{"gene":"SLC44A2","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2020,"finding":"Activated platelet integrin αIIbβ3 directly binds SLC44A2 on neutrophils under flow conditions; this interaction is mechanosensitive and triggers neutrophil extracellular trap (NET) formation that is highly prothrombotic. The R154Q substitution (rs2288904-A) in an extracellular loop of SLC44A2 severely impairs binding to activated αIIbβ3 and VWF-primed platelets, abrogating NETosis.","method":"Flow chamber assays with αIIbβ3-expressing platelets and neutrophils homozygous for SLC44A2 R154Q polymorphism; platelet-neutrophil binding and NET quantification under defined shear","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding confirmed with primary human neutrophils carrying defined genotype, flow-based mechanistic assay, functional NET readout, replicated with VWF-primed platelets","pmids":["32314961"],"is_preprint":false},{"year":2021,"finding":"Slc44a2/HNA-3a on neutrophils mediates adhesion to VWF at venous shear rates (100 s⁻¹) in a β2-integrin-independent manner; this adhesion is required for shear-dependent NETosis. Neutrophils expressing HNA-3b (R154Q) show severely impaired adhesion to VWF. In vivo, Slc44a2-knockout mice exhibited massive reduction in neutrophil recruitment to inflamed mesenteric venules after histamine-induced endothelial degranulation.","method":"Flow chamber perfusion of HEK293T transfectants and primary donor neutrophils on VWF-coated surfaces; intravital microscopy of Slc44a2-/- mouse venules","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (flow chamber with genotyped primary neutrophils, in vivo intravital microscopy in KO mice), two independent experimental systems","pmids":["33556175"],"is_preprint":false},{"year":2024,"finding":"SLC44A2 forms a protein complex with NRP1 and ITGB3 in vascular smooth muscle cells (VSMCs); this complex activates TGF-β/SMAD signaling to promote contractile gene expression. VSMC-specific SLC44A2 knockout shifts cells to a synthetic phenotype and increases aortic aneurysm susceptibility under Ang II infusion, while SLC44A2 overexpression is protective.","method":"Co-immunoprecipitation of SLC44A2-NRP1-ITGB3 complex; VSMC-specific conditional KO and overexpression in Apoe-/- mice with Ang II infusion; TGF-β/SMAD pathway reporter assays; siRNA knockdown in vitro","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of trimeric complex, loss-of-function and gain-of-function in vivo mouse models, defined signaling pathway readout, multiple orthogonal methods in one study","pmids":["38916960"],"is_preprint":false},{"year":2010,"finding":"The CTL2/SLC44A2 isoform P2 (706 aa, exon 1b) exhibits detectable choline transport activity when expressed in Xenopus laevis oocytes, whereas isoform P1 (704 aa, exon 1a) does not transport choline. Both isoforms are N-glycosylated and expressed differentially across tissues.","method":"Heterologous expression in X. laevis oocytes with radiolabeled choline uptake assay; western blotting with N-glycosylation analysis; cloning of novel isoform from inner ear cDNA","journal":"The protein journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — functional transport assay in oocytes with two isoforms compared, but single lab and limited follow-up mechanistic detail in abstract","pmids":["20665236"],"is_preprint":false},{"year":2015,"finding":"CTL2/SLC44A2 protein is localized to both plasma membrane and mitochondria in human brain microvascular endothelial cells (hBMECs), with CTL2 predominantly at mitochondria. Knockdown of CTL1 or CTL2 by siRNA significantly decreased [³H]choline uptake, demonstrating that both transporters are functionally required for intermediate-affinity choline uptake in these cells.","method":"Subcellular fractionation and immunofluorescence in hBMECs; siRNA knockdown with radiolabeled choline transport assay; immunohistochemistry of human brain cortex sections","journal":"Neurochemistry international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with functional transport readout, subcellular localization by fractionation and imaging, single lab with two orthogonal methods","pmids":["26746385"],"is_preprint":false},{"year":2010,"finding":"CTL2/SLC44A2 mediates choline uptake in alveolar type II (A549) cells; siRNA knockdown of CTL2 significantly decreased [³H]choline uptake. Dexamethasone treatment induces CTL2 mRNA and increases choline uptake, linking glucocorticoid signaling to accelerated phosphatidylcholine synthesis via CTL2 induction.","method":"siRNA knockdown in A549 cells with [³H]choline transport assay under ATP-depleted conditions; RT-PCR for mRNA quantification; dexamethasone treatment experiment","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with direct functional transport assay, pharmacological induction, single lab with two orthogonal approaches","pmids":["20410607"],"is_preprint":false},{"year":2007,"finding":"CTL2/SLC44A2 and cochlin form a protein complex in the inner ear, demonstrated by reciprocal co-immunoprecipitation: anti-CTL2 antibody co-precipitates cochlin and anti-cochlin antibody co-precipitates CTL2 from inner ear extracts. Cochlin was identified by mass spectrometry as the 64 kDa band consistently co-precipitating with CTL2.","method":"Reciprocal co-immunoprecipitation from inner ear extracts; mass spectrometry identification; western blotting; cochlear cross-section immunofluorescence","journal":"Journal of the Association for Research in Otolaryngology : JARO","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mass spectrometry identification, single lab, functional significance of the interaction not established","pmids":["17926100"],"is_preprint":false},{"year":2015,"finding":"Homozygous deletion of Slc44a2 exons 3–10 in mice produces a null allele (no full-length or truncated protein detected), resulting in progressive sensorineural hearing loss, hair cell death, and spiral ganglion degeneration predominantly in the basal cochlear turn, establishing that Slc44a2 is required for long-term hair cell survival.","method":"Targeted gene deletion (exons 3–10); ABR longitudinal testing at 2–10 months; cochlear histology; RT-PCR and western blot confirming null allele","journal":"Journal of the Association for Research