Affinage

SLC35F2

Queuine/queuosine transporter SLC35F2 · UniProt Q8IXU6

Length
374 aa
Mass
41.2 kDa
Annotated
2026-04-28
14 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC35F2 is a solute carrier family member that functions as the primary high-affinity transporter of the micronutrients queuine (Km ~67 nM) and queuosine (Km ~174 nM) and also mediates cellular import of the anticancer compound YM155, linking its transport activity to both tRNA modification and drug sensitivity (PMID:40526720, PMID:25064833). SLC35F2 localizes to the plasma membrane and Golgi apparatus and exhibits high substrate selectivity, excluding canonical ribonucleobases and ribonucleosides (PMID:40526720). SLC35F2 protein turnover is tightly regulated by multiple E3 ubiquitin ligases — APC/C^Cdh1 and βTrCP1 — which ubiquitinate and destabilize it, with the deubiquitinase USP32 paradoxically also promoting its degradation via ER-associated pathways (PMID:37689217, PMID:37801987, PMID:34815782). Beyond its transporter function, SLC35F2 suppresses ferroptosis in pancreatic cancer by competitively binding the E3 ligase SYVN1, thereby stabilizing TRIM59 and enhancing TRIM59-mediated p53 degradation (PMID:37740007).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2013 Low

    Initial evidence that SLC35F2 is not merely a passive transporter but actively promotes cancer cell proliferation and cell cycle progression, raising the question of its molecular function.

    Evidence siRNA knockdown in H1299 lung cancer cells caused G0/G1 arrest and reduced proliferation and migration

    PMID:23879892

    Open questions at the time
    • Single knockdown approach with no molecular mechanism identified
    • No transport substrate or direct molecular target defined
    • Not independently confirmed in additional cell lines
  2. 2014 High

    A haploid genetic screen identified SLC35F2 as the obligate importer of the anticancer compound YM155, establishing that it functions as a drug transporter whose loss abolishes YM155-mediated DNA damage — the first defined transport substrate for this orphan SLC.

    Evidence Haploid genetic screen in KBM7 cells, CRISPR knockout validation, in vitro and in vivo drug sensitivity assays

    PMID:25064833

    Open questions at the time
    • Endogenous physiological substrate unknown
    • Transport mechanism (electrochemical coupling, stoichiometry) not characterized
    • No structural model of SLC35F2
  3. 2021 Medium

    Discovery that the deubiquitinase USP32 destabilizes SLC35F2 via ER-associated degradation revealed that SLC35F2 protein levels are actively controlled by the ubiquitin-proteasome system, providing a mechanism for acquired YM155 resistance.

    Evidence Genome-scale USP CRISPR knockout screen with protein stability assays and in vivo experiments

    PMID:34815782

    Open questions at the time
    • Mechanism by which a DUB promotes degradation rather than stabilization is unusual and not fully resolved
    • No identification of the E3 ligase counteracting USP32 at the ER
    • Correlation between USP32 and SLC35F2 across cancers not confirmed by direct genetic epistasis in patients
  4. 2023 Medium

    Parallel studies identified APC/C^Cdh1 and βTrCP1 as two distinct E3 ubiquitin ligases that ubiquitinate SLC35F2 and control its protein half-life, establishing that SLC35F2 stability is a convergence point for multiple degradation pathways that in turn regulate pro-tumorigenic phenotypes.

    Evidence In vitro ubiquitination assays, co-IP, proximity ligation, and half-life analyses in cancer cell lines

    PMID:37689217 PMID:37801987

    Open questions at the time
    • Degron motifs on SLC35F2 recognized by each E3 ligase not mapped
    • Functional interplay or redundancy between APC/C^Cdh1, βTrCP1, and USP32 not tested in the same system
    • Whether ubiquitination regulates SLC35F2 transporter activity or only protein abundance is unknown
  5. 2023 Medium

    Beyond its transporter role, SLC35F2 was shown to suppress ferroptosis in pancreatic cancer by a protein–protein interaction mechanism: it competitively sequesters SYVN1 away from TRIM59, stabilizing TRIM59 which then degrades p53 — revealing a non-canonical scaffolding/adaptor function.

    Evidence Co-immunoprecipitation, competitive binding assays, in vitro and in vivo ferroptosis assays, protein structure modeling

    PMID:37740007

    Open questions at the time
    • Whether the SYVN1 interaction interface overlaps with SLC35F2 transport function is unknown
    • Generalizability beyond pancreatic cancer not tested
    • Structural basis for competitive SYVN1 binding not resolved at atomic level
  6. 2023 Medium

    Decitabine-induced upregulation of SLC35F2 transcription via AKT/p38 MAPK–Sp1–TET–p300 signaling established a pharmacologically actionable transcriptional circuit controlling SLC35F2 expression and YM155 synergy in AML.

    Evidence Pharmacological inhibitors, reporter assays, ectopic expression and knockdown in AML cell lines

    PMID:38066391

    Open questions at the time
    • Direct TET-mediated demethylation at the SLC35F2 promoter not demonstrated by bisulfite sequencing
    • Whether this transcriptional circuit operates in non-AML contexts is unknown
  7. 2025 High

    The long-standing question of SLC35F2's endogenous physiological substrate was resolved: it is the sole high-affinity transporter for queuine and queuosine in human cells, localizing to the plasma membrane and Golgi, and displaying high selectivity against canonical nucleobases.

