SLC3A2

UniProt ID: P08195
Organism: Homo sapiens
Review Status: COMPLETE
πŸ“ Provide Detailed Feedback

Gene Description

SLC3A2 (also known as 4F2hc, CD98 heavy chain) encodes the essential heavy chain subunit of heteromeric amino acid transporters (HATs). It functions as a type II transmembrane glycoprotein that forms disulfide-linked heterodimers with various SLC7 family light chain transporters (SLC7A5/LAT1, SLC7A6/y+LAT2, SLC7A7/y+LAT1, SLC7A8/LAT2, SLC7A10/Asc-1, SLC7A11/xCT). SLC3A2 acts as a chaperone essential for the trafficking, plasma membrane localization, and stability of these light chain partners, which provide the actual catalytic transport activity. The SLC3A2/SLC7A5 (LAT1) complex mediates Na+-independent transport of large neutral amino acids (leucine, phenylalanine, tryptophan, tyrosine) and is critical for mTORC1 activation. The SLC3A2/SLC7A11 (xCT) complex functions as the cystine/glutamate antiporter system xc-, important for glutathione synthesis and protection against ferroptosis. SLC3A2 also modulates integrin signaling independently of its transport functions. High-resolution cryo-EM structures have elucidated the molecular architecture of these complexes.

