Affinage

SLC3A2

Amino acid transporter heavy chain SLC3A2 · UniProt P08195

Length
529 aa
Mass
57.9 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC3A2 (4F2hc/CD98hc) is a type II membrane glycoprotein that serves as the obligatory heavy-chain subunit of heteromeric amino acid transporters, pairing with multiple light chains to assemble transport systems of distinct substrate specificity, while independently coupling integrins to mechanosignaling (PMID:9726963, PMID:9751058, PMID:9915839, PMID:15625115). It covalently links to its light-chain partners through a Cys109 disulfide bond, and loss of this cysteine abolishes heterodimer formation and transport (PMID:9829974, PMID:10897033, PMID:9761775). Through this association SLC3A2 reconstitutes system L transport with LAT1 and LAT2 (large/small neutral amino acids), system y+L transport with y+LAT-1 and y+LAT2 (cationic/neutral amino acid antiport), and cystine/glutamate exchange with xCT (PMID:9726963, PMID:9751058, PMID:9915839, PMID:9829974, PMID:10903140, PMID:10391915, PMID:26945935). SLC3A2 controls the intracellular trafficking, plasma-membrane delivery, and stability of its light chains and modulates their substrate affinity, while its own surface delivery and stability depend on N-glycosylation at Asn365/381/424/506 (PMID:9915839, PMID:11311135, PMID:33066406, PMID:36028562). Structurally, its (βα)8-barrel ectodomain — related to bacterial α-glycosidases but catalytically dead — covers the extracellular face of the light chain and makes extensive contacts across the membrane and on the intracellular side, as resolved by crystallography and cryo-EM of the LAT1-4F2hc complex (PMID:17724034, PMID:24516142, PMID:30867591). Independently of transport, SLC3A2 binds β1/β3 integrin cytoplasmic tails via its transmembrane/cytoplasmic domains and drives integrin-dependent Akt, Rac, RhoA, FAK and PI3K signaling that controls cell spreading, migration, survival, proliferation, fibronectin matrix assembly, and stiffness-dependent mechanosensing through ROCK and YAP/TAZ (PMID:11121428, PMID:15625115, PMID:15485886, PMID:17597067, PMID:17682053, PMID:25267066). Its amino-acid transport function feeds anabolic and redox programs: leucine/isoleucine uptake activates mTORC1 (including at the lysosome via LAPTM4b) to sustain regulatory T-cell maintenance and angiogenesis, while xCT-mediated cystine import maintains glutathione and protects against ferroptosis (PMID:25998567, PMID:26945935, PMID:29141216, PMID:38755144). SLC3A2 abundance is set post-translationally by ubiquitin ligases and glycosyltransferases (Skp2, B3GNT3, PTPRJ, p62) that gate its membrane localization and ferroptosis-relevant activity (PMID:29805737, PMID:37479744, PMID:39079969, PMID:37771765). SLC3A2 additionally acts as a cell-surface receptor co-opted by Plasmodium vivax PvRBP2a and human β-defensin 3, and an SLC3A2-NRG1 transmembrane fusion drives ERBB-dependent oncogenic signaling (PMID:34294905, PMID:25641165, PMID:29959202).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Established that SLC3A2 is the obligatory heavy chain enabling functional surface amino acid transport, defining its core role as a transporter assembly subunit rather than a transporter itself.

    Evidence Expression cloning and functional reconstitution of LAT1 with 4F2hc in Xenopus oocytes

    PMID:9726963 PMID:9751058 PMID:9915839

    Open questions at the time
    • Did not resolve whether 4F2hc contributes transport residues or only chaperones the light chain
    • Substrate selectivity determinants not mapped
  2. 1998 High

    Identified the covalent basis of heavy/light chain pairing, showing a single disulfide bond is required for complex assembly and transport.

    Evidence C109S site-directed mutagenesis with co-IP and transport assays in oocytes

    PMID:10897033 PMID:9761775 PMID:9829974

    Open questions at the time
    • Did not establish the order of folding/assembly relative to disulfide formation
  3. 1998 High

    Showed a single heavy chain pairs with multiple light chains to generate different transport systems, explaining how one gene supports diverse amino acid fluxes.

    Evidence Functional co-expression of 4F2hc with y+LAT-1 (and later LAT2, y+LAT2, xCT) in oocytes

    PMID:10903140 PMID:9829974

    Open questions at the time
    • Tissue-level pairing preferences not defined
    • Did not address how a cell selects which light chain to assemble
  4. 2000 High

    Separated SLC3A2's transport and integrin functions onto distinct domains, revealing it as a bifunctional protein.

    Evidence CD98hc/CD69 chimeras with isoleucine transport and integrin signaling readouts; cysteine mutants in transformation assays

    PMID:10897033 PMID:11121428

    Open questions at the time
    • Did not identify the direct integrin-tail contact residues at this stage
    • Downstream effectors of the integrin function unmapped here
  5. 2004 High

    Demonstrated genetically that the integrin-binding/signaling function, independent of amino acid transport, drives spreading, migration, and survival via Akt/Rac.

    Evidence CD98hc-null cells with transport-dead/integrin-competent rescue mutants and Akt/Rac assays; TM domain mapping and transformation assays

    PMID:15485886 PMID:15625115

    Open questions at the time
    • Mechanism linking integrin tail engagement to GTPase activation not fully resolved
    • Did not address mechanotransduction directly
  6. 2007 High

    Defined the structural fold of the ectodomain and the reciprocal integrin-tail interaction interface, and tied SLC3A2 to RhoA-driven matrix assembly.

