{"gene":"GRAMD1B","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2021,"finding":"The GRAM domain of GRAMD1B acts as a coincidence detector for accessible cholesterol and anionic lipids (including phosphatidylserine) at the plasma membrane, with distinct but synergistic binding sites for each. A human intellectual-disability-associated mutation within the GRAM domain specifically impairs cholesterol sensing without affecting PS sensitivity. Another engineered point mutation enhances cholesterol sensitivity without altering PS sensitivity. Cell-free reconstitution and cell-based assays demonstrated that GRAM domain cholesterol sensing regulates membrane tethering and determines the rate of non-vesicular cholesterol transport from the plasma membrane to the ER by GRAMD1b.","method":"Cell-free reconstitution, cell-based assays, site-directed mutagenesis, lipid-binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro combined with mutagenesis and cell-based functional assays in a single rigorous study; multiple orthogonal methods","pmids":["33604931"],"is_preprint":false},{"year":2017,"finding":"GRAMD1B expression is positively regulated by JAK/STAT signaling in gastric cancer cells, and GRAMD1B knockdown decreases STAT3 levels, indicating a positive feedback loop. GRAMD1B and JAK/STAT signaling act synergistically to promote gastric cancer cell survival by upregulating the anti-apoptotic molecule Bcl-xL. The Drosophila ortholog of GRAMD1B was identified in a genome-wide RNAi screen as a novel component of the JAK/STAT pathway.","method":"RNAi knockdown, epistasis analysis (genome-wide RNAi screen in Drosophila), western blotting, immunohistochemistry","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi knockdown with defined molecular readouts (STAT3 levels, Bcl-xL expression) and genetic epistasis from Drosophila screen; single lab, two orthogonal approaches","pmids":["29383166"],"is_preprint":false},{"year":2018,"finding":"GRAMD1B knockdown in MDA-MB-231 breast cancer cells causes membrane ruffling and protrusions and significantly enhances cell migration, with increased levels of Rho family GTPases. The pro-migratory phenotype induced by GRAMD1B inhibition is associated with JAK2/STAT3 and Akt activation. Epistasis analysis showed that JAK2 inhibition (AG490) increases p-Akt levels via regulation of GRAMD1B expression, placing GRAMD1B downstream of JAK2 and upstream of Akt in this pathway.","method":"siRNA knockdown, cell migration assay, western blotting, pharmacological inhibition (JAK2 inhibitor AG490, Akt inhibitor), Rho GTPase activity assay, epistasis analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotype and pathway epistasis, single lab, multiple orthogonal methods","pmids":["29934528"],"is_preprint":false}],"current_model":"GRAMD1B encodes an ER-localized protein whose GRAM domain acts as a coincidence detector for accessible cholesterol and anionic lipids (phosphatidylserine) at the plasma membrane, enabling non-vesicular transport of cholesterol from the PM to the ER; it also functions as a component of the JAK/STAT signaling pathway, where it is transcriptionally upregulated by STAT3, feeds back to maintain STAT3 levels, promotes cell survival via Bcl-xL, and suppresses cell migration by restraining JAK2/STAT3 and Akt activity and Rho GTPase levels."},"narrative":{"mechanistic_narrative":"GRAMD1B is an endoplasmic reticulum-associated lipid-transfer protein whose GRAM domain functions as a coincidence detector for accessible cholesterol and anionic lipids, including phosphatidylserine, at the plasma membrane [PMID:33604931]. Distinct but synergistic binding sites for each lipid couple GRAM-domain cholesterol sensing to membrane tethering and set the rate of non-vesicular cholesterol transport from the plasma membrane to the ER; a human intellectual-disability-associated GRAM-domain mutation selectively abolishes cholesterol sensing while sparing PS sensitivity, and an engineered point mutation conversely enhances cholesterol sensitivity [PMID:33604931]. Independently of this lipid-transport role, GRAMD1B operates within JAK/STAT signaling: it is transcriptionally upregulated by JAK/STAT activity and feeds back to maintain STAT3 levels, acting with the pathway to promote cancer cell survival through the anti-apoptotic protein Bcl-xL [PMID:29383166]. Loss of GRAMD1B drives membrane ruffling, elevated Rho-family GTPase levels, and enhanced cell migration accompanied by JAK2/STAT3 and Akt activation, positioning GRAMD1B downstream of JAK2 and upstream of Akt as a restraint on the pro-migratory program [PMID:29934528].","teleology":[{"year":2017,"claim":"Established GRAMD1B as a genetically validated component of JAK/STAT signaling rather than an unconnected ER protein, linking it to a positive feedback loop sustaining STAT3 and to cancer cell survival.","evidence":"RNAi knockdown with STAT3 and Bcl-xL readouts in gastric cancer cells plus genome-wide RNAi epistasis