Existing Annotations Review

GO Term Evidence Action Reason
GO:1903801 L-leucine import across plasma membrane
IBA
GO_REF:0000033
ACCEPT
Summary: SLC3A2 partners with LAT1 (SLC7A5) and LAT2 (SLC7A8) to form heterodimeric amino acid transporters that mediate leucine import. This is a core function well-supported by phylogenetic analysis and experimental evidence from multiple studies (PMID:9751058, PMID:10574970, PMID:11557028, PMID:30867591).
Reason: L-leucine import is a well-established core function of SLC3A2-containing heterodimeric transporters. The IBA annotation is consistent with extensive experimental evidence.
Supporting Evidence:
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
file:human/SLC3A2/SLC3A2-deep-research-falcon.md
model: Edison Scientific Literature
GO:0015823 phenylalanine transport
IBA
GO_REF:0000033
ACCEPT
Summary: Phenylalanine is a well-established substrate for the LAT1-4F2hc and LAT2-4F2hc complexes. Multiple experimental studies confirm phenylalanine transport activity.
Reason: Phenylalanine transport is a core function of SLC3A2-containing HAT complexes, supported by phylogenetic and experimental evidence.
Supporting Evidence:
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0016323 basolateral plasma membrane
IBA
GO_REF:0000033
ACCEPT
Summary: SLC3A2 localizes to both apical and basolateral plasma membranes in polarized epithelial cells. Basolateral localization is well-documented for kidney and intestinal epithelia where it partners with LAT2.
Reason: Basolateral localization is supported by phylogenetic inference and consistent with experimental data from polarized epithelial cells (PMID:31791063).
Supporting Evidence:
PMID:31791063
Quantitative Protein Expression in the Human Retinal Pigment Epithelium: Comparison Between Apical and Basolateral Plasma Membranes With Emphasis on Transporters.
GO:0016324 apical plasma membrane
IBA
GO_REF:0000033
ACCEPT
Summary: SLC3A2 is found at the apical membrane of syncytiotrophoblasts and other polarized cells. Apical localization depends on the light chain partner.
Reason: Apical localization is well-documented in multiple cell types and tissues.
Supporting Evidence:
PMID:31791063
Quantitative Protein Expression in the Human Retinal Pigment Epithelium: Comparison Between Apical and Basolateral Plasma Membranes With Emphasis on Transporters.
GO:1904273 L-alanine import across plasma membrane
IBA
GO_REF:0000033
ACCEPT
Summary: L-alanine transport is mediated by the LAT2-4F2hc complex. LAT2 has broader specificity for small and large neutral amino acids compared to LAT1.
Reason: L-alanine import is established function of the SLC3A2/LAT2 complex based on experimental evidence (PMID:10391915).
Supporting Evidence:
PMID:10391915
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.
GO:0001618 virus receptor activity
IEA
GO_REF:0000043
KEEP AS NON CORE
Summary: SLC3A2/CD98 has been demonstrated to act as a receptor for Plasmodium vivax entry into immature red blood cells (PMID:34294905) and facilitates hepatitis C virus entry (PMID:30341327). This represents a secondary function exploited by pathogens.
Reason: While virus/pathogen receptor activity is experimentally validated, it represents exploitation of SLC3A2 by pathogens rather than a core physiological function.
Supporting Evidence:
PMID:34294905
2021 Jul 22. Plasmodium vivax binds host CD98hc (SLC3A2) to enter immature red blood cells.
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation.
GO:0005765 lysosomal membrane
IEA
GO_REF:0000044
ACCEPT
Summary: SLC3A2 is recruited to lysosomes by LAPTM4B where the LAT1-4F2hc complex promotes leucine uptake into lysosomes, facilitating mTORC1 activation (PMID:25998567).
Reason: Lysosomal localization is experimentally verified and functionally important for mTORC1 signaling.
Supporting Evidence:
PMID:25998567
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.
GO:0005886 plasma membrane
IEA
GO_REF:0000120
ACCEPT
Summary: Plasma membrane localization is the primary site of SLC3A2 function where it forms heterodimeric transporters. Extensively validated by experimental studies and structural biology.
Reason: Core localization supported by cryo-EM structures and numerous functional studies.
Supporting Evidence:
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
GO:0005975 carbohydrate metabolic process
IEA
GO_REF:0000002
REMOVE
Summary: This annotation is based on the glycoside hydrolase domain annotation in InterPro. However, SLC3A2 does NOT function as a glycoside hydrolase - it functions as an amino acid transporter chaperone. The alpha-amylase-like fold is structural but not catalytically active. This is an erroneous electronic annotation.
Reason: SLC3A2 does not participate in carbohydrate metabolism. While it contains an alpha-amylase-like domain fold, this domain has been repurposed for structural roles in membrane association and heterodimer formation, not carbohydrate hydrolysis. Recent structural studies (PMID:30867591, PMID:33298890) confirm this domain mediates protein-protein interactions, not enzymatic activity.
Supporting Evidence:
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
GO:0006865 amino acid transport
IEA
GO_REF:0000120
ACCEPT
Summary: Amino acid transport is the primary function of SLC3A2 when complexed with SLC7 family light chains. This is a core function.
Reason: Core function well-established by extensive experimental evidence.
GO:0015823 phenylalanine transport
IEA
GO_REF:0000117
ACCEPT
Summary: Duplicate of IBA annotation above. Phenylalanine transport is a well-established substrate for LAT1 and LAT2 complexes with SLC3A2.
Reason: Core function - phenylalanine is a well-characterized substrate.
GO:0015827 tryptophan transport
IEA
GO_REF:0000117
ACCEPT
Summary: Tryptophan is a substrate for LAT1-4F2hc and LAT2-4F2hc complexes. Experimentally verified in multiple studies.
Reason: Core function supported by experimental evidence (PMID:10574970, PMID:11557028, PMID:11564694).
Supporting Evidence:
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
GO:0016020 membrane
IEA
GO_REF:0000117
ACCEPT
Summary: Generic membrane annotation. SLC3A2 is a type II transmembrane protein - more specific annotations (plasma membrane, lysosomal membrane) are also present.
Reason: Valid but general annotation. More specific CC annotations are preferable.
GO:0016323 basolateral plasma membrane
IEA
GO_REF:0000044
ACCEPT
Summary: Duplicate of IBA annotation. Valid localization for SLC3A2 in polarized epithelial cells.
Reason: Well-supported localization.
GO:0016324 apical plasma membrane
IEA
GO_REF:0000044
ACCEPT
Summary: Duplicate of IBA annotation. Valid localization.
Reason: Well-supported localization in polarized cells.
GO:0042470 melanosome
IEA
GO_REF:0000044
KEEP AS NON CORE
Summary: SLC3A2 was identified in melanosome proteomics studies. This likely reflects amino acid transporter activity in these specialized organelles.
Reason: Melanosome localization is based on proteomics data but not a core localization.
GO:0046982 protein heterodimerization activity
IEA