    Evidence X-ray crystallography of the ectodomain; β3 tail mutagenesis with co-IP; CD98hc-KO fibronectin matrix assembly and RhoA assays

    PMID:17597067 PMID:17682053 PMID:17724034

    Open questions at the time
    • Ectodomain structure lacked the light chain and membrane context
    • How RhoA activation is mechanically coupled was unresolved
  7. 2009 High

    Showed the integrin-binding domain, not transport, is required for lymphocyte proliferation in vivo, generalizing the signaling function to immune development.

    Evidence B cell-specific conditional KO with domain rescue, Erk1/2 and p27 readouts

    PMID:19270713

    Open questions at the time
    • Did not separate cell-intrinsic vs niche contributions fully
    • Receptor input upstream of Erk1/2 not defined
  8. 2011 High

    Extended SLC3A2's chaperone role beyond amino acid light chains by showing it stabilizes GLUT1 and boosts glucose uptake.

    Evidence Split-ubiquitin Y2H, endogenous reciprocal co-IP, cycloheximide chase, glucose uptake

    PMID:21270293

    Open questions at the time
    • Structural basis of GLUT1 stabilization unknown
    • Whether the interaction is direct in the membrane not shown
  9. 2014 High

    Provided the membrane-context structure showing the ectodomain caps the light chain, and linked SLC3A2 to stiffness sensing via ROCK/YAP-TAZ in carcinogenesis.

    Evidence EM single-particle analysis and proteoliposome reconstitution of 4F2hc-LAT2; conditional KO carcinogenesis model with ROCK/YAP-TAZ readouts

    PMID:24516142 PMID:25267066

    Open questions at the time
    • EM resolution insufficient for atomic contacts
    • Feedback loop quantification incomplete
  10. 2015 High

    Connected SLC3A2 transport activity to mTORC1 signaling and to redox homeostasis/ferroptosis protection, establishing two metabolic outputs.

    Evidence LAPTM4b co-IP, lysosomal fractionation and mTORC1 assays; CD98hc chimera rescue with ROS/GSH/ferroptosis readouts; β-defensin 3 SPR binding

    PMID:25641165 PMID:25998567 PMID:26945935

    Open questions at the time
    • How lysosomal vs plasma-membrane pools are partitioned unclear
    • xCT-specific contribution vs other light chains not fully isolated
  11. 2018 High

    Resolved a lipid-based mechanism for SLC3A2 mechanosensing and identified a transmembrane fusion and UPR-coupling roles.

    Evidence Conditional KO with lipidomics and Src/GEF-H1/RhoA rescue; SLC3A2-NRG1 fusion binding/signaling assays; siRNA UPR epistasis in cardiomyocytes

    PMID:29959202 PMID:30451822 PMID:30592731

    Open questions at the time
    • UPR coupling shown only by knockdown epistasis (Medium)
    • Direct lipid-binding by SLC3A2 not demonstrated
  12. 2019 High

    Delivered near-atomic LAT1-4F2hc cryo-EM structures and linked SLC3A2-driven amino acid supply to nucleotide pools and genome stability.

    Evidence Cryo-EM at 3.3 Å of LAT1-4F2hc; metabolomics and nucleoside rescue in CD98hc-KO cells; PTPRJ pulldown/degradation

    PMID:29805737 PMID:30867591 PMID:31575908

    Open questions at the time
    • Conformational cycle of the full transport mechanism not complete
    • PTPRJ-driven degradation mechanism (Medium) not fully mapped
  13. 2021 High

    Captured inhibitor-bound transport conformations and identified SLC3A2 as a pathogen invasion receptor, broadening its functional scope.

    Evidence Inhibitor-bound LAT1-4F2hc cryo-EM at 2.7–2.8 Å; PvRBP2a MS/flow/binding/invasion assays

    PMID:33758168 PMID:34294905

    Open questions at the time
    • Pharmacology of distinct light-chain complexes not generalized
    • Structural basis of PvRBP2a binding not resolved
  14. 2022 High

    Defined N-glycosylation as a stability/trafficking requirement and identified polarity-complex and receptor partnerships controlling localization and function.

    Evidence Quadruple N-glycosylation mutants with biotinylation/BFA assays; SCRIB/LLGL2 quaternary complex co-IP/PLA; AGR2 receptor co-IP with xCT/RhoA readouts

    PMID:35086885 PMID:35501367 PMID:36028562

    Open questions at the time
    • SCRIB and AGR2 findings are single-lab (Medium)
    • Which glycans drive specific complexes unresolved
  15. 2023 High

    Established post-translational control of SLC3A2 membrane abundance by glycosyltransferases and ubiquitin machinery, dictating xCT-dependent ferroptosis outcomes.

    Evidence B3GNT3 glycoproteomics/KO; Skp2 K48-ubiquitination and Neu5Ac/p62 degradation studies with ferroptosis readouts

    PMID:37479744 PMID:37771765 PMID:39079969

    Open questions at the time
    • Several degradation pathways are single-lab (Medium)
    • Cross-talk among Skp2, B3GNT3, p62 regulation not integrated
  16. 2024 High

    Placed SLC3A2 expression under transcriptional control of FOXC1 in endothelium, coupling its amino acid transport to mTOR-dependent angiogenesis.