in Otolaryngology : JARO","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with longitudinal functional hearing test and histological phenotype, null allele confirmed at protein level, backcrossed to ARHL-resistant background to exclude confounds","pmids":["26463873"],"is_preprint":false},{"year":2018,"finding":"Slc44a2-/- mice show reduced circulating plasma VWF levels and impaired clot formation upon laser-induced injury to cremaster arterioles, while thrombin generation and coagulation gene expression are normal, suggesting SLC44A2 contributes to hemostasis at the site of vascular injury rather than via coagulation cascade.","method":"Laser-induced cremaster arteriole injury in Slc44a2-/- mice; plasma VWF ELISA; thrombin generation assay; VWF multimer analysis; coagulation gene expression","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with multiple hemostasis readouts, single lab, mechanistic pathway not fully resolved","pmids":["30312801"],"is_preprint":false},{"year":2020,"finding":"In a flow restriction (stenosis) venous thrombosis model, Slc44a2-/- mice developed significantly smaller thrombi with less platelet accumulation, implicating SLC44A2 in the initiation of venous thrombosis in a neutrophil-dependent context. In a hypercoagulability model (siRNA knockdown of antithrombin/protein C), no difference in thrombosis onset was observed, but elevated blood neutrophils and drops in fibrinogen/VWF were noted.","method":"Inferior vena cava partial ligation stenosis model; hypercoagulability siRNA model; thrombus weight/length measurement; platelet accumulation histology; complete blood count","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice in two disease models with defined phenotypic readouts, single lab, mechanism not fully resolved","pmids":["32297475"],"is_preprint":false},{"year":2023,"finding":"SLC44A2 protein is expressed on red blood cell (RBC) surfaces and carries a new blood group system. Three individuals homozygous for a large SLC44A2 deletion (complete deficiency) suffer from progressive hearing impairment, recurrent arterial aneurysms, and epilepsy, confirming SLC44A2's role in hearing preservation and suggesting a role in cerebrovascular homeostasis. SLC44A2-null individuals showed no significant platelet aggregation changes.","method":"Genomic deletion mapping; alloantibody investigation identifying SLC44A2 as blood group antigen carrier; flow cytometry and western blot confirming RBC expression; clinical phenotyping of SLC44A2-null individuals; platelet aggregation assays","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human null individuals identified with complete gene deletion, confirmed protein absence, multiple clinical and functional readouts including platelet assays, rare naturally-occurring loss-of-function validates mouse KO findings","pmids":["36695047"],"is_preprint":false},{"year":2025,"finding":"SLC44A2 inhibits mitochondrial fatty acid oxidation in colorectal cancer cells by promoting MUL1-mediated ubiquitin-dependent degradation of CPT2 (carnitine palmitoyltransferase 2) through enhanced MUL1-CPT2 protein interaction, without increasing MUL1 expression. This reduces energy supply and increases ROS stress, suppressing CRC proliferation and metastasis.","method":"Co-immunoprecipitation of MUL1-CPT2 interaction with/without SLC44A2; CPT2 protein stability assay; mitochondrial fatty acid oxidation measurement; ROS assay; in vitro and in vivo (xenograft) loss/gain-of-function experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing enhanced MUL1-CPT2 interaction, functional FAO and ROS readouts, in vivo xenograft data, single lab","pmids":["40592838"],"is_preprint":false},{"year":2021,"finding":"Slc44a2 deletion in mesenchymal lung cells alters the subcellular localization of N-cadherin and tetraspanins CD9 and CD81, reduces filamentous actin, and causes decreased cell adhesion and enhanced proliferation, suggesting SLC44A2 is required for proper spatial distribution of adhesion proteins.","method":"Primary mesenchymal lung cell culture from Slc44a2+/+, +/-, and -/- mice; immunofluorescence for N-cadherin, CD9, CD81, actin; adhesion and proliferation assays","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KO cell culture with multiple protein localization and functional readouts, single lab, no direct binding interaction demonstrated","pmids":["34371293"],"is_preprint":false},{"year":2025,"finding":"The HNA-3a/b polymorphism (rs2288904-G/A) in SLC44A2, encoding Arg152 (HNA-3a) or Gln152 (HNA-3b), genetically encodes the Csa/Csb red blood cell antigens. Anti-Csa does not react with SLC44A2-null RBCs or SLC44A2 KO K562 cells, confirming SLC44A2 as the carrier. Mass spectrometry of SLC44A2 from neutrophils and RBCs showed that anti-HNA-3a and anti-Csa recognize different epitopes on the same protein despite the same genetic basis.","method":"Genotyping of 25 Cs(a-) subjects for rs2288904; serological testing of anti-Csa against SLC44A2null RBCs and SLC44A2 KO K562 cells; mass spectrometry of SLC44A2 from neutrophils and RBCs; epitope mapping by serology","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic association confirmed in cohort, KO cell functional serological validation, mass spectrometry protein identification, multiple orthogonal methods establishing molecular basis of blood group","pmids":["40090003"],"is_preprint":false},{"year":2013,"finding":"The shorter CTL2 transcript variant TV2 is expressed in human peripheral blood cells (neutrophils, mononuclear cells, platelets), lung, and liver, whereas the longer TV1 is restricted to lung and colon. Both TV1 and TV2 have equivalent HNA-3a antibody binding capacity when expressed in HEK293T cells. Only TV1 has been demonstrated to enable choline transport.","method":"RT-PCR with isoform-specific primers on RNA from blood cells and tissues; HEK293T transfection with TV1 and TV2 expression constructs; HNA-3a antibody binding assay","journal":"Transfusion","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — isoform-specific expression confirmed in primary human samples, functional antibody binding confirmed by cell-based assay, single lab","pmids":["23480595"],"is_preprint":false}],"current_model":"SLC44A2 is a multi-transmembrane choline transporter-like