GO_REF:0000117
ACCEPT
Summary: Heterodimerization with SLC7 family members is THE core molecular function of SLC3A2. It forms obligate disulfide-linked heterodimers with light chains.
Reason: Core molecular function. SLC3A2 forms heterodimers with at least 6 different SLC7 family members (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10, SLC7A11).
Supporting Evidence:
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
PMID:34880232
Molecular basis for redox control by the human cystine/glutamate antiporter system xc().
GO:0070161 anchoring junction
IEA
GO_REF:0000044
KEEP AS NON CORE
Summary: SLC3A2 localizes to cell-cell adhesion sites and interacts with integrins. This relates to its integrin signaling modulation function.
Reason: Junction localization is secondary to its transport function.
GO:0005515 protein binding
IPI
PMID:20374249
The pathogenic E. coli type III effector EspZ interacts with...
MARK AS OVER ANNOTATED
Summary: This annotation is based on interaction with E. coli EspZ effector protein. Represents pathogen exploitation of SLC3A2.
Reason: Generic protein binding annotation - more specific MF terms exist for the relevant interactions (heterodimerization with SLC7 proteins).
Supporting Evidence:
PMID:20374249
The pathogenic E. coli type III effector EspZ interacts with host CD98 and facilitates host cell prosurvival signalling.
GO:0005515 protein binding
IPI
PMID:28298427
Systematic protein-protein interaction mapping for clinicall...
MARK AS OVER ANNOTATED
Summary: Interaction with GPR37. Represents a GPCR interaction study.
Reason: Generic protein binding - should be replaced with more specific term if functional significance is established.
Supporting Evidence:
PMID:28298427
Systematic protein-protein interaction mapping for clinically relevant human GPCRs.
GO:0005515 protein binding
IPI
PMID:30867591
Structure of the human LAT1-4F2hc heteromeric amino acid tra...
MODIFY
Summary: Structural study demonstrating interaction with SLC7A5/LAT1.
Reason: This is heterodimerization with SLC7A5 - should use GO:0046982 protein heterodimerization activity, which is also present.
Supporting Evidence:
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
GO:0005515 protein binding
IPI
PMID:34880232
Molecular basis for redox control by the human cystine/gluta...
MODIFY
Summary: Structural study of xCT/SLC7A11 interaction with SLC3A2.
Reason: This is heterodimerization - more specific term exists.
Supporting Evidence:
PMID:34880232
Molecular basis for redox control by the human cystine/glutamate antiporter system xc().
GO:0005515 protein binding
IPI
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human ce...
MARK AS OVER ANNOTATED
Summary: OpenCell high-throughput study detecting LAT1 interaction.
Reason: Generic protein binding from HT study - heterodimerization terms are more informative.
Supporting Evidence:
PMID:35271311
2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding
IPI
PMID:40355756
The solute carrier superfamily interactome.
MARK AS OVER ANNOTATED
Summary: SLC transporter interactome study.
Reason: Generic protein binding - specific interactions should use more specific terms.
Supporting Evidence:
PMID:40355756
2025 May 12. The solute carrier superfamily interactome.
GO:0005515 protein binding
IPI
PMID:9878049
Amino acid transport of y+L-type by heterodimers of 4F2hc/CD...
MODIFY
Summary: Early study establishing y+LAT interaction with 4F2hc.
Reason: This demonstrates heterodimerization with SLC7A7.
Supporting Evidence:
PMID:9878049
Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.
GO:0015820 L-leucine transport
IEA
GO_REF:0000107
ACCEPT
Summary: Leucine transport is a core function of SLC3A2-containing complexes, especially LAT1-4F2hc. Critical for mTORC1 signaling.
Reason: Well-established core function.
GO:0042803 protein homodimerization activity
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Crystal structure of the SLC3A2 ectodomain (PMID:17724034) shows it can form homodimers, though heterodimer formation with SLC7 proteins is its primary functional form.
Reason: Homodimerization has been structurally observed but heterodimerization with SLC7 light chains is the functional form.
Supporting Evidence:
GO:0043025 neuronal cell body
IEA
GO_REF:0000107
ACCEPT
Summary: Neuronal localization transferred from mouse ortholog. SLC3A2/LAT1 is expressed in neurons and at the blood-brain barrier.
Reason: Neuronal expression is well-documented for amino acid transport functions.
GO:0044225 apical pole of neuron
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Specific neuronal localization from ortholog transfer.
Reason: Valid but cell-type specific localization.
GO:0045202 synapse
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: Synaptic localization likely reflects amino acid transporter function at synapses. Asc-1/CD98hc transports D-serine and glycine, key NMDAR co-agonists.
Reason: Synaptic localization is relevant for neuromodulator transport.
GO:0005886 plasma membrane
IDA
GO_REF:0000052
ACCEPT
Summary: HPA immunofluorescence data confirming plasma membrane localization.
Reason: Core localization validated by immunofluorescence.
GO:0089718 amino acid import across plasma membrane
NAS
PMID:10734121
Identification and characterization of a Na(+)-independent n...
ACCEPT
Summary: Small neutral amino acid transporter asc-2/SLC7A10 association with 4F2hc for amino acid import.
Reason: Amino acid import is a core function of SLC3A2-containing transporters.
Supporting Evidence:
PMID:10734121
Identification and characterization of a Na(+)-independent neutral amino acid transporter that associates with the 4F2 heavy chain and exhibits substrate selectivity for small neutral D- and L-amino acids.
GO:0089718 amino acid import across plasma membrane
IDA
PMID:10903140
The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediat...
ACCEPT
Summary: Demonstrates arginine efflux in exchange with glutamine via y+LAT2/4F2hc.
Reason: Core function - amino acid exchange across plasma membrane.
Supporting Evidence:
PMID:10903140
The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine.
GO:0089718 amino acid import across plasma membrane
IDA
PMID:11417227
Identification and characterisation of human xCT that co-exp...
ACCEPT
Summary: Key paper identifying xCT/SLC7A11 as the partner of 4F2hc for system xc- activity (cystine/glutamate antiporter). Cystine import is critical.
Reason: Core function - cystine import is essential for glutathione synthesis.
Supporting Evidence:
PMID:11417227
Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-.
GO:0089718 amino acid import across plasma membrane
IDA
PMID:30867591
Structure of the human LAT1-4F2hc heteromeric amino acid tra...
ACCEPT
Summary: Cryo-EM structure of LAT1-4F2hc complex with functional characterization.
Reason: Core function supported by structural and functional studies.
Supporting Evidence:
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
GO:0089718 amino acid import across plasma membrane
IDA
PMID:33758168
Mechanism of substrate transport and inhibition of the human...