screen of the Drosophila ortholog","pmids":["29383166"],"confidence":"Medium","gaps":["Molecular mechanism by which GRAMD1B maintains STAT3 levels is undefined","Whether the lipid-transfer function relates to the JAK/STAT role is untested","Single-lab finding without independent replication"]},{"year":2018,"claim":"Placed GRAMD1B in a defined signaling hierarchy as a suppressor of cell migration, situating it downstream of JAK2 and upstream of Akt and Rho GTPase regulation.","evidence":"siRNA knockdown, migration assays, Rho GTPase activity assays and pharmacological epistasis (AG490, Akt inhibitor) in MDA-MB-231 breast cancer cells","pmids":["29934528"],"confidence":"Medium","gaps":["Direct molecular link between GRAMD1B and JAK2/Akt/Rho is not resolved","Whether migration phenotype depends on lipid transport activity is unknown","Single cell line, single lab"]},{"year":2021,"claim":"Defined the biochemical mechanism of GRAMD1B at the membrane, showing its GRAM domain is a dual cholesterol/anionic-lipid coincidence detector that gates non-vesicular cholesterol transport from the PM to the ER.","evidence":"Cell-free reconstitution, lipid-binding assays, site-directed mutagenesis (including a disease mutation), and cell-based transport assays","pmids":["33604931"],"confidence":"High","gaps":["Structural basis of the two distinct lipid-binding sites not resolved","Physiological consequences of altered cholesterol transport in tissues not established","Relationship to the JAK/STAT signaling role not addressed"]},{"year":null,"claim":"How GRAMD1B's biochemically defined cholesterol-transport function mechanistically connects to its role in JAK/STAT signaling and migration control remains unresolved.","evidence":"No timeline study integrates the lipid-transfer and signaling functions","pmids":[],"confidence":"Low","gaps":["No experiment tests whether cholesterol transport activity is required for STAT3 maintenance or migration suppression","No structural model of the GRAM domain","Tissue- and disease-level consequences of the ID-associated mutation uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q3KR37","full_name":"Protein Aster-B","aliases":["GRAM domain-containing protein 1B"],"length_aa":738,"mass_kda":85.4,"function":"Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (By similarity). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER (By similarity). Plays a crucial role in cholesterol homeostasis in the adrenal gland and has the unique ability to localize to the PM based on the level of membrane cholesterol (By similarity). In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain (By similarity). At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q3KR37/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRAMD1B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRAMD1B","total_profiled":1310},"omim":[{"mim_id":"620180","title":"GRAM DOMAIN-CONTAINING PROTEIN 1C; GRAMD1C","url":"https://www.omim.org/entry/620180"},{"mim_id":"620179","title":"GRAM DOMAIN-CONTAINING PROTEIN 1B; GRAMD1B","url":"https://www.omim.org/entry/620179"},{"mim_id":"620178","title":"GRAM DOMAIN-CONTAINING PROTEIN 1A; GRAMD1A","url":"https://www.omim.org/entry/620178"},{"mim_id":"612559","title":"LEUKEMIA, CHRONIC LYMPHOCYTIC, SUSCEPTIBILITY TO, 5","url":"https://www.omim.org/entry/612559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":204.1},{"tissue":"brain","ntpm":111.7},{"tissue":"retina","ntpm":89.2}],"url":"https://www.proteinatlas.org/search/GRAMD1B"},"hgnc":{"alias_symbol":["LAMb","KIAA1201"],"prev_symbol":["LINC01059"]},"alphafold":{"accession":"Q3KR37","domains":[{"cath_id":"2.30.29.30","chopping":"88-221","consensus_level":"high","plddt":89.1348,"start":88,"end":221},{"cath_id":"3.30.530.20","chopping":"373-546","consensus_level":"high","plddt":92.5252,"start":373,"end":546}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3KR37","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q3KR37-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q3KR37-F1-predicted_aligned_error_v6.png","plddt_mean":67.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRAMD1B","jax_strain_url":"https://www.jax.org/strain/search?query=GRAMD1B"},"sequence":{"accession":"Q3KR37","fasta_url":"https://rest.uniprot.org/uniprotkb/Q3KR37.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q3KR37/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3KR37"}},"corpus_meta":[{"pmid":"7834826","id":"PMC_7834826","title":"Apoptosis (programmed cell death) in arteries of the neonatal lamb.","date":"1995","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/7834826","citation_count":184,"is_preprint":false},{"pmid":"31159860","id":"PMC_31159860","title":"Ruminal microbiome-host crosstalk stimulates the development of the ruminal epithelium in a lamb model.","date":"2019","source":"Microbiome","url":"https://pubmed.ncbi.nlm.nih.gov/31159860","citation_count":157,"is_preprint":false},{"pmid":"11252496","id":"PMC_11252496","title":"Escherichia coli O157 in cattle and sheep at slaughter, on beef and lamb carcasses and in raw beef and lamb products in South Yorkshire, UK.","date":"2001","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11252496","citation_count":130,"is_preprint":false},{"pmid":"15321788","id":"PMC_15321788","title":"Vascular changes after intra-amniotic endotoxin in preterm lamb lungs.","date":"2004","source":"American journal of physiology. 