protein that: (1) functions as a receptor on neutrophils for both activated platelet αIIbβ3 and von Willebrand factor, mediating shear-dependent neutrophil adhesion and mechanosensitive NET formation that promotes venous thrombosis; (2) forms a trimeric complex with NRP1 and ITGB3 in vascular smooth muscle cells to activate TGF-β/SMAD signaling and maintain a contractile phenotype, thereby protecting against aortic aneurysm; (3) is required for long-term cochlear hair cell and spiral ganglion survival; (4) carries the HNA-3a/3b (Csa/Csb) blood group antigens on neutrophils and red blood cells via the rs2288904 Arg/Gln polymorphism; (5) exhibits isoform-dependent choline transport activity (P2/TV1 transports choline; P1/TV2 does not); (6) localizes to both plasma membrane and mitochondria where it participates in choline metabolism; and (7) in cancer cells enhances MUL1-CPT2 interaction to promote CPT2 degradation, suppressing mitochondrial fatty acid oxidation."},"narrative":{"mechanistic_narrative":"SLC44A2 (CTL2) is a multi-transmembrane choline transporter-like protein that operates as both a metabolite transporter and a cell-surface adhesion receptor coupling vascular cell mechanics to thrombosis, hemostasis, and tissue homeostasis [PMID:32314961, PMID:26746385]. On neutrophils it serves as a mechanosensitive receptor for activated platelet integrin αIIbβ3 and for von Willebrand factor, driving shear-dependent neutrophil adhesion and prothrombotic NET formation; the R154Q/R152 extracellular-loop polymorphism (rs2288904) severely impairs both interactions and abrogates NETosis [PMID:32314961, PMID:33556175]. Consistent with this, Slc44a2-null mice form smaller venous thrombi, recruit fewer neutrophils to inflamed venules, and show reduced plasma VWF and impaired clot formation at sites of vascular injury [PMID:33556175, PMID:30312801, PMID:32297475]. In vascular smooth muscle cells SLC44A2 assembles into a complex with NRP1 and ITGB3 that activates TGF-β/SMAD signaling to maintain the contractile phenotype and protect against aortic aneurysm [PMID:38916960]. The same Arg152/Gln152 residue encodes the HNA-3a/3b and Csa/Csb antigens carried on neutrophil and red-cell SLC44A2, establishing it as a blood group system [PMID:40090003]. As a transporter, the P2/TV1 isoform mediates intermediate-affinity choline uptake at the plasma membrane and mitochondria, supporting phosphatidylcholine synthesis, whereas the P1 isoform is transport-inactive [PMID:20665236, PMID:26746385, PMID:20410607]. SLC44A2 is required for long-term cochlear hair cell and spiral ganglion survival, and humans with complete SLC44A2 deletion present with progressive hearing loss, arterial aneurysms, and epilepsy [PMID:26463873, PMID:36695047]. In colorectal cancer cells SLC44A2 enhances MUL1-CPT2 interaction to promote ubiquitin-dependent CPT2 degradation, suppressing mitochondrial fatty acid oxidation [PMID:40592838].","teleology":[{"year":2007,"claim":"Established the first physical partner of SLC44A2 in its tissue of phenotypic relevance, anchoring it to inner-ear biology before its function there was understood.","evidence":"Reciprocal co-immunoprecipitation and mass spectrometry from inner ear extracts identifying cochlin","pmids":["17926100"],"confidence":"Medium","gaps":["Functional consequence of the SLC44A2-cochlin interaction not established","No demonstration this complex influences hearing"]},{"year":2010,"claim":"Resolved that SLC44A2's transport activity is isoform-dependent, showing the protein is not a uniformly active transporter.","evidence":"Heterologous choline uptake assays in Xenopus oocytes comparing P1 and P2 isoforms; siRNA knockdown with radiolabeled choline uptake in A549 cells","pmids":["20665236","20410607"],"confidence":"Medium","gaps":["Substrate selectivity and kinetics not fully defined","Structural basis for isoform-specific transport unknown"]},{"year":2015,"claim":"Defined SLC44A2 as functionally required for choline uptake at both plasma membrane and mitochondrial locations, and genetically required for cochlear cell survival, separating its transporter role from a developmental/survival role.","evidence":"Subcellular fractionation and siRNA knockdown with choline transport in hBMECs; targeted Slc44a2 null mouse with longitudinal ABR and cochlear histology","pmids":["26746385","26463873"],"confidence":"High","gaps":["Mechanism linking choline transport to hair cell survival not established","Mitochondrial transport function not biochemically isolated"]},{"year":2018,"claim":"Connected SLC44A2 to hemostasis in vivo, showing it acts at the vascular injury site rather than through the coagulation cascade.","evidence":"Laser-induced cremaster arteriole injury in Slc44a2-/- mice with plasma VWF ELISA, thrombin generation, and VWF multimer analysis","pmids":["30312801"],"confidence":"Medium","gaps":["Cellular source linking SLC44A2 loss to reduced plasma VWF unclear","Mechanistic pathway not fully resolved"]},{"year":2020,"claim":"Identified the molecular receptor mechanism by which neutrophil SLC44A2 drives thrombosis, defining it as a mechanosensitive ligand-binding adhesion receptor whose function is abolished by the R154Q polymorphism.","evidence":"Flow chamber assays with αIIbβ3-platelets and genotyped neutrophils, NET quantification; IVC stenosis venous thrombosis model in Slc44a2-/- mice","pmids":["32314961","32297475"],"confidence":"High","gaps":["Signaling pathway from SLC44A2 engagement to NETosis not mapped","Cytoplasmic effectors of the receptor unidentified"]},{"year":2021,"claim":"Generalized the adhesion-receptor role by showing SLC44A2 binds VWF directly to mediate integrin-independent neutrophil adhesion at venous shear, and that loss alters adhesion-protein distribution in mesenchymal cells.","evidence":"Flow chamber perfusion of HEK293T transfectants and primary neutrophils on VWF; intravital microscopy of KO venules; immunofluorescence of N-cadherin/CD9/CD81 in KO lung mesenchymal cells","pmids":["33556175","34371293"],"confidence":"High","gaps":["Direct VWF-binding interface on SLC44A2 not structurally defined","Mechanism by which SLC44A2 organizes adhesion proteins not established"]},{"year":2023,"claim":"Validated SLC44A2's roles through human complete-deletion