ACCEPT
Summary: Mechanism of substrate transport and inhibition of LAT1-4F2hc.
Reason: Core function with mechanistic detail.
Supporting Evidence:
PMID:33758168
Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter.
GO:0089718 amino acid import across plasma membrane
IDA
PMID:9878049
Amino acid transport of y+L-type by heterodimers of 4F2hc/CD...
ACCEPT
Summary: Early characterization of y+L-type transport by 4F2hc heterodimers.
Reason: Foundational paper establishing amino acid transport function.
Supporting Evidence:
PMID:9878049
Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family.
GO:0150104 transport across blood-brain barrier
NAS
PMID:27912058
Impaired Amino Acid Transport at the Blood Brain Barrier Is ...
KEEP AS NON CORE
Summary: LAT1-4F2hc at the blood-brain barrier transports essential amino acids. Impaired transport is linked to autism spectrum disorder.
Reason: Tissue-specific function reflecting amino acid transport at BBB.
Supporting Evidence:
PMID:27912058
Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.
GO:0046982 protein heterodimerization activity
IDA
PMID:33298890
Structural insight into the substrate recognition and transp...
ACCEPT
Summary: Cryo-EM structure of LAT2-4F2hc complex demonstrating heterodimer architecture.
Reason: Core molecular function directly demonstrated by structural biology.
Supporting Evidence:
PMID:33298890
Structural insight into the substrate recognition and transport mechanism of the human LAT2-4F2hc complex.
GO:0140272 exogenous protein binding
IDA
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2...
KEEP AS NON CORE
Summary: Binding to hepatitis C virus envelope proteins facilitating viral entry.
Reason: Pathogen exploitation of SLC3A2 - not a core function.
Supporting Evidence:
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation.
GO:0140272 exogenous protein binding
IDA
PMID:34294905
Plasmodium vivax binds host CD98hc (SLC3A2) to enter immatur...
KEEP AS NON CORE
Summary: CD98hc serves as a receptor for Plasmodium vivax entry into reticulocytes.
Reason: Pathogen receptor function - exploited by malaria parasite.
Supporting Evidence:
PMID:34294905
2021 Jul 22. Plasmodium vivax binds host CD98hc (SLC3A2) to enter immature red blood cells.
GO:0005515 protein binding
IPI
PMID:33298890
Structural insight into the substrate recognition and transp...
MODIFY
Summary: Interaction with SLC7A8/LAT2 demonstrated structurally.
Reason: Heterodimerization - more specific term available.
Supporting Evidence:
PMID:33298890
Structural insight into the substrate recognition and transport mechanism of the human LAT2-4F2hc complex.
GO:0005886 plasma membrane
IDA
PMID:11311135
Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 ...
ACCEPT
Summary: Study showing domain requirements for 4F2hc association with LAT1, LAT2, y+LAT2.
Reason: Well-established core localization.
Supporting Evidence:
PMID:11311135
Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains.
GO:0005886 plasma membrane
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: LAT1 characterization showing plasma membrane localization.
Reason: Core localization.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0005886 plasma membrane
IDA
PMID:12225859
Characterization of the system L amino acid transporter in T...
ACCEPT
Summary: System L amino acid transporter in T24 bladder carcinoma cells.
Reason: Core localization.
Supporting Evidence:
PMID:12225859
Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells.
GO:0015818 isoleucine transport
IDA
PMID:11311135
Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 ...
ACCEPT
Summary: Isoleucine is transported by LAT1-4F2hc and LAT2-4F2hc complexes.
Reason: Core function - isoleucine is a branched-chain amino acid substrate.
Supporting Evidence:
PMID:11311135
Association of 4F2hc with light chains LAT1, LAT2 or y+LAT2 requires different domains.
GO:0015818 isoleucine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: LAT1 characterization showing isoleucine transport.
Reason: Core function.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0015820 L-leucine transport
IDA
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid tra...
ACCEPT
Summary: LAT2 characterization showing leucine transport.
Reason: Core function - leucine is essential for mTORC1 signaling.
Supporting Evidence:
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
GO:0015820 L-leucine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: LAT1 characterization in tumor cells.
Reason: Core function.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0015820 L-leucine transport
IDA
PMID:11564694
Thyroid hormone transport by the heterodimeric human system ...
ACCEPT
Summary: System L transporter characterization.
Reason: Core function.
Supporting Evidence:
PMID:11564694
Thyroid hormone transport by the heterodimeric human system L amino acid transporter.
GO:0015820 L-leucine transport
IDA
PMID:12225859
Characterization of the system L amino acid transporter in T...
ACCEPT
Summary: T24 bladder carcinoma cell characterization.
Reason: Core function.
Supporting Evidence:
PMID:12225859
Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells.
GO:0015820 L-leucine transport
IDA
PMID:15769744
Identification of stereoselective transporters for S-nitroso...
ACCEPT
Summary: S-nitroso-L-cysteine transport via LAT1/LAT2.
Reason: Core function with additional substrate discovery.
Supporting Evidence:
PMID:15769744
2005 Mar 15. Identification of stereoselective transporters for S-nitroso-L-cysteine: role of LAT1 and LAT2 in biological activity of S-nitrosothiols.
GO:0015820 L-leucine transport
IDA
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and membe...
ACCEPT
Summary: Foundational paper establishing 4F2hc permease heterodimer transport.
Reason: Core function - seminal paper.
Supporting Evidence:
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.
GO:0015821 methionine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: LAT1 transports methionine, which is important for methylation reactions.
Reason: Core function.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0015823 phenylalanine transport
IDA
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid tra...
ACCEPT
Summary: LAT2 phenylalanine transport characterization.
Reason: Core function.
Supporting Evidence:
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
GO:0015823 phenylalanine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: LAT1 phenylalanine transport.
Reason: Core function.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0015823 phenylalanine transport
IDA
PMID:11564694
Thyroid hormone transport by the heterodimeric human system ...
ACCEPT
Summary: System L transporter phenylalanine transport.
Reason: Core function.
Supporting Evidence:
PMID:11564694
Thyroid hormone transport by the heterodimeric human system L amino acid transporter.
GO:0015823 phenylalanine transport
IDA
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and membe...
ACCEPT
Summary: Foundational study on 4F2hc heterodimer transport.
Reason: Core function.