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stimulatory factor for lamb thymus RNA polymerase II.","date":"1979","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/435487","citation_count":22,"is_preprint":false},{"pmid":"35940100","id":"PMC_35940100","title":"Phosphorylation and acetylation of glycolytic enzymes cooperatively regulate their activity and lamb meat quality.","date":"2022","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35940100","citation_count":21,"is_preprint":false},{"pmid":"6228707","id":"PMC_6228707","title":"Phage lambda receptor (lamB protein) in Escherichia coli.","date":"1983","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/6228707","citation_count":21,"is_preprint":false},{"pmid":"17644783","id":"PMC_17644783","title":"Polymorphism at the ovine beta3-adrenergic receptor locus (ADRB3) and its association with lamb mortality.","date":"2007","source":"Journal of animal 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nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/3620435","citation_count":20,"is_preprint":false},{"pmid":"1634391","id":"PMC_1634391","title":"Subclinical mastitis in ewes and its effect on lamb performance.","date":"1992","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/1634391","citation_count":20,"is_preprint":false},{"pmid":"36736126","id":"PMC_36736126","title":"Integrating identification and targeted proteomics to discover the potential indicators of postmortem lamb meat quality.","date":"2023","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/36736126","citation_count":19,"is_preprint":false},{"pmid":"31412585","id":"PMC_31412585","title":"Isolation and Full-Length Sequence Analysis of a Pestivirus from Aborted Lamb Fetuses in Italy.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31412585","citation_count":19,"is_preprint":false},{"pmid":"6455415","id":"PMC_6455415","title":"Arrangement of bacteriophage lambda receptor protein (LamB) in the cell surface of Escherichia coli: a reconstitution study.","date":"1981","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6455415","citation_count":19,"is_preprint":false},{"pmid":"6086567","id":"PMC_6086567","title":"Topography of the insertion of LamB protein into the outer membrane of Escherichia coli wild-type and lac-lamB cells.","date":"1984","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6086567","citation_count":19,"is_preprint":false},{"pmid":"26658008","id":"PMC_26658008","title":"Microstructural, protein denaturation and water holding properties of lamb under pulse vacuum brining.","date":"2015","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/26658008","citation_count":18,"is_preprint":false},{"pmid":"3301537","id":"PMC_3301537","title":"Sequence determinants in the lamB gene of Escherichia coli influencing the binding and pore selectivity of maltoporin.","date":"1987","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/3301537","citation_count":18,"is_preprint":false},{"pmid":"19214729","id":"PMC_19214729","title":"Whole genome sequencing of lamb rotavirus and comparative analysis with other mammalian rotaviruses.","date":"2009","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/19214729","citation_count":18,"is_preprint":false},{"pmid":"19897628","id":"PMC_19897628","title":"Metabolic maturity at birth and neonate lamb survival: association among maternal factors, litter size, lamb birth weight, and plasma metabolic and endocrine factors on survival and behavior.","date":"2009","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/19897628","citation_count":17,"is_preprint":false},{"pmid":"2532541","id":"PMC_2532541","title":"Antibodies against synthetic peptides and the topology of LamB, an outer membrane protein from Escherichia coli K12.","date":"1989","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2532541","citation_count":17,"is_preprint":false},{"pmid":"29383166","id":"PMC_29383166","title":"GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29383166","citation_count":16,"is_preprint":false},{"pmid":"28625789","id":"PMC_28625789","title":"Maltoporin LamB Unfolds β Hairpins along Mechanical Stress-Dependent Unfolding Pathways.","date":"2017","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/28625789","citation_count":15,"is_preprint":false},{"pmid":"22054553","id":"PMC_22054553","title":"Lamb and mutton flavour: Contributing factors and chemical aspects.","date":"1977","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/22054553","citation_count":15,"is_preprint":false},{"pmid":"15774827","id":"PMC_15774827","title":"ATP