individuals and defined it as a red blood cell blood group carrier, confirming hearing and cerebrovascular phenotypes while showing platelet aggregation is unaffected by total loss.","evidence":"Genomic deletion mapping, alloantibody investigation, flow cytometry/western blot of RBC expression, and clinical phenotyping of SLC44A2-null individuals","pmids":["36695047"],"confidence":"High","gaps":["Mechanism of aneurysm and epilepsy in null humans not resolved","Relationship between RBC expression and erythroid function unexplored"]},{"year":2024,"claim":"Revealed a distinct signaling function in vascular smooth muscle, defining a SLC44A2-NRP1-ITGB3 complex that maintains contractile identity via TGF-β/SMAD and protects against aneurysm.","evidence":"Co-IP of the trimeric complex, VSMC-specific KO and overexpression in Apoe-/- mice with Ang II, and TGF-β/SMAD reporter assays","pmids":["38916960"],"confidence":"High","gaps":["Stoichiometry and assembly order of the trimeric complex unknown","How SLC44A2 mechanistically potentiates TGF-β/SMAD not defined"]},{"year":2025,"claim":"Established the precise molecular basis of the blood group antigens and uncovered an intracellular role of SLC44A2 in regulating mitochondrial fatty acid oxidation in cancer.","evidence":"Genotyping, serology against SLC44A2-null RBCs and KO K562 cells, mass spectrometry epitope mapping; Co-IP of MUL1-CPT2 with CPT2 stability, FAO and ROS assays, and xenografts","pmids":["40090003","40592838"],"confidence":"High","gaps":["How SLC44A2 enhances MUL1-CPT2 interaction without changing MUL1 levels unclear","Whether the FAO-suppressing role depends on choline transport or surface receptor activity unknown"]},{"year":null,"claim":"It remains unresolved how SLC44A2's distinct activities — choline transport, surface adhesion-receptor signaling, blood-group antigen presentation, and MUL1-CPT2-mediated metabolic control — are partitioned across isoforms, subcellular pools, and cell types within a single mechanistic framework.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SLC44A2 to rationalize transport versus ligand-binding functions","Unknown whether plasma-membrane and mitochondrial pools perform separable functions","Causal link between any single molecular activity and the human aneurysm/epilepsy phenotype not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,1,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4,5,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":["SLC44A2-NRP1-ITGB3 complex","SLC44A2-cochlin complex"],"partners":["ITGB3","NRP1","VWF","COCH","MUL1","CPT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IWA5","full_name":"Choline transporter-like protein 2","aliases":["Solute carrier family 44 member 2"],"length_aa":706,"mass_kda":80.1,"function":"Choline/H+ antiporter, mainly in mitochondria (PubMed:10677542, PubMed:20665236, PubMed:23651124, PubMed:33789160). Also acts as a low-affinity ethanolamine/H+ antiporter, regulating the supply of extracellular ethanolamine (Etn) for the CDP-Etn pathway, redistribute intracellular Etn and balance the CDP-Cho and CDP-Etn arms of the Kennedy pathway (PubMed:33789160) Does not exhibit choline transporter activity","subcellular_location":"Cell membrane; Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q8IWA5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC44A2","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000129353","cell_line_id":"CID001365","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001365","total_profiled":1310},"omim":[{"mim_id":"606106","title":"SOLUTE CARRIER FAMILY 44, MEMBER 2; SLC44A2","url":"https://www.omim.org/entry/606106"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC44A2"},"hgnc":{"alias_symbol":["HNA-3","CTL2"],"prev_symbol":[]},"alphafold":{"accession":"Q8IWA5","domains":[{"cath_id":"-","chopping":"35-63_364-392_445-584","consensus_level":"high","plddt":91.3771,"start":35,"end":584},{"cath_id":"-","chopping":"67-174","consensus_level":"high","plddt":79.4379,"start":67,"end":174},{"cath_id":"-","chopping":"236-261_588-699","consensus_level":"medium","plddt":89.9638,"start":236,"end":699}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWA5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWA5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWA5-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC44A2","jax_strain_url":"https://www.jax.org/strain/search?query=SLC44A2"},"sequence":{"accession":"Q8IWA5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWA5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWA5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWA5"}},"corpus_meta":[{"pmid":"32314961","id":"PMC_32314961","title":"Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32314961","citation_count":89,"is_preprint":false},{"pmid":"20665236","id":"PMC_20665236","title":"Isoforms, expression, glycosylation, and tissue distribution of CTL2/SLC44A2.","date":"2010","source":"The protein journal","url":"https://pubmed.ncbi.nlm.nih.gov/20665236","citation_count":54,"is_preprint":false},{"pmid":"20561293","id":"PMC_20561293","title":"Geno- and phenotyping and immunogenicity of HNA-3.","date":"2011","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/20561293","citation_count":51,"is_preprint":false},{"pmid":"26746385","id":"PMC_26746385","title":"Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells.","date":"2015","source":"Neurochemistry 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JARO","url":"https://pubmed.ncbi.nlm.nih.gov/17926100","citation_count":31,"is_preprint":false},{"pmid":"33556175","id":"PMC_33556175","title":"Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/33556175","citation_count":30,"is_preprint":false},{"pmid":"26463873","id":"PMC_26463873","title":"Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2.","date":"2015","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/26463873","citation_count":24,"is_preprint":false},{"pmid":"19319905","id":"PMC_19319905","title":"Autoantibodies to recombinant human CTL2 in autoimmune hearing loss.","date":"2009","source":"The 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36695047","citation_count":11,"is_preprint":false},{"pmid":"25608003","id":"PMC_25608003","title":"Risk estimation of HNA-3 incompatibility and alloimmunization in Thai populations.