Supporting Evidence:
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.
GO:0015824 proline transport
IDA
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid tra...
ACCEPT
Summary: Proline transport by LAT2-4F2hc.
Reason: LAT2 has broader substrate specificity including proline.
Supporting Evidence:
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
GO:0015827 tryptophan transport
IDA
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid tra...
ACCEPT
Summary: Tryptophan transport by LAT2.
Reason: Core function.
Supporting Evidence:
PMID:10574970
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
GO:0015827 tryptophan transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: Tryptophan transport by LAT1.
Reason: Core function - large neutral aromatic amino acid.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0015827 tryptophan transport
IDA
PMID:11564694
Thyroid hormone transport by the heterodimeric human system ...
ACCEPT
Summary: System L tryptophan transport.
Reason: Core function.
Supporting Evidence:
PMID:11564694
Thyroid hormone transport by the heterodimeric human system L amino acid transporter.
GO:0015828 tyrosine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: Tyrosine transport by LAT1.
Reason: Core function - aromatic amino acid.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0015828 tyrosine transport
IDA
PMID:11564694
Thyroid hormone transport by the heterodimeric human system ...
ACCEPT
Summary: System L tyrosine transport.
Reason: Core function.
Supporting Evidence:
PMID:11564694
Thyroid hormone transport by the heterodimeric human system L amino acid transporter.
GO:0015829 valine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: Valine transport by LAT1.
Reason: Core function - branched-chain amino acid.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:0070327 thyroid hormone transport
IDA
PMID:11564694
Thyroid hormone transport by the heterodimeric human system ...
KEEP AS NON CORE
Summary: LAT1 and LAT2 transport thyroid hormones (T3, T4) which structurally resemble tyrosine.
Reason: Valid function but secondary to amino acid transport - thyroid hormones are structurally similar to tyrosine.
Supporting Evidence:
PMID:11564694
Thyroid hormone transport by the heterodimeric human system L amino acid transporter.
GO:1902024 L-histidine transport
IDA
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterizati...
ACCEPT
Summary: Histidine transport by LAT1.
Reason: Core function.
Supporting Evidence:
PMID:11557028
Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines.
GO:1902024 L-histidine transport
IDA
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and membe...
ACCEPT
Summary: Histidine transport by 4F2hc heterodimers.
Reason: Core function.
Supporting Evidence:
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.
GO:0005515 protein binding
IPI
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2...
KEEP AS NON CORE
Summary: Interaction with HCV E2 envelope protein.
Reason: Pathogen interaction - exogenous protein binding term more appropriate.
Supporting Evidence:
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation.
GO:0015820 L-leucine transport
IMP
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2...
ACCEPT
Summary: Leucine transport enhanced during HCV infection promoting mTORC1 signaling.
Reason: Core function demonstrated by mutant phenotype.
Supporting Evidence:
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation.
GO:0046718 symbiont entry into host cell
IMP
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2...
KEEP AS NON CORE
Summary: SLC3A2 facilitates HCV entry into host cells.
Reason: Pathogen exploitation function - not a normal physiological role.
Supporting Evidence:
PMID:30341327
Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation.
GO:0005886 plasma membrane
IDA
PMID:28112518
LC-MS/MS Based Quantitation of ABC and SLC Transporter Prote...
ACCEPT
Summary: Mass spectrometry quantitation in retinal pigment epithelial cells.
Reason: Core localization.
Supporting Evidence:
PMID:28112518
Epub 2017 Feb 14. LC-MS/MS Based Quantitation of ABC and SLC Transporter Proteins in Plasma Membranes of Cultured Primary Human Retinal Pigment Epithelium Cells and Immortalized ARPE19 Cell Line.
GO:0015180 L-alanine transmembrane transporter activity
IGI
PMID:10391915
Identification of a membrane protein, LAT-2, that Co-express...
ACCEPT
Summary: LAT2-4F2hc complex transports alanine - shown by co-expression with SLC7A8.
Reason: Core molecular function demonstrated by genetic interaction.
Supporting Evidence:
PMID:10391915
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.
GO:0015190 L-leucine transmembrane transporter activity
IGI
PMID:10391915
Identification of a membrane protein, LAT-2, that Co-express...
ACCEPT
Summary: LAT2-4F2hc leucine transporter activity.
Reason: Core molecular function.
Supporting Evidence:
PMID:10391915
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.
GO:1903801 L-leucine import across plasma membrane
IGI
PMID:10391915
Identification of a membrane protein, LAT-2, that Co-express...
ACCEPT
Summary: Leucine import by LAT2-4F2hc.
Reason: Core function.
Supporting Evidence:
PMID:10391915
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.
GO:1904273 L-alanine import across plasma membrane
IGI
PMID:10391915
Identification of a membrane protein, LAT-2, that Co-express...
ACCEPT
Summary: Alanine import by LAT2-4F2hc.
Reason: Core function.
Supporting Evidence:
PMID:10391915
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.
GO:0009925 basal plasma membrane
ISS
GO_REF:0000024
ACCEPT
Summary: Basal membrane localization inferred from sequence similarity.
Reason: Valid localization consistent with basolateral distribution.
GO:0016323 basolateral plasma membrane
IDA
PMID:31791063
Quantitative Protein Expression in the Human Retinal Pigment...
ACCEPT
Summary: Direct experimental evidence for basolateral localization in RPE cells.
Reason: Core localization validated experimentally.
Supporting Evidence:
PMID:31791063
Quantitative Protein Expression in the Human Retinal Pigment Epithelium: Comparison Between Apical and Basolateral Plasma Membranes With Emphasis on Transporters.
GO:0016324 apical plasma membrane
ISS
GO_REF:0000024
ACCEPT
Summary: Apical localization from sequence similarity.
Reason: Valid localization.
GO:0016324 apical plasma membrane
IDA
PMID:31791063
Quantitative Protein Expression in the Human Retinal Pigment...
ACCEPT
Summary: Direct evidence for apical localization in RPE cells.
Reason: Core localization validated experimentally.
Supporting Evidence:
PMID:31791063
Quantitative Protein Expression in the Human Retinal Pigment Epithelium: Comparison Between Apical and Basolateral Plasma Membranes With Emphasis on Transporters.
GO:0015173 aromatic amino acid transmembrane transporter activity
IGI
PMID:15589117
Human LAT1 single nucleotide polymorphism N230K does not alt...
ACCEPT
Summary: LAT1-4F2hc aromatic amino acid transporter activity demonstrated.
Reason: Core molecular function - LAT1 preferentially transports large neutral aromatics.