depletion and cell death in the neonatal lamb ductus arteriosus.","date":"2005","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/15774827","citation_count":15,"is_preprint":false},{"pmid":"17060422","id":"PMC_17060422","title":"Association analyses between the prion protein locus and reproductive and lamb weight traits in Ripollesa sheep.","date":"2006","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/17060422","citation_count":15,"is_preprint":false},{"pmid":"10749711","id":"PMC_10749711","title":"Platelet-activating factor receptors in lamb lungs are downregulated immediately after birth.","date":"2000","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10749711","citation_count":15,"is_preprint":false},{"pmid":"8652346","id":"PMC_8652346","title":"Survival and growth of Aeromonas hydrophila on modified atmosphere packaged normal and high pH lamb.","date":"1996","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8652346","citation_count":14,"is_preprint":false},{"pmid":"8192249","id":"PMC_8192249","title":"Fine structure of taste buds located on the lamb epiglottis.","date":"1994","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/8192249","citation_count":14,"is_preprint":false},{"pmid":"6278260","id":"PMC_6278260","title":"rho Mutations restore lamB expression in E. coli K12 strains with an inactive malB region.","date":"1981","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/6278260","citation_count":13,"is_preprint":false},{"pmid":"31063536","id":"PMC_31063536","title":"Prepartum fatty acid supplementation in sheep. IV. Effect of calcium salts with eicosapentaenoic acid and docosahexaenoic acid in the maternal and finishing diet on lamb liver and adipose tissue during the lamb finishing period1.","date":"2019","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/31063536","citation_count":13,"is_preprint":false},{"pmid":"2977630","id":"PMC_2977630","title":"Expression of the Escherichia coli lamB gene in Vibrio cholerae.","date":"1986","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/2977630","citation_count":13,"is_preprint":false},{"pmid":"23401383","id":"PMC_23401383","title":"Developmental changes in diaphragm muscle function in the preterm and postnatal lamb.","date":"2013","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/23401383","citation_count":13,"is_preprint":false},{"pmid":"31825558","id":"PMC_31825558","title":"Lamb as a potential source of Toxoplasma gondii infection for Australians.","date":"2019","source":"Australian and New Zealand journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/31825558","citation_count":13,"is_preprint":false},{"pmid":"32120943","id":"PMC_32120943","title":"Lamb Fattening Under Intensive Pasture-Based Systems: A Review.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32120943","citation_count":12,"is_preprint":false},{"pmid":"4095376","id":"PMC_4095376","title":"[Protein metabolism in the newborn lamb. II. Influence of diet on protein synthesis and turnover].","date":"1985","source":"Reproduction, nutrition, developpement","url":"https://pubmed.ncbi.nlm.nih.gov/4095376","citation_count":12,"is_preprint":false},{"pmid":"36517795","id":"PMC_36517795","title":"Respiratory strategy at birth initiates distinct lung injury phenotypes in the preterm lamb lung.","date":"2022","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/36517795","citation_count":12,"is_preprint":false},{"pmid":"24338411","id":"PMC_24338411","title":"Expression of calpastatin and myostatin genes associated with lamb meat quality.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/24338411","citation_count":11,"is_preprint":false},{"pmid":"30040835","id":"PMC_30040835","title":"Comparison of transcriptomic landscapes of different lamb muscles using RNA-Seq.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30040835","citation_count":11,"is_preprint":false},{"pmid":"6413998","id":"PMC_6413998","title":"Maturation of the hypothalamic--pituitary--gonadal axis in the male lamb: a review.","date":"1983","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/6413998","citation_count":11,"is_preprint":false},{"pmid":"32380293","id":"PMC_32380293","title":"The effects of improving low dietary protein utilization on the proteome of lamb tissues.","date":"2020","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32380293","citation_count":11,"is_preprint":false},{"pmid":"36419828","id":"PMC_36419828","title":"miRNA transcriptome and myofiber characteristics of lamb skeletal muscle during hypertrophic growth1.