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SLC44A2

Choline transporter-like protein 2 · UniProt Q8IWA5

Length
706 aa
Mass
80.1 kDa
Annotated
2026-06-10
31 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/8 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    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

    PMID:17926100

    Open questions at the time
    • Functional consequence of the SLC44A2-cochlin interaction not established
    • No demonstration this complex influences hearing
  2. 2010 Medium

    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

    PMID:20410607 PMID:20665236

    Open questions at the time
    • Substrate selectivity and kinetics not fully defined
    • Structural basis for isoform-specific transport unknown
  3. 2015 High

    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

    PMID:26463873 PMID:26746385

    Open questions at the time
    • Mechanism linking choline transport to hair cell survival not established
    • Mitochondrial transport function not biochemically isolated
  4. 2018 Medium

    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

    PMID:30312801

    Open questions at the time
    • Cellular source linking SLC44A2 loss to reduced plasma VWF unclear
    • Mechanistic pathway not fully resolved
  5. 2020 High

    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

    PMID:32297475 PMID:32314961

    Open questions at the time
    • Signaling pathway from SLC44A2 engagement to NETosis not mapped
    • Cytoplasmic effectors of the receptor unidentified
  6. 2021 High

    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

    PMID:33556175 PMID:34371293

    Open questions at the time
    • Direct VWF-binding interface on SLC44A2 not structurally defined
    • Mechanism by which SLC44A2 organizes adhesion proteins not established
  7. 2023 High

    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

    PMID:36695047

    Open questions at the time
    • Mechanism of aneurysm and epilepsy in null humans not resolved
    • Relationship between RBC expression and erythroid function unexplored
  8. 2024 High

    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

    PMID:38916960

    Open questions at the time
    • Stoichiometry and assembly order of the trimeric complex unknown
    • How SLC44A2 mechanistically potentiates TGF-β/SMAD not defined
  9. 2025 High

    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

    PMID:40090003 PMID:40592838

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-109582 Hemostasis 4 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 2 R-HSA-162582 Signal Transduction 1
Partners
COCHCPT2ITGB3MUL1NRP1VWF
Complex memberships
SLC44A2-NRP1-ITGB3 complexSLC44A2-cochlin complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 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. Flow chamber assays with αIIbβ3-expressing platelets and neutrophils homozygous for SLC44A2 R154Q polymorphism; platelet-neutrophil binding and NET quantification under defined shear eLife High 32314961
2021 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. Flow chamber perfusion of HEK293T transfectants and primary donor neutrophils on VWF-coated surfaces; intravital microscopy of Slc44a2-/- mouse venules Blood High 33556175
2024 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. 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 The Journal of clinical investigation High 38916960
2010 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. 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 The protein journal Medium 20665236
2015 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. Subcellular fractionation and immunofluorescence in hBMECs; siRNA knockdown with radiolabeled choline transport assay; immunohistochemistry of human brain cortex sections Neurochemistry international Medium 26746385
2010 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. siRNA knockdown in A549 cells with [³H]choline transport assay under ATP-depleted conditions; RT-PCR for mRNA quantification; dexamethasone treatment experiment Biological & pharmaceutical bulletin Medium 20410607
2007 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. Reciprocal co-immunoprecipitation from inner ear extracts; mass spectrometry identification; western blotting; cochlear cross-section immunofluorescence Journal of the Association for Research in Otolaryngology : JARO Medium 17926100
2015 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. Targeted gene deletion (exons 3–10); ABR longitudinal testing at 2–10 months; cochlear histology; RT-PCR and western blot confirming null allele Journal of the Association for Research in Otolaryngology : JARO High 26463873
2018 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. Laser-induced cremaster arteriole injury in Slc44a2-/- mice; plasma VWF ELISA; thrombin generation assay; VWF multimer analysis; coagulation gene expression Thrombosis research Medium 30312801
2020 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. Inferior vena cava partial ligation stenosis model; hypercoagulability siRNA model; thrombus weight/length measurement; platelet accumulation histology; complete blood count Journal of thrombosis and haemostasis : JTH Medium 32297475
2023 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. 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 EMBO molecular medicine High 36695047
2025 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. 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 Cell death & disease Medium 40592838
2021 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. Primary mesenchymal lung cell culture from Slc44a2+/+, +/-, and -/- mice; immunofluorescence for N-cadherin, CD9, CD81, actin; adhesion and proliferation assays Tissue & cell Medium 34371293
2025 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. 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 Blood High 40090003
2013 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. 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 Transfusion Medium 23480595