Supporting Evidence:
PMID:15589117
Human LAT1 single nucleotide polymorphism N230K does not alter phenylalanine transport.
GO:0015823 phenylalanine transport
IGI
PMID:15589117
Human LAT1 single nucleotide polymorphism N230K does not alt...
ACCEPT
Summary: Phenylalanine transport by LAT1-4F2hc.
Reason: Core function.
Supporting Evidence:
PMID:15589117
Human LAT1 single nucleotide polymorphism N230K does not alter phenylalanine transport.
GO:0015175 neutral L-amino acid transmembrane transporter activity
IGI
PMID:17197568
Ornithine transport via cationic amino acid transporter-1 is...
ACCEPT
Summary: Neutral amino acid transporter activity demonstrated for SLC3A2-containing complexes.
Reason: Core molecular function.
Supporting Evidence:
PMID:17197568
Ornithine transport via cationic amino acid transporter-1 is involved in ornithine cytotoxicity in retinal pigment epithelial cells.
GO:1903801 L-leucine import across plasma membrane
IGI
PMID:17197568
Ornithine transport via cationic amino acid transporter-1 is...
ACCEPT
Summary: Leucine import function.
Reason: Core function.
Supporting Evidence:
PMID:17197568
Ornithine transport via cationic amino acid transporter-1 is involved in ornithine cytotoxicity in retinal pigment epithelial cells.
GO:0005886 plasma membrane
IDA
PMID:23137377
Quantitative targeted absolute proteomic analysis of transpo...
ACCEPT
Summary: Quantitative proteomics in cerebral microvascular endothelial cells.
Reason: Core localization at blood-brain barrier.
Supporting Evidence:
PMID:23137377
Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model.
GO:1990184 amino acid transport complex
IDA
PMID:30867591
Structure of the human LAT1-4F2hc heteromeric amino acid tra...
ACCEPT
Summary: Cryo-EM structure directly demonstrating SLC3A2 as part of heteromeric amino acid transporter complex.
Reason: Core function - SLC3A2 is an obligate component of HAT complexes.
Supporting Evidence:
PMID:30867591
Mar 13. Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
GO:0045296 cadherin binding
HDA
PMID:25468996
E-cadherin interactome complexity and robustness resolved by...
KEEP AS NON CORE
Summary: High-throughput study identifying E-cadherin interactome. SLC3A2 localized to cell-cell junctions.
Reason: Secondary function related to cell adhesion role.
Supporting Evidence:
PMID:25468996
E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
GO:0005515 protein binding
IPI
PMID:25998567
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes...
ACCEPT
Summary: Interaction with LAPTM4B for lysosomal recruitment.
Reason: Functionally important interaction for mTORC1 activation.
Supporting Evidence:
PMID:25998567
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.
GO:0005886 plasma membrane
IDA
PMID:25998567
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes...
ACCEPT
Summary: Plasma membrane and lysosomal localization study.
Reason: Core localization.
Supporting Evidence:
PMID:25998567
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.
GO:0005515 protein binding
IPI
PMID:12270127
Molecular cloning and characterization of CT120, a novel mem...
KEEP AS NON CORE
Summary: Interaction with CT120/TLCD3A.
Reason: Minor interaction - function unclear.
Supporting Evidence:
PMID:12270127
Molecular cloning and characterization of CT120, a novel membrane-associated gene involved in amino acid transport and glutathione metabolism.
GO:0005886 plasma membrane
IDA
PMID:12270127
Molecular cloning and characterization of CT120, a novel mem...
ACCEPT
Summary: Plasma membrane localization.
Reason: Core localization.
Supporting Evidence:
PMID:12270127
Molecular cloning and characterization of CT120, a novel membrane-associated gene involved in amino acid transport and glutathione metabolism.
GO:0009986 cell surface
IDA
PMID:25063885
KSHV attachment and entry are dependent on Ξ±VΞ²3 integrin loc...
ACCEPT
Summary: Cell surface localization detected - relevant for pathogen binding.
Reason: Valid localization term.
Supporting Evidence:
PMID:25063885
2014 Jul 24. KSHV attachment and entry are dependent on Ξ±VΞ²3 integrin localized to specific cell surface microdomains and do not correlate with the presence of heparan sulfate.
GO:0009986 cell surface
HDA
PMID:19581412
Quantitative proteomics identifies a Dab2/integrin module re...
ACCEPT
Summary: Proteomics study on cell surface proteins.
Reason: Valid localization.
Supporting Evidence:
PMID:19581412
Jul 6. Quantitative proteomics identifies a Dab2/integrin module regulating cell migration.
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres...
KEEP AS NON CORE
Summary: Detected in prostatic exosomes by proteomics.
Reason: Secondary localization - exosomal presence common for membrane proteins.
Supporting Evidence:
PMID:23533145
2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0016020 membrane
HDA
PMID:19946888
Defining the membrane proteome of NK cells.
ACCEPT
Summary: NK cell membrane proteome.
Reason: Valid general localization.
Supporting Evidence:
PMID:19946888
Defining the membrane proteome of NK cells.
GO:0003723 RNA binding
HDA
PMID:22658674
Insights into RNA biology from an atlas of mammalian mRNA-bi...
MARK AS OVER ANNOTATED
Summary: High-throughput mRNA interactome study detected SLC3A2. This is likely non-specific or secondary.
Reason: SLC3A2 is a membrane transporter chaperone with no known RNA-related function. High-throughput RNA binding studies can capture non-specific associations. No structural or functional evidence supports RNA binding.
Supporting Evidence:
PMID:22658674
May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0070062 extracellular exosome
HDA
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multid...
KEEP AS NON CORE
Summary: Parotid gland exosome proteomics.
Reason: Secondary localization.
Supporting Evidence:
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos...
KEEP AS NON CORE
Summary: Urinary exosome proteomics.
Reason: Secondary localization.
Supporting Evidence:
PMID:19056867
2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes.
GO:0003725 double-stranded RNA binding
IDA
PMID:21266579
Raftlin is involved in the nucleocapture complex to induce p...
KEEP AS NON CORE
Summary: Study on raftlin involvement in poly(I:C)-mediated TLR3 activation found SLC3A2 in nucleocapture complex. This appears to be a specialized immunological context.
Reason: This is a specialized immune function in TLR3 signaling, not a core function of SLC3A2. The dsRNA binding may be indirect through complex formation.
Supporting Evidence:
PMID:21266579
2011 Jan 25. Raftlin is involved in the nucleocapture complex to induce poly(I:C)-mediated TLR3 activation.
GO:0043330 response to exogenous dsRNA
IMP
PMID:21266579
Raftlin is involved in the nucleocapture complex to induce p...
KEEP AS NON CORE
Summary: Involvement in TLR3 response to poly(I:C).
Reason: Specialized immune function, not core transporter role.
Supporting Evidence:
PMID:21266579
2011 Jan 25. Raftlin is involved in the nucleocapture complex to induce poly(I:C)-mediated TLR3 activation.