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36419828","citation_count":10,"is_preprint":false},{"pmid":"8567487","id":"PMC_8567487","title":"Impact of composition manipulation on lean lamb production in the United States.","date":"1995","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/8567487","citation_count":10,"is_preprint":false},{"pmid":"2066322","id":"PMC_2066322","title":"Fish meal as a protein supplement in finishing lamb diets.","date":"1991","source":"Journal of animal science","url":"https://pubmed.ncbi.nlm.nih.gov/2066322","citation_count":10,"is_preprint":false},{"pmid":"35448491","id":"PMC_35448491","title":"Evaluation of the Links between Lamb Feed Efficiency and Rumen and Plasma Metabolomic Data.","date":"2022","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/35448491","citation_count":9,"is_preprint":false},{"pmid":"33494236","id":"PMC_33494236","title":"Detection of Infectious Cryptosporidium parvum Oocysts from Lamb's Lettuce: CC-qPCR's Intake.","date":"2021","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/33494236","citation_count":9,"is_preprint":false},{"pmid":"32238226","id":"PMC_32238226","title":"Distinct patterns of mutational sensitivity for λ resistance and maltodextrin transport in Escherichia coli LamB.","date":"2020","source":"Microbial genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32238226","citation_count":9,"is_preprint":false},{"pmid":"31652726","id":"PMC_31652726","title":"Transcriptomic Revelation of Phenolic Compounds Involved in Aluminum Toxicity Responses in Roots of Cunninghamia lanceolata (Lamb.) Hook.","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/31652726","citation_count":9,"is_preprint":false},{"pmid":"36759900","id":"PMC_36759900","title":"Clinical characterization of Lamb-Shaffer syndrome: a case report and literature review.","date":"2023","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36759900","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47653,"output_tokens":1310,"usd":0.081305,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7643,"output_tokens":1861,"usd":0.04237,"stage2_stop_reason":"end_turn"},"total_usd":0.123675,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about GRAMD1B (the human/mammalian gene). Let me classify each paper:\n\n- Papers [1]-[5], [13]-[16], [19]-[22], [26]-[45], [47]-[50], [53]-[57], [59]-[68], [70]-[72], [74]-[97], [99]-[100]: These are about actual lambs (the animal), E. coli LamB protein, bacteriophage systems, or other unrelated genes. NOT about GRAMD1B.\n\n- Paper [17]: About GRAMD1b's GRAM domain sensing accessible cholesterol and phosphatidylserine (PS) in the PM — directly about GRAMD1B. INCLUDE.\n\n- Paper [27]: About GRAMD1B regulating cell migration in breast cancer cells via JAK/STAT and Akt signaling. INCLUDE.\n\n- Paper [73]: About GRAMD1B as a component of JAK/STAT signaling in gastric carcinogenesis. INCLUDE.\n\nNow extracting mechanistic discoveries:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"The GRAM domain of GRAMD1B acts as a coincidence detector for accessible cholesterol and anionic lipids (including phosphatidylserine) at the plasma membrane, with distinct but synergistic binding sites for each. A human intellectual-disability-associated mutation within the GRAM domain specifically impairs cholesterol sensing without affecting PS sensitivity. Another engineered point mutation enhances cholesterol sensitivity without altering PS sensitivity. Cell-free reconstitution and cell-based assays demonstrated that GRAM domain cholesterol sensing regulates membrane tethering and determines the rate of non-vesicular cholesterol transport from the plasma membrane to the ER by GRAMD1b.\",\n      \"method\": \"Cell-free reconstitution, cell-based assays, site-directed mutagenesis, lipid-binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro combined with mutagenesis and cell-based functional assays in a single rigorous study; multiple orthogonal methods\",\n      \"pmids\": [\"33604931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GRAMD1B expression is positively regulated by JAK/STAT signaling in gastric cancer cells, and GRAMD1B knockdown decreases STAT3 levels, indicating a positive feedback loop. GRAMD1B and JAK/STAT signaling act synergistically to promote gastric cancer cell survival by upregulating the anti-apoptotic molecule Bcl-xL. The Drosophila ortholog of GRAMD1B was identified in a genome-wide RNAi screen as a novel component of the JAK/STAT pathway.\",\n      \"method\": \"RNAi knockdown, epistasis analysis (genome-wide RNAi screen in Drosophila), western blotting, immunohistochemistry\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi knockdown with defined molecular readouts (STAT3 levels, Bcl-xL expression) and genetic epistasis from Drosophila screen; single lab, two orthogonal approaches\",\n      \"pmids\": [\"29383166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GRAMD1B knockdown in MDA-MB-231 breast cancer cells causes membrane ruffling and protrusions and significantly enhances cell migration, with increased levels of Rho family GTPases. The pro-migratory phenotype induced by GRAMD1B inhibition is associated with JAK2/STAT3 and Akt activation. Epistasis analysis showed that JAK2 inhibition (AG490) increases p-Akt levels via regulation of GRAMD1B expression, placing GRAMD1B downstream of JAK2 and upstream of Akt in this pathway.