    Evidence Endothelial Foxc1 conditional KO with retinal angiogenesis, mTOR readout and agonist rescue

    PMID:38755144

    Open questions at the time
    • Direct FOXC1 binding to the SLC3A2 promoter not detailed here
    • Transport vs signaling contribution to angiogenesis not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same heavy chain selects among light chains in a given cell, and how its transport, integrin-signaling, chaperone, and receptor functions are coordinately regulated, remains unresolved.
  • No unified model linking light-chain selection to physiological context
  • Quantitative partitioning of plasma-membrane vs lysosomal vs adhesion-site pools unknown
  • Integration of competing degradation pathways (Skp2, p62, PTPRJ) not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 5 GO:0005198 structural molecule activity 3 GO:0060089 molecular transducer activity 3 GO:0140104 molecular carrier activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-382551 Transport of small molecules 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-1474244 Extracellular matrix organization 1
Partners
ITGB1ITGB3LAPTM4BSCRIBSLC2A1SLC7A11SLC7A5TRPV4
Complex memberships
4F2hc/LAT1 (SLC7A5) heteromeric amino acid transporter4F2hc/xCT (SLC7A11) system Xc-CD98hc/β1-integrin/TRPV4 focal adhesion complexSCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SLC3A2 (4F2hc/CD98hc) heavy chain is required for functional surface expression of the LAT1 light chain; co-expression in Xenopus oocytes reconstitutes Na+-independent system L amino acid transport of large neutral amino acids with branched or aromatic side chains. Expression cloning and functional reconstitution in Xenopus oocytes The Journal of biological chemistry High 9726963 9751058 9915839
1998 4F2hc (SLC3A2) cysteine 109 (Cys-109) forms a disulfide bond that covalently links the heavy chain to its light chain subunits; mutation C109S abolishes heterodimer formation and drastically reduces co-expressed amino acid transport activity. Site-directed mutagenesis, co-immunoprecipitation, transport assay in Xenopus oocytes The Journal of biological chemistry High 10897033 9761775 9829974
1998 4F2hc (SLC3A2) associates with y+LAT-1 to form a heterodimer mediating system y+L amino acid transport (cationic and neutral amino acids exchanged with sodium); this is the molecular basis of the y+L transport system. Functional co-expression in Xenopus oocytes, co-immunoprecipitation The Journal of biological chemistry High 10903140 9829974
1999 SLC3A2 (4F2hc) controls intracellular trafficking and plasma membrane localization of its light chain partners: 4F2hc reaches the plasma membrane alone, but the light chain (LAT1) requires 4F2hc for surface expression. In cells expressing cadherins, 4F2hc is selectively localized to cell-cell adhesion sites. Mammalian cell transfection, immunofluorescence, flow cytometry The Journal of biological chemistry High 9915839
1999 LAT-2 co-expressed with 4F2hc (SLC3A2) mediates Na+-independent, broad-specificity system L transport of small and large zwitterionic amino acids via an exchanger mechanism; LAT-2 alone has intracellular location and no transport activity. Functional co-expression in Xenopus oocytes, tagged protein localization The Journal of biological chemistry High 10391915
2000 The 4F2hc/y+LAT2 heterodimer mediates arginine efflux in exchange for extracellular glutamine and leucine (antiport mechanism); arginine has the highest affinity for the intracellular binding site, making arginine release the main physiological function. Functional reconstitution in Xenopus oocytes, radiolabeled amino acid transport assays The Biochemical journal High 10903140
2000 The cytoplasmic and transmembrane domains of CD98hc (SLC3A2) are required for its effects on integrin function, while the extracellular domain is required for stimulation of amino acid (isoleucine) transport; these two functions are separable and require distinct domains. CD98hc/CD69 chimera construction, isoleucine transport assays, integrin signaling readouts in mammalian cells The Journal of biological chemistry High 11121428
2000 The 4F2hc/LAT1 heterodimeric complex mediates Na+-independent L-DOPA transport across the blood-brain barrier; LAT1 is predominantly expressed in brain microvessels and forms a heterodimer with 4F2hc in brain capillary endothelial cells. Northern hybridization, immunoblotting, radiolabeled L-DOPA uptake assay, immunohistochemistry Brain research Medium 11011012
2001 The extracellular domain of 4F2hc (SLC3A2) is specifically required for surface expression of LAT2 and y+LAT2 but not LAT1; truncated 4F2hc containing only the cytosolic N-terminus and transmembrane helix retains partial ability to promote LAT1 surface expression. C-terminal truncation mutants of 4F2hc co-expressed with light chains in Xenopus oocytes and mammalian cells The Biochemical journal High 11311135