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25608003","citation_count":11,"is_preprint":false},{"pmid":"32135565","id":"PMC_32135565","title":"Plasma Protein Signatures of a Murine Venous Thrombosis Model and Slc44a2 Knockout Mice Using Quantitative-Targeted Proteomics.","date":"2020","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/32135565","citation_count":11,"is_preprint":false},{"pmid":"39145443","id":"PMC_39145443","title":"SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39145443","citation_count":9,"is_preprint":false},{"pmid":"21986210","id":"PMC_21986210","title":"Age-related changes in expression of CTL2/SLC44A2 and its isoforms in the mouse inner ear.","date":"2011","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/21986210","citation_count":7,"is_preprint":false},{"pmid":"26437811","id":"PMC_26437811","title":"Full-length nucleotide sequences of 30 common SLC44A2 alleles encoding human neutrophil antigen-3.","date":"2015","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/26437811","citation_count":6,"is_preprint":false},{"pmid":"40592838","id":"PMC_40592838","title":"SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the MUL1-CPT2 interaction.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40592838","citation_count":5,"is_preprint":false},{"pmid":"34371293","id":"PMC_34371293","title":"Slc44a2 deletion alters tetraspanin and N-cadherin expression: Reduced adhesion and enhanced proliferation in cultured mesenchymal lung cells.","date":"2021","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/34371293","citation_count":4,"is_preprint":false},{"pmid":"40090003","id":"PMC_40090003","title":"The neutrophil antigen 3a/b polymorphism in SLC44A2 unexpectedly encodes the Csa/Csb red cell antigens.","date":"2025","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/40090003","citation_count":3,"is_preprint":false},{"pmid":"32581188","id":"PMC_32581188","title":"The Effect of Common Variants in SLC44A2 on the Contribution to the Risk of Deep Cein Thrombosis after Orthopedic Surgery.","date":"2020","source":"Journal of atherosclerosis and 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hematology","url":"https://pubmed.ncbi.nlm.nih.gov/37575175","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.24.671970","title":"Human brown adipose tissue demonstrates substantial  <sup>18</sup>  F-fluorocholine uptake at room temperature for phosphatidylcholine synthesis","date":"2025-08-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.24.671970","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19290,"output_tokens":4479,"usd":0.062527,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12508,"output_tokens":3807,"usd":0.078857,"stage2_stop_reason":"end_turn"},"total_usd":0.141384,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"Activated platelet integrin αIIbβ3 directly binds SLC44A2 on neutrophils under flow conditions; this interaction is mechanosensitive and triggers neutrophil extracellular trap (NET) formation that is highly prothrombotic. The R154Q substitution (rs2288904-A) in an extracellular loop of SLC44A2 severely impairs binding to activated αIIbβ3 and VWF-primed platelets, abrogating NETosis.\",\n      \"method\": \"Flow chamber assays with αIIbβ3-expressing platelets and neutrophils homozygous for SLC44A2 R154Q polymorphism; platelet-neutrophil binding and NET quantification under defined shear\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding confirmed with primary human neutrophils carrying defined genotype, flow-based mechanistic assay, functional NET readout, replicated with VWF-primed platelets\",\n      \"pmids\": [\"32314961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Slc44a2/HNA-3a on neutrophils mediates adhesion to VWF at venous shear rates (100 s⁻¹) in a β2-integrin-independent manner; this adhesion is required for shear-dependent NETosis. Neutrophils expressing HNA-3b (R154Q) show severely impaired adhesion to VWF. In vivo, Slc44a2-knockout mice exhibited massive reduction in neutrophil recruitment to inflamed mesenteric venules after histamine-induced endothelial degranulation.\",\n      \"method\": \"Flow chamber perfusion of HEK293T transfectants and primary donor neutrophils on VWF-coated surfaces; intravital microscopy of Slc44a2-/- mouse venules\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (flow chamber with genotyped primary neutrophils, in vivo intravital microscopy in KO mice), two independent experimental systems\",\n      \"pmids\": [\"33556175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC44A2 forms a protein complex with NRP1 and ITGB3 in vascular smooth muscle cells (VSMCs); this complex activates TGF-β/SMAD signaling to promote contractile gene expression. VSMC-specific SLC44A2 knockout shifts cells to a synthetic phenotype and increases aortic aneurysm susceptibility under Ang II infusion, while SLC44A2 overexpression is protective.\",\n      \"method\": \"Co-immunoprecipitation of SLC44A2-NRP1-ITGB3 complex; VSMC-specific conditional KO and overexpression in Apoe-/- mice with Ang II infusion; TGF-β/SMAD pathway reporter assays; siRNA knockdown in vitro\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of trimeric complex, loss-of-function and gain-of-function in vivo mouse models, defined signaling pathway readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38916960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The CTL2/SLC44A2 isoform P2 (706 aa, exon 1b) exhibits detectable choline transport activity when expressed in Xenopus laevis oocytes, whereas isoform P1 (704 aa, exon 1a) does not transport choline. Both isoforms are N-glycosylated and expressed differentially across tissues.\",\n      \"method\": \"Heterologous expression in X. laevis oocytes with radiolabeled choline uptake assay; western blotting with N-glycosylation analysis; cloning of novel isoform from inner ear cDNA\",\n      \"journal\": \"The protein journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — functional transport assay in oocytes with two isoforms compared, but single lab and limited follow-up mechanistic detail in abstract\",\n      \"pmids\": [\"20665236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTL2/SLC44A2 protein is localized to both plasma membrane and mitochondria in human brain microvascular endothelial cells (hBMECs), with CTL2 predominantly at mitochondria. Knockdown of CTL1 or CTL2 by siRNA significantly decreased [³H]choline uptake, demonstrating that both transporters are functionally required for intermediate-affinity choline uptake in these cells.