Affinage

SLC35F2

Queuine/queuosine transporter SLC35F2 · UniProt Q8IXU6

Length
374 aa
Mass
41.2 kDa
Annotated
2026-06-10
14 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC35F2 is a plasma membrane- and Golgi-localized solute carrier that functions as a selective, high-affinity importer of the micronutrient queuine and its nucleoside queuosine, with sub-micromolar Km values, and is the sole transporter for queuosine while not transporting other canonical ribonucleobases or ribonucleosides (PMID:40526720). This same transport activity opportunistically imports the anticancer compound YM155, making SLC35F2 the principal determinant of YM155-mediated DNA damage and cytotoxicity in cells and xenografts (PMID:25064833). SLC35F2 protein abundance is set post-translationally by competing ubiquitination machinery: the E3 ligases APC/C^Cdh1 (PMID:37689217) and βTrCP1/BTRC (PMID:37801987) each bind SLC35F2, promote its ubiquitination, and shorten its half-life, with their depletion accumulating SLC35F2 and driving proliferation, migration, and invasion; the deubiquitinating enzyme USP32 destabilizes SLC35F2 through ER-associated degradation, and elevated USP32 confers YM155 resistance (PMID:34815782). Beyond transport, SLC35F2 competitively interacts with the E3 ligase SYVN1 (HRD1) to stabilize TRIM59, thereby promoting TRIM59-mediated p53 ubiquitination and degradation and suppressing wild-type p53-dependent ferroptosis in pancreatic cancer (PMID:37740007).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2014 High

    Established the first molecular function of SLC35F2 by identifying it as the cellular importer required for YM155 uptake and YM155-dependent DNA damage, defining the transporter as the determinant of an anticancer drug's toxicity.

    Evidence Haploid genetic screen plus CRISPR genome editing and drug uptake/DNA damage assays, validated in vivo

    PMID:25064833

    Open questions at the time
    • Did not identify the physiological endogenous substrate
    • No transport kinetics or structural basis for substrate recognition
  2. 2013 Low

    Linked SLC35F2 expression to malignant phenotype by showing knockdown impairs proliferation, migration, invasion and arrests the cell cycle, but without mechanistic placement.

    Evidence Lentiviral shRNA knockdown with proliferation, migration, and cell-cycle flow cytometry in H1299 lung cancer cells

    PMID:23879892

    Open questions at the time
    • Single-lab RNAi phenotype with no molecular mechanism connecting transport function to cell-cycle control
    • No pathway placement
  3. 2021 Medium

    Resolved how SLC35F2 protein levels and YM155 response are controlled by showing the deubiquitinase USP32 destabilizes SLC35F2 via ERAD, with consequences for drug resistance.

    Evidence Genome-scale CRISPR USP knockout screen with protein stability assays and in vitro/in vivo validation in breast cancer

    PMID:34815782

    Open questions at the time
    • The paradoxical role of a deubiquitinase promoting degradation was not mechanistically reconstituted
    • Direct ubiquitination of SLC35F2 by a partner ligase not defined here
  4. 2021 Medium

    Confirmed in a second cancer context that SLC35F2 abundance gates YM155 sensitivity, while revealing additional cell-line-specific determinants.

    Evidence Hydroquinone-induced SLC35F2 upregulation and forced expression in AML cell lines with viability assays

    PMID:33831396

    Open questions at the time
    • Effect was cell-line dependent and confounded by MPO activity
    • Relied on indirect upregulation rather than defined genetic control
  5. 2023 Medium

    Identified two E3 ligases, APC/C^Cdh1 and βTrCP1, that bind and ubiquitinate SLC35F2 to limit its half-life, establishing ubiquitin-mediated turnover as a control point for SLC35F2-driven oncogenic phenotypes.

    Evidence Co-IP, proximity ligation, in vitro ubiquitination, half-life analysis, and CRISPR/knockdown oncogenic assays in HeLa cells

    PMID:37689217 PMID:37801987

    Open questions at the time
    • Degron sites on SLC35F2 not mapped
    • Relative contribution of each ligase and crosstalk with USP32 not resolved
    • Single lab
  6. 2023 Medium

    Uncovered a transport-independent role: SLC35F2 competes for the E3 ligase SYVN1 to stabilize TRIM59, driving p53 degradation and suppressing ferroptosis.

    Evidence Co-IP, multi-omics, structural analysis, and in vitro/in vivo ferroptosis assays with PDX models in pancreatic cancer

    PMID:37740007

    Open questions at the time
    • Direct binding interface of SLC35F2-SYVN1 competition not biophysically defined
    • Whether transport activity is dispensable for this axis not tested
    • Single lab
  7. 2023 Low

    Placed SLC35F2 downstream of drug-induced signaling by showing decitabine upregulates it via AKT/p38/TET/Sp1/p300 to enable synergy with YM155.