2004 CD98hc (SLC3A2) physically associates with β1 integrins and is required for integrin-dependent cell spreading, migration, and protection from apoptosis; loss of CD98hc impairs adhesion-induced Akt and Rac GTPase activation. A CD98hc mutant that interacts with β1 integrins but not light chains restores integrin signaling, showing amino acid transport is dispensable for these functions. Gene knockout (CD98hc-null cells), rescue with domain mutants, cell spreading/migration assays, Akt/Rac activation assays Proceedings of the National Academy of Sciences of the United States of America High 15625115
2004 CD98hc (SLC3A2) interaction with β1 integrins requires its transmembrane domain (amino acids 82-87); this association drives FAK-dependent PI3K activation and cellular transformation (anchorage-independent growth). CD98hc/CD69 chimeras, co-immunoprecipitation, PI3K activation assays, soft-agar colony formation, xenograft tumor assay The Journal of biological chemistry High 15485886
2007 Crystal structure of the 4F2hc (SLC3A2) ectodomain reveals a (βα)8 barrel and antiparallel β sandwich related to bacterial α-glycosidases but lacking catalytic residues; Cys109 is located near the transmembrane domain and participates in a disulfide-linked homodimer at the cell surface. X-ray crystallography (2.1 Å and 2.8 Å crystal forms), cross-linking experiments, cell surface homodimerization assays The Journal of biological chemistry High 17724034
2007 CD98hc (SLC3A2) interacts with integrin β cytoplasmic domain via the C-terminal 8 residues of β3 (Thr755–Thr762); point mutations T755K or T758M in β3 abolish CD98hc association and impair integrin-mediated cell spreading. Homology scanning mutagenesis, co-immunoprecipitation, cell spreading assays with Drosophila βPS gain-of-function mutations The Journal of biological chemistry High 17597067
2007 CD98hc (SLC3A2) participates in fibronectin matrix assembly by enabling RhoA GTPase activation downstream of integrins; CD98hc is not required for Fn biosynthesis or integrin repertoire/affinity but is required for force generation on the matrix. CD98hc knockout cells, fibronectin matrix assembly assay, RhoA activity assay, in vitro and in vivo matrix assembly The Journal of cell biology High 17682053
2009 B cell-specific deletion of CD98hc (SLC3A2) abolishes B cell proliferation and plasma cell formation; the integrin-binding domain of CD98hc (not the amino acid transport function) is required for B cell proliferation, acting via Erk1/2 activation and p27 downregulation. B cell-specific conditional knockout, domain-specific rescue mutants, Erk1/2 activation assays, FACS cell cycle analysis Nature immunology High 19270713
2011 4F2hc (SLC3A2) stabilizes GLUT1 protein at the plasma membrane and increases glucose uptake; 4F2hc and GLUT1 physically associate (co-immunoprecipitation confirmed endogenously in mouse brain and HeLa cells), and 4F2hc overexpression or knockdown respectively increases or decreases GLUT1 protein stability without affecting GLUT1 mRNA. Split-ubiquitin membrane yeast two-hybrid, co-immunoprecipitation, cycloheximide chase, radiolabeled glucose uptake assay, siRNA knockdown American journal of physiology. Cell physiology High 21270293
2013 4F2hc (SLC3A2) silencing in HeLa cells impairs FAK/Akt/ERK1/2 integrin signaling, reduces MMP-2 expression/activity, and allows galectin-3 accumulation that cannot signal due to impaired 4F2hc interaction; loss of 4F2hc disrupts 4F2hc/β1-integrin/CD147 heterocomplexes, leading to β-catenin proteasomal degradation. Stable miRNA-mediated silencing, co-immunoprecipitation, FAK/Akt/ERK phosphorylation assays, MMP-2 activity assay, xenograft tumor model Biochimica et biophysica acta Medium 23651923
2014 4F2hc (SLC3A2) extracellular domain covers the extracellular face of the LAT2 light chain and stabilizes it in detergent-solubilized membranes; the 4F2hc ectodomain alone is sufficient to stabilize LAT2 and allows functional reconstitution in proteoliposomes. Transmission electron microscopy single-particle analysis, docking, crosslinking, proteoliposome reconstitution, stability assay Proceedings of the National Academy of Sciences of the United States of America High 24516142
2014 CD98hc (SLC3A2) loss protects against Ras-driven skin carcinogenesis; CD98hc mediates stiffness sensing by increasing Rho kinase (ROCK) activity and YAP/TAZ-mediated transcription in response to matrix rigidity, amplifying a positive feedback loop that increases ECM stiffness. Conditional KO mouse model, chemical carcinogenesis, tumor regression after inducible deletion, RhoA/ROCK activity assays, YAP/TAZ reporter Cancer research High 25267066
2015 The lysosomal protein LAPTM4b binds LAT1-4F2hc (SLC7A5-SLC3A2) and recruits this complex to lysosomes, enabling leucine uptake into lysosomes and mTORC1 activation via V-ATPase stimulation. Co-immunoprecipitation, lysosomal fractionation, leucine uptake assays, mTORC1 activation (S6K phosphorylation), LAPTM4b knockdown Nature communications High 25998567