GO:0070062 extracellular exosome
HDA
PMID:20458337
MHC class II-associated proteins in B-cell exosomes and pote...
KEEP AS NON CORE
Summary: B-cell exosome proteomics.
Reason: Secondary localization.
Supporting Evidence:
PMID:20458337
2010 May 11. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-352191
ACCEPT
Summary: Reactome annotation for SLC7A8-mediated uptake with SLC3A2.
Reason: Core localization.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-352232
ACCEPT
Summary: Reactome annotation for SLC7A5:SLC3A2 transport.
Reason: Core localization.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-375131
ACCEPT
Summary: Basigin binding to CD98 complex at plasma membrane.
Reason: Valid localization.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-376200
ACCEPT
Summary: SLC7A10-mediated uptake with SLC3A2.
Reason: Core localization for Asc-1/4F2hc complex.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-378513
ACCEPT
Summary: SLC7A11-mediated cystine/glutamate exchange - system xc-.
Reason: Core localization for xCT/4F2hc (system xc-).
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-379415
ACCEPT
Summary: SLC7A7:SLC3A2 arginine/leucine exchange.
Reason: Core localization for y+LAT1/4F2hc.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-379426
ACCEPT
Summary: SLC7A6 (y+LAT2) with SLC3A2.
Reason: Core localization.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5660910
ACCEPT
Summary: Defective SLC7A7 pathway annotation.
Reason: Valid localization context.
GO:1903801 L-leucine import across plasma membrane
ISS
GO_REF:0000024
ACCEPT
Summary: Leucine import inferred from sequence similarity.
Reason: Core function consistent with experimental evidence.
GO:0005515 protein binding
IPI
PMID:10506149
Cloning and expression of a b(0,+)-like amino acid transport...
MODIFY
Summary: Cloning of b(0,+)-like transporter (SLC7A9 homolog) associating with 4F2hc.
Reason: This is heterodimerization with SLC7 family member.
Supporting Evidence:
PMID:10506149
Cloning and expression of a b(0,+)-like amino acid transporter functioning as a heterodimer with 4F2hc instead of rBAT.
GO:0005515 protein binding
IPI
PMID:10631289
Cloning and functional characterization of a Na(+)-independe...
MODIFY
Summary: Cloning of asc-1 (SLC7A10) interacting with 4F2hc.
Reason: This is heterodimerization with SLC7A10.
Supporting Evidence:
PMID:10631289
Cloning and functional characterization of a Na(+)-independent, broad-specific neutral amino acid transporter from mammalian intestine.
GO:0015827 tryptophan transport
ISS
GO_REF:0000024
ACCEPT
Summary: Tryptophan transport from sequence similarity.
Reason: Core function consistent with experimental evidence.
GO:0006816 calcium ion transport
NAS
PMID:3036867
Primary structure of the human 4F2 antigen heavy chain predi...
REMOVE
Summary: This annotation references the original cloning paper from 1987. Early speculation about calcium transport was not confirmed. SLC3A2 functions as an amino acid transporter chaperone, not a calcium transporter.
Reason: No evidence supports calcium transport function for SLC3A2. This appears to be a legacy annotation from early characterization before the amino acid transport function was established. Modern structural and functional studies confirm amino acid transport exclusively.
Supporting Evidence:
PMID:3036867
Primary structure of the human 4F2 antigen heavy chain predicts a transmembrane protein with a cytoplasmic NH2 terminus.
GO:0006865 amino acid transport
TAS
PMID:10673541
Heterodimeric amino acid transporters: expression of heavy b...
ACCEPT
Summary: Review on heterodimeric amino acid transporters in placenta.
Reason: Core function.
Supporting Evidence:
PMID:10673541
Heterodimeric amino acid transporters: expression of heavy but not light chains of CD98 correlates with induction of amino acid transport systems in human placental trophoblast.
GO:0016020 membrane
NAS
PMID:3476959
Molecular cloning of complementary DNAs encoding the heavy c...
ACCEPT
Summary: Original cloning paper establishing membrane localization.
Reason: Valid core localization from foundational paper.
Supporting Evidence:
PMID:3476959
Molecular cloning of complementary DNAs encoding the heavy chain of the human 4F2 cell-surface antigen: a type II membrane glycoprotein involved in normal and neoplastic cell growth.
GO:0015327 cystine:glutamate antiporter activity
IDA
PMID:11417227
Identification and characterisation of human xCT that co-exp...
NEW
Summary: SLC3A2/4F2hc partners with xCT/SLC7A11 to form system xc-, the cystine/glutamate antiporter. The complex mediates Na+-independent exchange of extracellular cystine for intracellular glutamate (PMID:11417227, PMID:34880232). This is a core molecular function of the SLC3A2-xCT complex.
Reason: This core molecular function term was not present in existing GOA annotations but is well-supported by multiple experimental studies including the original characterization (PMID:11417227) and recent cryo-EM structures (PMID:34880232). System xc- activity is essential for cysteine homeostasis and ferroptosis regulation.
Supporting Evidence:
PMID:11417227
Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-.
PMID:34880232
Molecular basis for redox control by the human cystine/glutamate antiporter system xc().
GO:0006749 glutathione metabolic process
IMP
PMID:34880232
Molecular basis for redox control by the human cystine/gluta...
NEW
Summary: The xCT-4F2hc (system xc-) complex provides cystine for glutathione biosynthesis. Cystine is reduced to cysteine intracellularly, and cysteine is the rate-limiting substrate for glutathione synthesis. Inhibition of system xc- depletes cellular glutathione leading to ferroptosis.
Reason: SLC3A2 involvement in glutathione metabolism is well-established through its partnership with xCT for cystine import. This biological process is directly downstream of the cystine:glutamate antiporter activity.
Supporting Evidence:
PMID:34880232
Molecular basis for redox control by the human cystine/glutamate antiporter system xc().
GO:0097707 ferroptosis
IMP
PMID:34880232
Molecular basis for redox control by the human cystine/gluta...
NEW
Summary: Inhibition of the xCT-4F2hc (system xc-) complex leads to cystine starvation, glutathione depletion, and ferroptotic cell death characterized by iron-dependent lipid peroxidation. System xc- is a major target for inducing ferroptosis in cancer therapy.
Reason: SLC3A2 plays a critical regulatory role in ferroptosis through its partnership with xCT. Genetic or pharmacological inhibition of system xc- triggers ferroptosis, establishing SLC3A2 as involved in this cell death process.
Supporting Evidence:
PMID:34880232
Molecular basis for redox control by the human cystine/glutamate antiporter system xc().
GO:0031929 TOR signaling
NAS NEW
Summary: Added to align core_functions with existing annotations.
Reason: Core function term not present in existing_annotations.
Supporting Evidence:
PMID:9751058
Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family.
PMID:25998567
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.