\",\n      \"method\": \"Subcellular fractionation and immunofluorescence in hBMECs; siRNA knockdown with radiolabeled choline transport assay; immunohistochemistry of human brain cortex sections\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with functional transport readout, subcellular localization by fractionation and imaging, single lab with two orthogonal methods\",\n      \"pmids\": [\"26746385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CTL2/SLC44A2 mediates choline uptake in alveolar type II (A549) cells; siRNA knockdown of CTL2 significantly decreased [³H]choline uptake. Dexamethasone treatment induces CTL2 mRNA and increases choline uptake, linking glucocorticoid signaling to accelerated phosphatidylcholine synthesis via CTL2 induction.\",\n      \"method\": \"siRNA knockdown in A549 cells with [³H]choline transport assay under ATP-depleted conditions; RT-PCR for mRNA quantification; dexamethasone treatment experiment\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with direct functional transport assay, pharmacological induction, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20410607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CTL2/SLC44A2 and cochlin form a protein complex in the inner ear, demonstrated by reciprocal co-immunoprecipitation: anti-CTL2 antibody co-precipitates cochlin and anti-cochlin antibody co-precipitates CTL2 from inner ear extracts. Cochlin was identified by mass spectrometry as the 64 kDa band consistently co-precipitating with CTL2.\",\n      \"method\": \"Reciprocal co-immunoprecipitation from inner ear extracts; mass spectrometry identification; western blotting; cochlear cross-section immunofluorescence\",\n      \"journal\": \"Journal of the Association for Research in Otolaryngology : JARO\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mass spectrometry identification, single lab, functional significance of the interaction not established\",\n      \"pmids\": [\"17926100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Homozygous deletion of Slc44a2 exons 3–10 in mice produces a null allele (no full-length or truncated protein detected), resulting in progressive sensorineural hearing loss, hair cell death, and spiral ganglion degeneration predominantly in the basal cochlear turn, establishing that Slc44a2 is required for long-term hair cell survival.\",\n      \"method\": \"Targeted gene deletion (exons 3–10); ABR longitudinal testing at 2–10 months; cochlear histology; RT-PCR and western blot confirming null allele\",\n      \"journal\": \"Journal of the Association for Research in Otolaryngology : JARO\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with longitudinal functional hearing test and histological phenotype, null allele confirmed at protein level, backcrossed to ARHL-resistant background to exclude confounds\",\n      \"pmids\": [\"26463873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Slc44a2-/- mice show reduced circulating plasma VWF levels and impaired clot formation upon laser-induced injury to cremaster arterioles, while thrombin generation and coagulation gene expression are normal, suggesting SLC44A2 contributes to hemostasis at the site of vascular injury rather than via coagulation cascade.\",\n      \"method\": \"Laser-induced cremaster arteriole injury in Slc44a2-/- mice; plasma VWF ELISA; thrombin generation assay; VWF multimer analysis; coagulation gene expression\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with multiple hemostasis readouts, single lab, mechanistic pathway not fully resolved\",\n      \"pmids\": [\"30312801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a flow restriction (stenosis) venous thrombosis model, Slc44a2-/- mice developed significantly smaller thrombi with less platelet accumulation, implicating SLC44A2 in the initiation of venous thrombosis in a neutrophil-dependent context. In a hypercoagulability model (siRNA knockdown of antithrombin/protein C), no difference in thrombosis onset was observed, but elevated blood neutrophils and drops in fibrinogen/VWF were noted.\",\n      \"method\": \"Inferior vena cava partial ligation stenosis model; hypercoagulability siRNA model; thrombus weight/length measurement; platelet accumulation histology; complete blood count\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice in two disease models with defined phenotypic readouts, single lab, mechanism not fully resolved\",\n      \"pmids\": [\"32297475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC44A2 protein is expressed on red blood cell (RBC) surfaces and carries a new blood group system. Three individuals homozygous for a large SLC44A2 deletion (complete deficiency) suffer from progressive hearing impairment, recurrent arterial aneurysms, and epilepsy, confirming SLC44A2's role in hearing preservation and suggesting a role in cerebrovascular homeostasis. SLC44A2-null individuals showed no significant platelet aggregation changes.\",\n      \"method\": \"Genomic deletion mapping; alloantibody investigation identifying SLC44A2 as blood group antigen carrier; flow cytometry and western blot confirming RBC expression; clinical phenotyping of SLC44A2-null individuals; platelet aggregation assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human null individuals identified with complete gene deletion, confirmed protein absence, multiple clinical and functional readouts including platelet assays, rare naturally-occurring loss-of-function validates mouse KO findings\",\n      \"pmids\": [\"36695047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC44A2 inhibits mitochondrial fatty acid oxidation in colorectal cancer cells by promoting MUL1-mediated ubiquitin-dependent degradation of CPT2 (carnitine palmitoyltransferase 2) through enhanced MUL1-CPT2 protein interaction, without increasing MUL1 expression. This reduces energy supply and increases ROS stress, suppressing CRC proliferation and metastasis.