2015 CD98hc-associated transporters (xCT, LAT1, y+LAT2) control reactive oxygen species and intracellular amino acid levels; CD98hc deletion causes ferroptosis due to inability to compensate CD98hc/xCT loss. CD98hc amino acid transport (not integrin signaling) is required for in vitro cell proliferation. CD98hc chimeric mutant rescue experiments, ROS measurement, GSH assay, β-mercaptoethanol rescue, ferroptosis inhibitor rescue The Journal of biological chemistry High 26945935
2016 Slc3a2 is required for maintenance of Foxp3+ regulatory T cells in vivo; Slc3a2-deficient Treg cells show impaired isoleucine-induced mTORC1 activation and altered metabolic state, and Slc3a2-specific Treg KO mice develop multi-organ inflammation. Treg-specific conditional knockout, in vivo proliferation assays, mTORC1 activation (S6K/4EBP1), metabolic profiling, BCAA-reduced diet experiments Cell reports High 29141216
2017 LAT1 stabilizes 4F2hc (SLC3A2) protein via a chaperone-like function in trophoblastic cells; LAT1 knockout drastically reduces 4F2hc protein (but not mRNA) and prevents syncytiotrophoblast formation, because 4F2hc has fusogenic activity required for trophoblast cell fusion. LAT1 knockout mice, trophoblast LAT1 knockdown (BeWo cells), western blot for 4F2hc, forskolin-induced cell fusion assay Molecular and cellular biology High 28320871
2018 CD98hc (SLC3A2) regulates integrin mechanosensing via sphingolipid biosynthesis: loss of CD98hc decreases sphingolipid availability, preventing membrane recruitment and activation of Src kinases and GEF-H1, and impairing RhoA activation in response to matrix rigidity. Conditional KO in dermal cells, sphingolipid profiling (lipidomics), DES2 expression analysis, RhoA/Src/GEF-H1 activity assays, rescue with sphingolipid supplementation Nature communications High 30451822
2019 Cryo-EM structure of human LAT1-4F2hc (SLC7A5-SLC3A2) heterodimer at 3.3 Å resolution reveals that besides the disulfide bond, LAT1 interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side; 4F2hc is essential for transport activity of the complex; LAT1 is in inward-open conformation. Cryo-electron microscopy (3.3 Å and 3.5 Å), inhibitor-bound structure, biochemical transport activity assays Nature High 30867591
2019 CD98hc (SLC3A2) deficiency causes replicative stress by reducing BCAA/aromatic amino acid availability, which diminishes glucose uptake/glycolysis, pentose phosphate pathway activity, and nucleotide pool; nucleoside supplementation rescues S-phase delay and proliferation defects. CD98hc KO cells, metabolomics, nucleotide pool measurement, DNA damage response (γH2AX), S-phase analysis by BrdU, nucleoside rescue Scientific reports High 31575908
2019 PTPRJ receptor tyrosine phosphatase physically interacts with CD98hc (SLC3A2) and promotes its proteasomal degradation; PTPRJ overexpression reduces CD98hc protein levels, and proteasome inhibitor MG132 reverses this. Proteomic pulldown, co-immunoprecipitation, proteasome inhibitor rescue, PTPRJ overexpression in lung cancer cells Oncotarget Medium 29805737
2020 4F2hc modulates the substrate affinity and specificity of its light chains LAT1 and LAT2; light chains are functional transporters without 4F2hc in Pichia pastoris, but association with 4F2hc alters their kinetic properties. Heterologous expression in Pichia pastoris, radiolabeled amino acid transport assays comparing HAT complexes vs light chains alone International journal of molecular sciences Medium 33066406
2020 CD98hc (SLC3A2) forms a molecular complex with β1 integrin and TRPV4 in focal adhesions; CD98hc knockdown inhibits TRPV4-mediated calcium influx induced by mechanical forces (but not by chemical activators); force must be transmitted from β1 integrin C-terminus via CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 for ultra-rapid mechanotransduction. Co-immunoprecipitation, co-localization imaging, CD98hc siRNA knockdown, calcium imaging with force application vs. chemical TRPV4 activation Journal of cell science Medium 32989042
2021 Cryo-EM structures of LAT1-4F2hc with potent inhibitors at 2.7–2.8 Å resolution reveal an outward-facing occluded conformation; inhibitors occupy the substrate binding pocket with tails wedged between the binding site and TM10 of LAT1, defining a distinct inhibition mechanism. A Diiodo-Tyr-bound structure reveals a possible intermediate between outward-occluded and outward-open states. Cryo-electron microscopy (2.7–3.4 Å), synthesis and IC50 measurement of inhibitors, transport assays Cell discovery High 33758168
2021 Plasmodium vivax merozoite surface protein PvRBP2a binds CD98hc (SLC3A2) on reticulocytes to mediate host cell invasion; CD98hc is expressed preferentially on immature reticulocytes (CD71+) and is a host receptor for P. vivax tropism. Mass spectrometry identification, flow cytometry, biochemical binding assays, parasite invasion inhibition assays Nature microbiology High 34294905
2022 N-glycosylation of 4F2hc (SLC3A2) at Asn365, Asn381, Asn424, and Asn506 is required for its stability and trafficking to the plasma membrane; quadruple mutation of these sites severely impairs membrane trafficking and correlates with reduced LAT1 (SLC7A5) surface expression and transport activity. Site-directed mutagenesis of all four N-glycosylation sites, biotinylation surface assay, brefeldin A trafficking assay, LAT1 co-expression and transport assay Scientific reports High 36028562