    Evidence Co-administration drug studies, pathway inhibitors, Sp1/TET/p300 Co-IP, and knockdown rescue in AML cells

    PMID:38066391

    Open questions at the time
    • Multi-step signaling chain inferred pharmacologically without reconstitution
    • Direct transcriptional regulation of SLC35F2 not demonstrated
  8. 2024 Low

    Extended drug-induced regulation by showing ONC212 raises SLC35F2 through an AKT/NOX4/HuR/ATF4 axis to potentiate YM155 cytotoxicity.

    Evidence Pharmacological inhibitors and forced expression/knockdown of pathway components with viability/apoptosis assays in AML cells

    PMID:38679209

    Open questions at the time
    • Pathway dissected pharmacologically without direct reconstitution
    • SLC35F2 role inferred from expression-dependent sensitization only
  9. 2025 High

    Defined the physiological substrate of SLC35F2 as the queuine/queuosine micronutrient, establishing it as a high-affinity and sole transporter for queuosine and reframing its YM155 import as an opportunistic activity.

    Evidence Cross-species bioinformatics, genetic disruption in HeLa/S. pombe/T. brucei, competition uptake, Km measurement, and immunofluorescence localization

    PMID:40526720

    Open questions at the time
    • Transport mechanism (coupling ion, directionality) not resolved
    • Relationship between queuine transport and the oncogenic/ferroptosis roles not connected
    • No structure of substrate-bound transporter
  10. 2025 Low

    Connected SLC35F2 loss to cAMP/CREB1 signaling as a driver of NSCLC malignancy, though without a direct mechanistic link to transport function.

    Evidence Knockdown with RT-qPCR, Western blot, proliferation/migration assays and pathway enrichment in NSCLC cells

    PMID:40667522

    Open questions at the time
    • No mechanistic link between transport activity and cAMP/CREB1 axis established
    • Correlative pathway enrichment only
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SLC35F2's defined queuine/queuosine transport function mechanistically connects to its ubiquitin-regulated abundance, its SYVN1-TRIM59-p53 ferroptosis axis, and its pro-proliferative roles in cancer remains unresolved.
  • No structural model of the transporter
  • Transport coupling and directionality undefined
  • Unknown whether transport activity is required for the protein-interaction/oncogenic functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2
Localization
GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-382551 Transport of small molecules 2
Partners
BTRCSYVN1TRIM59USP32