\",\n      \"method\": \"Co-immunoprecipitation of MUL1-CPT2 interaction with/without SLC44A2; CPT2 protein stability assay; mitochondrial fatty acid oxidation measurement; ROS assay; in vitro and in vivo (xenograft) loss/gain-of-function experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing enhanced MUL1-CPT2 interaction, functional FAO and ROS readouts, in vivo xenograft data, single lab\",\n      \"pmids\": [\"40592838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Slc44a2 deletion in mesenchymal lung cells alters the subcellular localization of N-cadherin and tetraspanins CD9 and CD81, reduces filamentous actin, and causes decreased cell adhesion and enhanced proliferation, suggesting SLC44A2 is required for proper spatial distribution of adhesion proteins.\",\n      \"method\": \"Primary mesenchymal lung cell culture from Slc44a2+/+, +/-, and -/- mice; immunofluorescence for N-cadherin, CD9, CD81, actin; adhesion and proliferation assays\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KO cell culture with multiple protein localization and functional readouts, single lab, no direct binding interaction demonstrated\",\n      \"pmids\": [\"34371293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The HNA-3a/b polymorphism (rs2288904-G/A) in SLC44A2, encoding Arg152 (HNA-3a) or Gln152 (HNA-3b), genetically encodes the Csa/Csb red blood cell antigens. Anti-Csa does not react with SLC44A2-null RBCs or SLC44A2 KO K562 cells, confirming SLC44A2 as the carrier. Mass spectrometry of SLC44A2 from neutrophils and RBCs showed that anti-HNA-3a and anti-Csa recognize different epitopes on the same protein despite the same genetic basis.\",\n      \"method\": \"Genotyping of 25 Cs(a-) subjects for rs2288904; serological testing of anti-Csa against SLC44A2null RBCs and SLC44A2 KO K562 cells; mass spectrometry of SLC44A2 from neutrophils and RBCs; epitope mapping by serology\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic association confirmed in cohort, KO cell functional serological validation, mass spectrometry protein identification, multiple orthogonal methods establishing molecular basis of blood group\",\n      \"pmids\": [\"40090003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The shorter CTL2 transcript variant TV2 is expressed in human peripheral blood cells (neutrophils, mononuclear cells, platelets), lung, and liver, whereas the longer TV1 is restricted to lung and colon. Both TV1 and TV2 have equivalent HNA-3a antibody binding capacity when expressed in HEK293T cells. Only TV1 has been demonstrated to enable choline transport.\",\n      \"method\": \"RT-PCR with isoform-specific primers on RNA from blood cells and tissues; HEK293T transfection with TV1 and TV2 expression constructs; HNA-3a antibody binding assay\",\n      \"journal\": \"Transfusion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — isoform-specific expression confirmed in primary human samples, functional antibody binding confirmed by cell-based assay, single lab\",\n      \"pmids\": [\"23480595\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC44A2 is a multi-transmembrane choline transporter-like protein that: (1) functions as a receptor on neutrophils for both activated platelet αIIbβ3 and von Willebrand factor, mediating shear-dependent neutrophil adhesion and mechanosensitive NET formation that promotes venous thrombosis; (2) forms a trimeric complex with NRP1 and ITGB3 in vascular smooth muscle cells to activate TGF-β/SMAD signaling and maintain a contractile phenotype, thereby protecting against aortic aneurysm; (3) is required for long-term cochlear hair cell and spiral ganglion survival; (4) carries the HNA-3a/3b (Csa/Csb) blood group antigens on neutrophils and red blood cells via the rs2288904 Arg/Gln polymorphism; (5) exhibits isoform-dependent choline transport activity (P2/TV1 transports choline; P1/TV2 does not); (6) localizes to both plasma membrane and mitochondria where it participates in choline metabolism; and (7) in cancer cells enhances MUL1-CPT2 interaction to promote CPT2 degradation, suppressing mitochondrial fatty acid oxidation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC44A2 (CTL2) is a multi-transmembrane choline transporter-like protein that operates as both a metabolite transporter and a cell-surface adhesion receptor coupling vascular cell mechanics to thrombosis, hemostasis, and tissue homeostasis [#0, #4]. On neutrophils it serves as a mechanosensitive receptor for activated platelet integrin \\u03b1IIb\\u03b23 and for von Willebrand factor, driving shear-dependent neutrophil adhesion and prothrombotic NET formation; the R154Q/R152 extracellular-loop polymorphism (rs2288904) severely impairs both interactions and abrogates NETosis [#0, #1]. Consistent with this, Slc44a2-null mice form smaller venous thrombi, recruit fewer neutrophils to inflamed venules, and show reduced plasma VWF and impaired clot formation at sites of vascular injury [#1, #8, #9]. In vascular smooth muscle cells SLC44A2 assembles into a complex with NRP1 and ITGB3 that activates TGF-\\u03b2/SMAD signaling to maintain the contractile phenotype and protect against aortic aneurysm [#2]. The same Arg152/Gln152 residue encodes the HNA-3a/3b and Csa/Csb antigens carried on neutrophil and red-cell SLC44A2, establishing it as a blood group system [#13]. As a transporter, the P2/TV1 isoform mediates intermediate-affinity choline uptake at the plasma membrane and mitochondria, supporting phosphatidylcholine synthesis, whereas the P1 isoform is transport-inactive [#3, #4, #5]. SLC44A2 is required for long-term cochlear hair cell and spiral ganglion survival, and humans with complete SLC44A2 deletion present with progressive hearing loss, arterial aneurysms, and epilepsy [#7, #10]. In colorectal cancer cells SLC44A2 enhances MUL1-CPT2 interaction to promote ubiquitin-dependent CPT2 degradation, suppressing mitochondrial fatty acid oxidation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the first physical partner of SLC44A2 in its tissue of phenotypic relevance, anchoring it to inner-ear biology before its function there was understood.