2022 The polarity protein SCRIB binds SLC3A2 N-terminus and facilitates formation of a SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the leucine transporter; both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ breast cancer. Co-immunoprecipitation, proximity ligation assay, siRNA knockdown of SCRIB and SLC3A2, membrane localization assay, cell proliferation assay Communications biology Medium 35501367
2022 Tumour-associated neutrophil-secreted AGR2 binds CD98hc (SLC3A2) as its functional receptor; AGR2 increases xCT transporter activity in a CD98hc-dependent manner, subsequently activating the RhoA/ROCK2 cascade to promote CRC cell migration. Co-immunoprecipitation, neutrophil-specific Agr2 KO mice, xCT activity assay, RhoA/ROCK2 phosphorylation, in vitro migration assay, in vivo liver metastasis model Gut Medium 35086885
2023 The glycosyltransferase B3GNT3 catalyzes N-glycosylation of 4F2hc (SLC3A2), stabilizes 4F2hc protein, and enhances interaction between 4F2hc and xCT; glycosylation-deficient 4F2hc fails to restore ferroptosis resistance and system Xc- activity in 4F2hc-deficient cells. N- and O-linked glycoproteomics, B3GNT3 KO, site-directed glycosylation mutants of 4F2hc, system Xc- activity (glutathione measurement), xenograft tumor model Cell death and differentiation High 37479744
2023 Skp2 E3 ligase controls SLC3A2 membrane localization and cystine/glutamate exchange function via K48-linked ubiquitination of SLC3A2; in sepsis, MEK/ERK pathway suppresses Skp2, reducing K48-ubiquitination of SLC3A2, impairing its membrane localization and triggering ferroptosis in pulmonary epithelial cells. Skp2 KO/overexpression, ubiquitination assay (K48 linkage), membrane fractionation, cystine uptake assay, lung injury model, Skp2 mRNA-LNP rescue Cellular and molecular life sciences Medium 39079969
2023 Neu5Ac (N-acetylneuraminic acid) promotes SLC3A2 binding to ubiquitin and p62-mediated degradation, leading to lipid peroxide accumulation and ferroptosis in vascular endothelial cells. Co-immunoprecipitation of SLC3A2 with ubiquitin/p62, ferroptosis markers (lipid peroxidation, GSH), ApoE-/- atherosclerosis mouse model, Fer-1 rescue Theranostics Medium 37771765
2024 FOXC1 transcription factor directly regulates endothelial Slc3a2 (and Slc7a5) expression; EC-specific Foxc1 deletion reduces SLC3A2/SLC7A5 expression, diminishes mTOR activity, and impairs retinal angiogenesis; mTOR agonist rescues the vascular growth defect. Endothelial-specific Foxc1 conditional KO, retinal angiogenesis assays, mTOR activity measurement, mTOR agonist rescue, OIR model Nature communications High 38755144
2018 The SLC3A2-NRG1 fusion protein (transmembrane domain of SLC3A2 fused to EGF-like domain of NRG1) binds ERBB3/ERBB4, promotes ERBB2-ERBB3 heterocomplex formation and phosphorylation, and activates PI3K/AKT and MAPK pathways, driving lung cancer cell proliferation. Ligand-receptor binding assays, co-immunoprecipitation of ERBB2/ERBB3, phosphorylation assays, colony formation, xenograft tumor model, siRNA targeting Molecular cancer therapeutics High 29959202
2018 SLC3A2 functions upstream of mTOR1 in the unfolded protein response (UPR) in cardiomyocytes; SLC3A2 knockdown reduces activity of ATF4, ATF6, and XBP1 UPR sensors, and mTOR1 acts as mediator between SLC3A2 and UPR activation. SLC3A2 inhibition also enhances apoptosis. siRNA knockdown of SLC3A2 and mTOR1 in H9C2/PC12 cells, western blot for UPR markers, RNA sequencing, flow cytometry apoptosis assay PloS one Medium 30592731
2019 Cryo-EM 3D-map (~13 Å) of human 4F2hc-LAT2 heterodimer places the 4F2hc ectodomain adjacent to the LAT2 transporter domain; the known 4F2hc ectodomain X-ray structure fits into the smaller density, revealing spatial relationship between subunits. Cryo-electron microscopy with Volta phase plate, single-particle analysis, fitting of X-ray ectodomain structure International journal of molecular sciences Medium 30795505
2015 CD98 (SLC3A2/4F2hc) acts as a cell surface receptor for human β-defensin 3 (hBD3) internalization in epithelial cells; CD98 and hBD3 directly bind (mapped to CD98 residues 304-414 by surface plasmon resonance), and CD98 knockdown impairs hBD3 cell surface binding and internalization. FRET, surface plasmon resonance, co-localization, CD98 knockdown, internalization assay Chemistry & biology Medium 25641165
2000 Transformation of BALB3T3 fibroblasts by CD98hc (SLC3A2) overexpression requires disulfide-linked association with CD98 light chain via Cys103 of the heavy chain; C103S mutation abolishes both light chain association and transformation activity, while C325S retains both. Stable transfection of wild-type and cysteine mutant CD98hc, immunoprecipitation for heterodimer detection, soft-agar colony formation, xenograft tumor assay International journal of cancer High 10897033