\",\n      \"method\": \"siRNA knockdown, cell migration assay, western blotting, pharmacological inhibition (JAK2 inhibitor AG490, Akt inhibitor), Rho GTPase activity assay, epistasis analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined cellular phenotype and pathway epistasis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29934528\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRAMD1B encodes an ER-localized protein whose GRAM domain acts as a coincidence detector for accessible cholesterol and anionic lipids (phosphatidylserine) at the plasma membrane, enabling non-vesicular transport of cholesterol from the PM to the ER; it also functions as a component of the JAK/STAT signaling pathway, where it is transcriptionally upregulated by STAT3, feeds back to maintain STAT3 levels, promotes cell survival via Bcl-xL, and suppresses cell migration by restraining JAK2/STAT3 and Akt activity and Rho GTPase levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRAMD1B is an endoplasmic reticulum-associated lipid-transfer protein whose GRAM domain functions as a coincidence detector for accessible cholesterol and anionic lipids, including phosphatidylserine, at the plasma membrane [#0]. Distinct but synergistic binding sites for each lipid couple GRAM-domain cholesterol sensing to membrane tethering and set the rate of non-vesicular cholesterol transport from the plasma membrane to the ER; a human intellectual-disability-associated GRAM-domain mutation selectively abolishes cholesterol sensing while sparing PS sensitivity, and an engineered point mutation conversely enhances cholesterol sensitivity [#0]. Independently of this lipid-transport role, GRAMD1B operates within JAK/STAT signaling: it is transcriptionally upregulated by JAK/STAT activity and feeds back to maintain STAT3 levels, acting with the pathway to promote cancer cell survival through the anti-apoptotic protein Bcl-xL [#1]. Loss of GRAMD1B drives membrane ruffling, elevated Rho-family GTPase levels, and enhanced cell migration accompanied by JAK2/STAT3 and Akt activation, positioning GRAMD1B downstream of JAK2 and upstream of Akt as a restraint on the pro-migratory program [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established GRAMD1B as a genetically validated component of JAK/STAT signaling rather than an unconnected ER protein, linking it to a positive feedback loop sustaining STAT3 and to cancer cell survival.\",\n      \"evidence\": \"RNAi knockdown with STAT3 and Bcl-xL readouts in gastric cancer cells plus genome-wide RNAi epistasis screen of the Drosophila ortholog\",\n      \"pmids\": [\"29383166\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism by which GRAMD1B maintains STAT3 levels is undefined\",\n        \"Whether the lipid-transfer function relates to the JAK/STAT role is untested\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed GRAMD1B in a defined signaling hierarchy as a suppressor of cell migration, situating it downstream of JAK2 and upstream of Akt and Rho GTPase regulation.\",\n      \"evidence\": \"siRNA knockdown, migration assays, Rho GTPase activity assays and pharmacological epistasis (AG490, Akt inhibitor) in MDA-MB-231 breast cancer cells\",\n      \"pmids\": [\"29934528\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct molecular link between GRAMD1B and JAK2/Akt/Rho is not resolved\",\n        \"Whether migration phenotype depends on lipid transport activity is unknown\",\n        \"Single cell line, single lab\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the biochemical mechanism of GRAMD1B at the membrane, showing its GRAM domain is a dual cholesterol/anionic-lipid coincidence detector that gates non-vesicular cholesterol transport from the PM to the ER.\",\n      \"evidence\": \"Cell-free reconstitution, lipid-binding assays, site-directed mutagenesis (including a disease mutation), and cell-based transport assays\",\n      \"pmids\": [\"33604931\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Structural basis of the two distinct lipid-binding sites not resolved\",\n        \"Physiological consequences of altered cholesterol transport in tissues not established\",\n        \"Relationship to the JAK/STAT signaling role not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GRAMD1B's biochemically defined cholesterol-transport function mechanistically connects to its role in JAK/STAT signaling and migration control remains unresolved.\",\n      \"evidence\": \"No timeline study integrates the lipid-transfer and signaling functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No experiment tests whether cholesterol transport activity is required for STAT3 maintenance or migration suppression\",\n        \"No structural model of the GRAM domain\",\n        \"Tissue- and disease-level consequences of the ID-associated mutation uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}