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2. eLife 89 32314961
2010 Isoforms, expression, glycosylation, and tissue distribution of CTL2/SLC44A2. The protein journal 54 20665236
2011 Geno- and phenotyping and immunogenicity of HNA-3. Transfusion 51 20561293
2015 Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells. Neurochemistry international 43 26746385
2010 Involvement of choline transporter-like proteins, CTL1 and CTL2, in glucocorticoid-induced acceleration of phosphatidylcholine synthesis via increased choline uptake. Biological & pharmaceutical bulletin 39 20410607
2024 SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm. The Journal of clinical investigation 34 38916960
2007 Cochlin isoforms and their interaction with CTL2 (SLC44A2) in the inner ear. Journal of the Association for Research in Otolaryngology : JARO 31 17926100
2021 Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates. Blood 30 33556175
2015 Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2. Journal of the Association for Research in Otolaryngology : JARO 24 26463873
2009 Autoantibodies to recombinant human CTL2 in autoimmune hearing loss. The Laryngoscope 22 19319905
2014 Spotlight on pathogenesis of TRALI: HNA-3a (CTL2) antibodies. Blood 21 25006121
2020 SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis. Journal of thrombosis and haemostasis : JTH 19 32297475
2011 Frequencies of SLC44A2 alleles encoding human neutrophil antigen-3 variants in the African American population. Transfusion 19 22040064
2016 SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease? Genomics 17 27829169
2013 HNA-3 gene frequencies in Brazilians and a new polymerase chain reaction-restriction fragment length polymorphism method for HNA-3a/3b genotyping. Transfusion 16 24236643
2018 Characterization of hemostasis in mice lacking the novel thrombosis susceptibility gene Slc44a2. Thrombosis research 15 30312801
2024 A C-type lectin (CTL2) mediated both humoral and cellular immunity against bacterial infection in Tribolium castaneum. Pesticide biochemistry and physiology 12 38685211
2013 Expression of the CTL2 transcript variants in human peripheral blood cells and human tissues. Transfusion 12 23480595
2023 Lack of the human choline transporter-like protein SLC44A2 causes hearing impairment and a rare red blood phenotype. EMBO molecular medicine 11 36695047
2020 Plasma Protein Signatures of a Murine Venous Thrombosis Model and Slc44a2 Knockout Mice Using Quantitative-Targeted Proteomics. Thrombosis and haemostasis 11 32135565
2015 Risk estimation of HNA-3 incompatibility and alloimmunization in Thai populations. PloS one 11 25608003
2024 SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm. The Journal of clinical investigation 9 39145443
2011 Age-related changes in expression of CTL2/SLC44A2 and its isoforms in the mouse inner ear. Hearing research 7 21986210
2015 Full-length nucleotide sequences of 30 common SLC44A2 alleles encoding human neutrophil antigen-3. Transfusion 6 26437811
2025 SLC44A2 negatively regulates mitochondrial fatty acid oxidation to suppress colorectal progression by blocking the MUL1-CPT2 interaction. Cell death & disease 5 40592838
2021 Slc44a2 deletion alters tetraspanin and N-cadherin expression: Reduced adhesion and enhanced proliferation in cultured mesenchymal lung cells. Tissue & cell 4 34371293
2025 The neutrophil antigen 3a/b polymorphism in SLC44A2 unexpectedly encodes the Csa/Csb red cell antigens. Blood 3 40090003
2020 The Effect of Common Variants in SLC44A2 on the Contribution to the Risk of Deep Cein Thrombosis after Orthopedic Surgery. Journal of atherosclerosis and thrombosis 3 32581188
2022 SLC44A2 Frequency, a New TaqMan Real-Time Polymerase Chain Reaction Method for HNA-3A/3B Genotyping, and a New Application of Droplet Digital PCR. Frontiers in genetics 2 35646052
2025 Beyond HNA-1: The anti-HNA-3 autoantibody as a protagonist in autoimmune neutropenia. Immunology letters 0 41015392
2023 Non-invasive prenatal testing for fetal Ss, Kidd, and CTL2 blood group prediction by multiplex digital droplet PCR. Therapeutic advances in hematology 0 37575175

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