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). The Journal of biological chemistry 940 9726963
1998 Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 478 9751058
1999 Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. The Journal of biological chemistry 342 10391915
1999 4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer. The Journal of biological chemistry 292 9915839
1998 Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance. The Journal of biological chemistry 286 9829974
2019 Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. Nature 272 30867591
2000 The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier. Brain research 231 11011012
2004 CD98hc (SLC3A2) mediates integrin signaling. Proceedings of the National Academy of Sciences of the United States of America 222 15625115
2015 LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nature communications 170 25998567
2000 The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine. The Biochemical journal 160 10903140
2021 Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment. Frontiers in immunology 135 33953707
2017 Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells. Cell reports 116 29141216
2000 Distinct domains of CD98hc regulate integrins and amino acid transport. The Journal of biological chemistry 115 11121428
2022 Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT. Gut 103 35086885
2009 CD98hc facilitates B cell proliferation and adaptive humoral immunity. Nature immunology 98 19270713
2007 The structure of human 4F2hc ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane. The Journal of biological chemistry 95 17724034
1989 Structure, expression and regulation of the murine 4F2 heavy chain. Nucleic acids research 95 2928113
2012 Relation of LAT1/4F2hc expression with pathological grade, proliferation and angiogenesis in human gliomas. BMC clinical pathology 87 22373026
2021 Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Cell discovery 79 33758168
2015 Decreased mRNA expression for the two subunits of system xc(-), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: Evidence in support of the hypo-glutamatergic hypothesis of schizophrenia. Journal of psychiatric research 77 26540405
2014 Structural bases for the interaction and stabilization of the human amino acid transporter LAT2 with its ancillary protein 4F2hc. Proceedings of the National Academy of Sciences of the United States of America 75 24516142
1994 A new family of proteins (rBAT and 4F2hc) involved in cationic and zwitterionic amino acid transport: a tale of two proteins in search of a transport function. The Journal of experimental biology 72 7823016
2019 SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed. Autophagy 71 31276435
2004 CD98hc (SLC3A2) interaction with beta 1 integrins is required for transformation. The Journal of biological chemistry 71 15485886
2023 Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE-/-mice. Theranostics 70 37771765
1988 Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation. Molecular and cellular biology 67 3265470
1998 The amino acid transport system y+L/4F2hc is a heteromultimeric complex. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 66 9761775
2001 Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in liver tumor lesions of rat models. Journal of surgical oncology 65 11745822
2023 SLC3A2 promotes tumor-associated macrophage polarization through metabolic reprogramming in lung cancer. Cancer science 63 36793241
2016 Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung. Oncotarget 63 27626312
2007 CD98hc (SLC3A2) participates in fibronectin matrix assembly by mediating integrin signaling. The Journal of cell biology 63 17682053
2002 Expression and regulation of 4F2hc and hLAT1 in human trophoblasts. American journal of physiology. Cell physiology 62 11742812
2007 CD98hc (SLC3A2) interaction with the integrin beta subunit cytoplasmic domain mediates adhesive signaling. The Journal of biological chemistry 59 17597067
2020 TMT-based quantitative proteomics reveals suppression of SLC3A2 and ATP1A3 expression contributes to the inhibitory role of acupuncture on airway inflammation in an OVA-induced mouse asthma model. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 58 33341053
2023 CD98hc is a target for brain delivery of biotherapeutics. Nature communications 57 37598178
1999 Cloning and expression of a b(0,+)-like amino acid transporter functioning as a heterodimer with 4F2hc instead of rBAT. A new candidate gene for cystinuria. The Journal of biological chemistry 55 10506149
2016 Amino Acid Transport Associated to Cluster of Differentiation 98 Heavy Chain (CD98hc) Is at the Cross-road of Oxidative Stress and Amino Acid Availability. The Journal of biological chemistry 54 26945935
2013 CD98hc (SLC3A2) drives integrin-dependent renal cancer cell behavior. Molecular cancer 54 24359579
2012 Discovery of SLC3A2 cell membrane protein as a potential gastric cancer biomarker: implications in molecular imaging. Journal of proteome research 53 23116296
2004 Expression of L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in oral squamous cell carcinoma and its precusor lesions. Anticancer research 52 15274339
2017 Essential Roles of L-Type Amino Acid Transporter 1 in Syncytiotrophoblast Development by Presenting Fusogenic 4F2hc. Molecular and cellular biology 51 28320871
2014 CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction. Cancer research 50 25267066
2023 Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs. Cell chemical biology 48 37890480
2021 Plasmodium vivax binds host CD98hc (SLC3A2) to enter immature red blood cells. Nature microbiology 46 34294905
2023 Targeting N-glycosylation of 4F2hc mediated by glycosyltransferase B3GNT3 sensitizes ferroptosis of pancreatic ductal adenocarcinoma. Cell death and differentiation 45 37479744
2024 Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization. Cancer letters 43 38360142
2019 CD98hc (SLC3A2) sustains amino acid and nucleotide availability for cell cycle progression. Scientific reports 43 31575908
2011 Genistein, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside induce cytochrome P450 4F2 expression through an AMP-activated protein kinase-dependent pathway. The Journal of pharmacology and experimental therapeutics 42 21205922
2004 Lysophosphatidylcholine enhances cytokine production of endothelial cells via induction of L-type amino acid transporter 1 and cell surface antigen 4F2. Arteriosclerosis, thrombosis, and vascular biology 42 15178563
2000 Transformation of BALB3T3 cells caused by over-expression of rat CD98 heavy chain (HC) requires its association with light chain: mis-sense mutation in a cysteine residue of CD98HC eliminates its transforming activity. International journal of cancer 42 10897033
2018 ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2. Chemotherapy 41 30481785
2001 Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains. The Biochemical journal 41 11311135