    Evidence Cross-species bioinformatic identification, genetic disruption in HeLa cells, competitive radiolabeled uptake assays, immunofluorescence

    PMID:40526720

    Open questions at the time
    • Transport mechanism (coupling ion, conformational cycle) not defined
    • No high-resolution structure of SLC35F2
    • Physiological consequences of queuine/queuosine transport loss in vivo (animal models) not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis for SLC35F2's dual substrate recognition (queuine/queuosine vs. YM155), the transport mechanism and energy coupling, and whether its non-canonical scaffolding interactions with SYVN1/TRIM59 are structurally and functionally separable from its transport activity.
  • No atomic-resolution structure of SLC35F2
  • Transport energetics and ion coupling unknown
  • Relationship between transport function and protein–protein interaction functions not dissected

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-392499 Metabolism of proteins 3 R-HSA-382551 Transport of small molecules 2 R-HSA-5357801 Programmed Cell Death 1
Partners
BTRCCDH1SYVN1TRIM59USP32

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 SLC35F2 functions as a drug importer that enables cellular uptake of the anticancer compound YM155; SLC35F2-dependent import of YM155 leads to DNA damage through intercalation, and knockout of SLC35F2 abolishes YM155-mediated DNA damage toxicity both in vitro and in vivo. Haploid genetic screen, targeted genome editing (CRISPR/knockout), in vitro and in vivo drug sensitivity assays Nature chemical biology High 25064833
2021 USP32, a deubiquitinating enzyme, destabilizes SLC35F2 protein via ER-associated degradation, reducing SLC35F2 levels and conferring YM155 resistance; USP32 and SLC35F2 expression are negatively correlated across cancer cell lines. CRISPR-based genome-scale USP knockout screen, in vitro and in vivo experiments including protein stability assays Theranostics Medium 34815782
2023 SLC35F2 inhibits ferroptosis in pancreatic cancer cells by competitively binding the E3 ubiquitin ligase SYVN1, thereby stabilizing TRIM59 and promoting TRIM59-mediated p53 degradation. Co-immunoprecipitation, protein interaction studies, in vitro and in vivo ferroptosis assays, protein 3D structure analysis Oncogene Medium 37740007
2023 APC/C^Cdh1 E3 ubiquitin ligase complex interacts with SLC35F2, promotes its ubiquitination, and reduces SLC35F2 protein half-life, thereby controlling SLC35F2 protein turnover; depletion of APC/C^Cdh1 increases SLC35F2 levels and promotes SLC35F2-mediated cell proliferation, migration, and invasion. Immunoprecipitation, Duolink proximity ligation assay, in vitro ubiquitination assay, CRISPR/Cas9 knockdown, half-life analysis Biochimica et biophysica acta. General subjects Medium 37689217
2023 βTrCP1 E3 ubiquitin ligase interacts with SLC35F2, promotes its ubiquitination, reduces SLC35F2 protein half-life, and depletion of βTrCP1 accumulates SLC35F2 protein and promotes SLC35F2-mediated cell growth, migration, invasion, and colony formation. Co-immunoprecipitation, ubiquitination assay, protein half-life analysis, siRNA knockdown, oncogenic assays in HeLa cells Biochemical and biophysical research communications Medium 37801987
2025 SLC35F2 is the sole high-affinity transporter for the micronutrients queuosine (Km 174 nM) and queuine (Km 67 nM) in human cells; SLC35F2 localizes to the cell membrane and Golgi apparatus; it does not transport canonical ribonucleobases or ribonucleosides, indicating high substrate selectivity. Cross-species bioinformatic search, gene disruption in human HeLa cells, competitive uptake assays, immunofluorescence localization Proceedings of the National Academy of Sciences of the United States of America High 40526720
2023 Decitabine (DAC) upregulates SLC35F2 expression through an AKT- and p38 MAPK-mediated pathway involving Ca2+/ROS-dependent signaling, Sp1 transcription factor, TET dioxygenases, and p300; elevated SLC35F2 expression is required for the synergistic cytotoxicity of DAC and YM155 in AML cells. Pharmacological inhibitors, ectopic expression/knockdown, Western blotting, reporter assays in AML cell lines Apoptosis : an international journal on programmed cell death Medium 38066391
2021 Increased SLC35F2 expression in AML U937 cells enhances cellular sensitivity to YM155-mediated cytotoxicity, consistent with its role as a YM155 importer. Continuous hydroquinone exposure to generate SLC35F2-overexpressing cells, cell viability and apoptosis assays Biochemical pharmacology Medium 33831396
2025 SLC35F2 knockdown activates the cAMP signaling pathway and upregulates the transcription factor CREB1 in NSCLC cells, suppressing proliferation, migration, and invasion, indicating SLC35F2 drives NSCLC progression via modulation of the cAMP/CREB1 axis. RT-qPCR, Western blot, CCK-8, EdU, colony formation, flow cytometry, Transwell assays, functional enrichment analysis Cytotechnology Low 40667522
2013 siRNA-mediated knockdown of SLC35F2 in lung cancer H1299 cells reduces proliferation and migration, and causes G0/G1 cell cycle arrest with decreased S and G2/M phase fractions, indicating SLC35F2 promotes cell cycle progression. Lentiviral siRNA knockdown, CCK-8 proliferation assay, Transwell migration assay, FACS cell cycle analysis Cancer cell international Low 23879892

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 140 25064833
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
2023 SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Oncogene 22 37740007
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
2024 ONC212 enhances YM155 cytotoxicity by triggering SLC35F2 expression and NOXA-dependent MCL1 degradation in acute myeloid leukemia cells. Biochemical pharmacology 3 38679209
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 2 40526720
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