untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying PITPNC1 as a functional target of miR-126 in metastatic breast cancer established it as a mediator of metastatic angiogenesis and colonization, positioning it within the broader miR-126/IGFBP2/MERTK network.\",\n      \"evidence\": \"miRNA overexpression, PITPNC1 knockdown, epistasis rescue, in vitro endothelial recruitment and in vivo metastasis assays\",\n      \"pmids\": [\"22170610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional versus post-transcriptional regulation by miR-126 on PITPNC1 mRNA not dissected at the binding-site level\", \"Relative contribution of PITPNC1 versus IGFBP2 and MERTK to metastatic phenotype is not quantitatively resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining the lipid specificity of PITPNC1 answered whether Class II PITPs share the phosphatidylcholine-transfer capacity of Class I PITPs: PITPNC1 transfers PA and PI but not PC, and phospholipase D activation shifts the cargo equilibrium from PI toward PA.\",\n      \"evidence\": \"Purified recombinant protein from E. coli, in vitro lipid transfer assays, permeabilized HL60 cell reconstitution, lipid mass spectrometry\",\n      \"pmids\": [\"22822086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for PA selectivity over PC is unknown\", \"In vivo lipid cargo under physiological conditions has not been validated\", \"Whether PA transfer has a dedicated cellular function distinct from PI transfer is unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connecting PITPNC1's lipid-binding activity to a specific organelle-level output resolved how it drives malignant secretion: PITPNC1 binds Golgi PI4P, recruits RAB1B, which localizes GOLPH3 to extend Golgi membranes and enhance vesicular secretion of pro-invasive/pro-angiogenic cargo.\",\n      \"evidence\": \"PI4P-binding assays, Co-IP of RAB1B and GOLPH3, subcellular fractionation, knockdown epistasis, secreted-proteome mass spectrometry in cancer cells\",\n      \"pmids\": [\"26977884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PITPNC1 directly presents PI4P to RAB1B or acts via an intermediate is unknown\", \"Contribution of PA transfer versus PI4P sensing to Golgi phenotype is not separated\", \"Regulation of PITPNC1 Golgi targeting is not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that PITPNC1 promotes anoikis resistance through fatty acid oxidation expanded its role beyond lipid transfer to metabolic reprogramming, linking the omental adipocyte microenvironment to PITPNC1-mediated upregulation of CD36 and CPT1B in gastric cancer.\",\n      \"evidence\": \"siRNA/overexpression, co-culture with adipocytes, FAO inhibitor rescue, in vivo metastasis models in gastric cancer\",\n      \"pmids\": [\"30555557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PITPNC1 upregulates CD36/CPT1B transcription is not defined\", \"Whether lipid transfer activity is required for FAO enhancement is untested\", \"Single-lab finding without independent replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Knockout mouse phenotyping revealed a physiological requirement for PITPNC1 in brown adipose tissue thermogenesis, linking its phospholipid homeostasis function to mitochondrial β-oxidation in vivo: Pitpnc1−/− mice accumulate PC and lose PA in brown adipocytes, causing cold intolerance.\",\n      \"evidence\": \"Pitpnc1 global knockout mice, acute cold exposure, lipidomics, mitochondrial function assays\",\n      \"pmids\": [\"36166181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the phenotype is cell-autonomous to brown adipocytes versus systemic is not resolved\", \"Molecular mechanism connecting PA depletion to defective β-oxidation is uncharacterized\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing PITPNC1 downstream of KRAS via MEK/JNK signaling and upstream of MYC stabilization and mTOR localization unified its oncogenic functions: PITPNC1 acts as a KRAS effector that suppresses autophagy and promotes proliferation in lung and pancreatic cancers.\",\n      \"evidence\": \"Genetic KRAS modulation, pharmacological MEK/JNK inhibition, RNA-seq, protein localization, in vivo tumor models\",\n      \"pmids\": [\"37210549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism by which PITPNC1 stabilizes MYC protein is unknown\", \"Whether lipid transfer activity is required for MYC/mTOR axis is untested\", \"Relationship between Golgi secretion function and KRAS/MYC/mTOR axis is not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying a PITPNC1/FASN/CD155 axis in radioresistant colorectal cancer showed that PITPNC1 can modulate immune evasion by regulating surface checkpoint ligand expression, with functional consequences for CD8+ T cell cytotoxicity.\",\n      \"evidence\": \"Co-IP and co-localization of PITPNC1–FASN–CD155, siRNA knockdown, co-culture with CD8+ T cells, in vivo tumor models\",\n      \"pmids\": [\"38291470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PITPNC1 to FASN-dependent CD155 surface expression is indirect\", \"Whether lipid transfer or scaffolding mediates the interaction is unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and biochemical model explaining how PITPNC1 lipid transfer specificity (PA vs PI vs PI4P) is coupled to its diverse downstream outputs — Golgi secretion, metabolic reprogramming, MYC stabilization, and immune modulation — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of PITPNC1 with bound lipid cargo exists\", \"Whether distinct lipid cargoes mediate distinct cellular functions is untested\", \"Integration of PITPNC1 phospholipid homeostasis role with its oncogenic signaling role has not been attempted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAB1B\",\n      \"GOLPH3\",\n      \"YWHAZ\",\n      \"ATRAP\",\n      \"FASN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}