2000 Differential influence of the 4F2 heavy chain and the protein related to b(0,+) amino acid transport on substrate affinity of the heteromeric b(0,+) amino acid transporter. The Journal of biological chemistry 41 10799513
1997 Expression of the surface antigen 4F2hc affects system-L-like neutral-amino-acid-transport activity in mammalian cells. The Biochemical journal 41 9182715
1991 Post-transcriptional regulation of the transferrin receptor and 4F2 antigen heavy chain mRNA during growth activation of spleen cells. European journal of biochemistry 38 1722457
2020 Co-Expression Effect of SLC7A5/SLC3A2 to Predict Response to Endocrine Therapy in Oestrogen-Receptor-Positive Breast Cancer. International journal of molecular sciences 37 32093034
2017 SLC3A2 is upregulated in human osteosarcoma and promotes tumor growth through the PI3K/Akt signaling pathway. Oncology reports 37 28350098
2009 CD98hc (SLC3A2), a novel marker in renal cell cancer. European journal of clinical investigation 37 19292886
2025 Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution. Nature communications 36 39979268
2006 Regulation of human cytochrome P450 4F2 expression by sterol regulatory element-binding protein and lovastatin. The Journal of biological chemistry 36 17142457
2018 Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway. Nature communications 35 30451822
2013 4F2hc-silencing impairs tumorigenicity of HeLa cells via modulation of galectin-3 and β-catenin signaling, and MMP-2 expression. Biochimica et biophysica acta 35 23651923
2011 4F2hc stabilizes GLUT1 protein and increases glucose transport activity. American journal of physiology. Cell physiology 35 21270293
2022 The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex: Physiological and pathophysiological implications. Basic & clinical pharmacology & toxicology 34 36460306
2018 Dual Targeting of ERBB2/ERBB3 for the Treatment of SLC3A2-NRG1-Mediated Lung Cancer. Molecular cancer therapeutics 34 29959202
2022 Linezolid Metabolism Is Catalyzed by Cytochrome P450 2J2, 4F2, and 1B1. Drug metabolism and disposition: the biological fate of chemicals 32 35042700
2022 SLC3A2 inhibits ferroptosis in laryngeal carcinoma via mTOR pathway. Hereditas 32 35057861
2013 CD98hc (SLC3A2) regulation of skin homeostasis wanes with age. The Journal of experimental medicine 32 23296466
1990 Relationship of 4F2 antigen with local growth and metastatic potential of squamous cell carcinoma of the larynx. Cancer 32 2208000
2020 Molecular mapping of transmembrane mechanotransduction through the β1 integrin-CD98hc-TRPV4 axis. Journal of cell science 31 32989042
2018 Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma. Human pathology 28 30300664
2021 Immunotherapy using IgE or CAR T cells for cancers expressing the tumor antigen SLC3A2. Journal for immunotherapy of cancer 27 34112739
2009 Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells. The Journal of clinical endocrinology and metabolism 26 19808856
2018 Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids. Journal of the American Society of Nephrology : JASN 25 29610403
2018 SLC3A2 is a novel endoplasmic reticulum stress-related signaling protein that regulates the unfolded protein response and apoptosis. PloS one 25 30592731
2023 Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia. Virologica Sinica 24 37690733
2022 N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98). Scientific reports 24 36028562
2020 Development of a high affinity Anticalin® directed against human CD98hc for theranostic applications. Theranostics 24 32089738
2020 The Heavy Chain 4F2hc Modulates the Substrate Affinity and Specificity of the Light Chains LAT1 and LAT2. International journal of molecular sciences 24 33066406
2015 Membrane protein 4F2/CD98 is a cell surface receptor involved in the internalization and trafficking of human β-Defensin 3 in epithelial cells. Chemistry & biology 24 25641165
2011 Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors. Oncology reports 23 21750865
2024 Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2. Cellular and molecular life sciences : CMLS 22 39079969
2021 Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1. Oncogene 21 34743207
2022 Characterizing the role of SLC3A2 in the molecular landscape and immune microenvironment across human tumors. Frontiers in molecular biosciences 20 35992269
1995 Identification of fusion regulatory protein (FRP)-1/4F2 related molecules: cytoskeletal proteins are associated with FRP-1 molecules that regulate multinucleated giant cell formation of monocytes and HIV-induced cell fusion. Cell structure and function 19 8825068
2022 Validation of CD98hc as a Therapeutic Target for a Combination of Radiation and Immunotherapies in Head and Neck Squamous Cell Carcinoma. Cancers 18 35406454
2015 Aryl hydrocarbon receptor-dependent up-regulation of the heterodimeric amino acid transporter LAT1 (SLC7A5)/CD98hc (SLC3A2) by diesel exhaust particle extract in human bronchial epithelial cells. Toxicology and applied pharmacology 18 26621329
2025 JMJD6 K375 acetylation restrains lung cancer progression by enhancing METTL14/m6A/SLC3A2 axis mediated cell ferroptosis. Journal of translational medicine 17 40011892
2024 Empagliflozin drives ferroptosis in anoikis-resistant cells by activating miR-128-3p dependent pathway and inhibiting CD98hc in breast cancer. Free radical biology & medicine 17 38734268
2024 FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation. Nature communications 17 38755144
2022 Polarity protein SCRIB interacts with SLC3A2 to regulate proliferation and tamoxifen resistance in ER+ breast cancer. Communications biology 17 35501367
2022 HCMV-miR-US33-5p promotes apoptosis of aortic vascular smooth muscle cells by targeting EPAS1/SLC3A2 pathway. Cellular & molecular biology letters 17 35596131
2018 The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells. Oncotarget 17 29805737
2021 Metabolic adaptations to hypoxia in the neonatal mouse forebrain can occur independently of the transporters SLC7A5 and SLC3A2. Scientific reports 16 33907288
2011 Extracellular domain of CD98hc is required for early murine development. Cell & bioscience 16 21711689
2024 Identification and validation of RNA-binding protein SLC3A2 regulates melanocyte ferroptosis in vitiligo by integrated analysis of single-cell and bulk RNA-sequencing. BMC genomics 15 38438962
2022 Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer. Journal of experimental & clinical cancer research : CR 15 35317825
1998 Cloning and functional expression of a cDNA from rat jejunal epithelium encoding a protein (4F2hc) with system y+L amino acid transport activity. The Biochemical journal 15 9480885
2022 SLC3A2 and SLC7A2 Mediate the Exogenous Putrescine-Induced Adipocyte Differentiation. Molecules and cells 14 36572564
2019 Volta Phase Plate Cryo-EM Structure of the Human Heterodimeric Amino Acid Transporter 4F2hc-LAT2. International journal of molecular sciences 14 30795505

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