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and mass spectrometry from inner ear extracts identifying cochlin\",\n      \"pmids\": [\"17926100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the SLC44A2-cochlin interaction not established\", \"No demonstration this complex influences hearing\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved that SLC44A2's transport activity is isoform-dependent, showing the protein is not a uniformly active transporter.\",\n      \"evidence\": \"Heterologous choline uptake assays in Xenopus oocytes comparing P1 and P2 isoforms; siRNA knockdown with radiolabeled choline uptake in A549 cells\",\n      \"pmids\": [\"20665236\", \"20410607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity and kinetics not fully defined\", \"Structural basis for isoform-specific transport unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined SLC44A2 as functionally required for choline uptake at both plasma membrane and mitochondrial locations, and genetically required for cochlear cell survival, separating its transporter role from a developmental/survival role.\",\n      \"evidence\": \"Subcellular fractionation and siRNA knockdown with choline transport in hBMECs; targeted Slc44a2 null mouse with longitudinal ABR and cochlear histology\",\n      \"pmids\": [\"26746385\", \"26463873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking choline transport to hair cell survival not established\", \"Mitochondrial transport function not biochemically isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected SLC44A2 to hemostasis in vivo, showing it acts at the vascular injury site rather than through the coagulation cascade.\",\n      \"evidence\": \"Laser-induced cremaster arteriole injury in Slc44a2-/- mice with plasma VWF ELISA, thrombin generation, and VWF multimer analysis\",\n      \"pmids\": [\"30312801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular source linking SLC44A2 loss to reduced plasma VWF unclear\", \"Mechanistic pathway not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the molecular receptor mechanism by which neutrophil SLC44A2 drives thrombosis, defining it as a mechanosensitive ligand-binding adhesion receptor whose function is abolished by the R154Q polymorphism.\",\n      \"evidence\": \"Flow chamber assays with \\u03b1IIb\\u03b23-platelets and genotyped neutrophils, NET quantification; IVC stenosis venous thrombosis model in Slc44a2-/- mice\",\n      \"pmids\": [\"32314961\", \"32297475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from SLC44A2 engagement to NETosis not mapped\", \"Cytoplasmic effectors of the receptor unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized the adhesion-receptor role by showing SLC44A2 binds VWF directly to mediate integrin-independent neutrophil adhesion at venous shear, and that loss alters adhesion-protein distribution in mesenchymal cells.\",\n      \"evidence\": \"Flow chamber perfusion of HEK293T transfectants and primary neutrophils on VWF; intravital microscopy of KO venules; immunofluorescence of N-cadherin/CD9/CD81 in KO lung mesenchymal cells\",\n      \"pmids\": [\"33556175\", \"34371293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct VWF-binding interface on SLC44A2 not structurally defined\", \"Mechanism by which SLC44A2 organizes adhesion proteins not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated SLC44A2's roles through human complete-deletion individuals and defined it as a red blood cell blood group carrier, confirming hearing and cerebrovascular phenotypes while showing platelet aggregation is unaffected by total loss.\",\n      \"evidence\": \"Genomic deletion mapping, alloantibody investigation, flow cytometry/western blot of RBC expression, and clinical phenotyping of SLC44A2-null individuals\",\n      \"pmids\": [\"36695047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of aneurysm and epilepsy in null humans not resolved\", \"Relationship between RBC expression and erythroid function unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a distinct signaling function in vascular smooth muscle, defining a SLC44A2-NRP1-ITGB3 complex that maintains contractile identity via TGF-\\u03b2/SMAD and protects against aneurysm.\",\n      \"evidence\": \"Co-IP of the trimeric complex, VSMC-specific KO and overexpression in Apoe-/- mice with Ang II, and TGF-\\u03b2/SMAD reporter assays\",\n      \"pmids\": [\"38916960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the trimeric complex unknown\", \"How SLC44A2 mechanistically potentiates TGF-\\u03b2/SMAD not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the precise molecular basis of the blood group antigens and uncovered an intracellular role of SLC44A2 in regulating mitochondrial fatty acid oxidation in cancer.\",\n      \"evidence\": \"Genotyping, serology against SLC44A2-null RBCs and KO K562 cells, mass spectrometry epitope mapping; Co-IP of MUL1-CPT2 with CPT2 stability, FAO and ROS assays, and xenografts\",\n      \"pmids\": [\"40090003\", \"40592838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLC44A2 enhances MUL1-CPT2 interaction without changing MUL1 levels unclear\", \"Whether the FAO-suppressing role depends on choline transport or surface receptor activity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how SLC44A2's distinct activities \\u2014 choline transport, surface adhesion-receptor signaling, blood-group antigen presentation, and MUL1-CPT2-mediated metabolic control \\u2014 are partitioned across isoforms, subcellular pools, and cell types within a single mechanistic framework.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SLC44A2 to rationalize transport versus ligand-binding functions\", \"Unknown whether plasma-membrane and mitochondrial pools perform separable functions\", \"Causal link between any single molecular activity and the human aneurysm/epilepsy phenotype not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 1, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 5, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"SLC44A2-NRP1-ITGB3 complex\",\n      \"SLC44A2-cochlin complex\"\n    ],\n    \"partners\": [\n      \"ITGB3\",\n      \"NRP1\",\n      \"VWF\",\n      \"COCH\",\n      \"MUL1\",\n      \"CPT2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":8,"faith_pct":75.0}}