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 SLC35F2 functions as a drug importer for the anticancer compound YM155; its expression is required for YM155 uptake, and YM155 exerts DNA damage through intercalation that is contingent on SLC35F2 drug-importing activity. Haploid genetic screen and targeted genome editing established SLC35F2 as the main determinant of YM155-mediated DNA damage toxicity in vitro and in vivo. Haploid genetic screen in human cells, targeted genome editing (CRISPR), cellular drug uptake/DNA damage assays, in vivo xenograft Nature chemical biology High 25064833
2025 SLC35F2 is a high-specificity transporter for the micronutrients queuine (nucleobase) and queuosine (nucleoside), with Km values of 67 nM and 174 nM respectively in human HeLa cells. It is the sole transporter for queuosine and a high-affinity transporter for queuine. SLC35F2 does not transport other canonical ribonucleobases or ribonucleosides. It localizes to the cell membrane and Golgi apparatus. Cross-species bioinformatic search, genetic disruption in human HeLa cells and S. pombe/T. brucei, competition uptake studies, Km measurement, immunofluorescence of labeled SLC35F2 Proceedings of the National Academy of Sciences of the United States of America High 40526720
2021 USP32, a deubiquitinating enzyme, governs resistance to YM155 by destabilizing SLC35F2 protein levels via ER-associated degradation (ERAD). CRISPR-based dual screening and in vitro/in vivo experiments established that USP32 negatively regulates SLC35F2 protein stability, and elevated USP32 expression is associated with low SLC35F2 expression and YM155 resistance in breast cancer cells. CRISPR-Cas9 genome-scale USP knockout screen, in vitro and in vivo experiments validating USP32–SLC35F2 relationship, protein stability assays Theranostics Medium 34815782
2023 The E3 ubiquitin ligase APC/CCdh1 interacts with SLC35F2, promotes its ubiquitination, and reduces its protein half-life. CRISPR/Cas9-mediated depletion of APC/CCdh1 increases SLC35F2 protein levels and promotes SLC35F2-mediated cell proliferation, migration, and invasion in HeLa cells. E3 ligase screen, immunoprecipitation, Duolink proximity ligation assay (PLA), in vitro ubiquitination assay, half-life analysis, CRISPR/Cas9 knockdown, in vitro oncogenic assays Biochimica et biophysica acta. General subjects Medium 37689217
2023 βTrCP1 (also known as BTRC) interacts with SLC35F2 and promotes its ubiquitination, thereby reducing SLC35F2 protein half-life. Depletion of βTrCP1 accumulates SLC35F2 protein and promotes SLC35F2-mediated cell growth, migration, invasion, and colony formation in HeLa cells. Co-immunoprecipitation, in vitro ubiquitination assay, protein half-life analysis, βTrCP1 knockdown/rescue in HeLa cells Biochemical and biophysical research communications Medium 37801987
2023 SLC35F2 inhibits ferroptosis in pancreatic cancer cells by facilitating TRIM59-mediated p53 degradation. Mechanistically, SLC35F2 competitively interacts with the E3 ubiquitin ligase SYVN1 (HRD1), thereby stabilizing TRIM59 expression, which consequently promotes p53 ubiquitination and degradation. This SLC35F2-SYVN1-TRIM59 axis suppresses wild-type p53-dependent ferroptosis. Co-immunoprecipitation, multi-omics analysis, in vitro and in vivo ferroptosis assays, protein 3D structure analysis, PDX models Oncogene Medium 37740007
2021 Increased SLC35F2 expression enhances YM155 uptake and sensitizes AML U937 cells to YM155-mediated cytotoxicity. The effect was cell-line specific: elevated SLC35F2 in U937/HQ cells increased YM155 sensitivity, while myeloperoxidase (MPO) activity was the additional determinant in HL-60 cells. Hydroquinone-induced SLC35F2 upregulation, cell viability assays, forced expression of MPO and SLC35F2 in AML cell lines Biochemical pharmacology Medium 33831396
2023 Decitabine (DAC) upregulates SLC35F2 expression via AKT- and p38 MAPK-mediated signaling, involving TET dioxygenases and p300 association with Sp1. The DAC-induced increase in SLC35F2 expression is required for synergistic cytotoxicity with YM155 in AML cells. Co-administration drug studies in AML cell lines, signaling pathway inhibitors, Sp1/TET/p300 co-immunoprecipitation, SLC35F2 knockdown rescue experiments Apoptosis : an international journal on programmed cell death Low 38066391
2024 ONC212 upregulates SLC35F2 expression through the AKT/NOX4/HuR/ATF4 pathway; HuR-mediated ATF4 mRNA stabilization stimulates SLC35F2 expression, and the synergistic cytotoxicity of ONC212 plus YM155 in AML cells is dependent on this ONC212-induced increase in SLC35F2. Pharmacological inhibitors, forced expression/knockdown of pathway components, cell viability and apoptosis assays in AML cell lines Biochemical pharmacology Low 38679209
2013 RNAi-mediated knockdown of SLC35F2 in lung cancer H1299 cells attenuates proliferation, migration, and invasion, and causes G0/G1 cell cycle arrest with decreased proportions of cells in S and G2/M phases. Lentiviral shRNA knockdown, CCK-8 proliferation assay, Transwell migration assay, flow cytometry cell cycle analysis Cancer cell international Low 23879892
2025 SLC35F2 knockdown in NSCLC cells activates the cAMP signaling pathway, particularly through upregulation of the transcription factor CREB1, implicating SLC35F2 in modulation of the cAMP/CREB1 axis to drive NSCLC proliferation, migration, and invasion. SLC35F2 knockdown, RT-qPCR, Western blot, CCK-8, EdU, colony formation, Transwell assays, pathway enrichment analysis Cytotechnology Low 40667522

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nature chemical biology 141 25064833
2023 SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Oncogene 23 37740007
2021 USP32 confers cancer cell resistance to YM155 via promoting ER-associated degradation of solute carrier protein SLC35F2. Theranostics 23 34815782
2011 Highly expressed SLC35F2 in non-small cell lung cancer is associated with pathological staging. Molecular medicine reports 23 21874247
2021 SLC35F2, a Transporter Sporadically Mutated in the Untranslated Region, Promotes Growth, Migration, and Invasion of Bladder Cancer Cells. Cells 15 33418944
2013 Influence on the behavior of lung cancer H1299 cells by silencing SLC35F2 expression. Cancer cell international 13 23879892
2021 Inhibition of Sp1-mediated survivin and MCL1 expression cooperates with SLC35F2 and myeloperoxidase to modulate YM155 cytotoxicity to human leukemia cells. Biochemical pharmacology 12 33831396
2023 Synergistic cytotoxicity of decitabine and YM155 in leukemia cells through upregulation of SLC35F2 and suppression of MCL1 and survivin expression. Apoptosis : an international journal on programmed cell death 9 38066391
2019 Knockdown of SLC35F2 Inhibits the Proliferation and Metastasis of Bladder Cancer Cells. OncoTargets and therapy 9 31849485
2023 E3 ubiquitin ligase APC/CCdh1 regulates SLC35F2 protein turnover and inhibits cancer progression in HeLa cells. Biochimica et biophysica acta. General subjects 4 37689217
2025 The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine. Proceedings of the National Academy of Sciences of the United States of America 3 40526720
2024 ONC212 enhances YM155 cytotoxicity by triggering SLC35F2 expression and NOXA-dependent MCL1 degradation in acute myeloid leukemia cells. Biochemical pharmacology 3 38679209
2025 SLC35F2 promotes the progression of NSCLC via regulating CREB1 expression. Cytotechnology 0 40667522
2023 βTrCP1 promotes SLC35F2 protein ubiquitination and inhibits cancer progression in HeLa cells. Biochemical and biophysical research communications 0 37801987

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