Core Functions

SLC3A2/4F2hc forms obligate disulfide-linked heterodimers with SLC7 family light chain transporters (LAT1/SLC7A5, LAT2/SLC7A8, y+LAT1/SLC7A7, y+LAT2/SLC7A6, Asc-1/SLC7A10, xCT/SLC7A11). The heavy chain provides trafficking, plasma membrane localization, and stability for the light chains which provide the catalytic transport activity. Cryo-EM structures have elucidated the heterodimer architecture (PMID:30867591, PMID:33298890, PMID:34880232).

Supporting Evidence:
  • PMID:30867591
    Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex
  • PMID:34880232
    Molecular basis for redox control by the human cystine/glutamate antiporter system xc()

The LAT1-4F2hc (SLC7A5-SLC3A2) complex mediates Na+-independent transport of large neutral amino acids, particularly leucine, which is critical for mTORC1 activation and cell growth. LAT2-4F2hc (SLC7A8-SLC3A2) also transports leucine with broader substrate specificity. This function is essential for nutrient sensing and cell proliferation.

Supporting Evidence:
  • PMID:9751058
    Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family
  • PMID:25998567
    LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation

The xCT-4F2hc (SLC7A11-SLC3A2) complex functions as system xc-, a cystine/glutamate antiporter that imports cystine in exchange for glutamate. This activity is essential for maintaining intracellular cysteine levels required for glutathione synthesis. The system xc- transporter is a critical regulator of ferroptosis - inhibition leads to iron-dependent lipid peroxidation and cell death (PMID:34880232, PMID:11417227).

Supporting Evidence:
  • PMID:11417227
    Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system xc-
  • PMID:34880232
    Molecular basis for redox control by the human cystine/glutamate antiporter system xc()

LAT1-4F2hc preferentially transports large neutral aromatic amino acids including phenylalanine, tyrosine, and tryptophan. This transport activity is Na+-independent and operates in exchange mode. LAT1 also transports thyroid hormones (T3, T4) which are structurally similar to tyrosine (PMID:11564694). LAT1 overexpression in tumors supports increased amino acid demand for cancer cell proliferation.

Supporting Evidence:
  • PMID:15589117
    rboado@mednet.ucla.edu The deleterious effects on the brain of phenylketonuria are caused by the saturation of the blood-brain barrier large neutral amino acid transporter type 1 (LAT1) by high plasma phenylalanine concentrations
  • PMID:11564694
    Thyroid hormone transport by the heterodimeric human system L amino acid transporter

References

Loading supporting content…

Download this section (compressed HTML)

Tags

ferroptosis

Deep Research

Falcon

(SLC3A2-deep-research-falcon.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“„ View Raw YAML

Loading supporting content…

Download this section (compressed HTML)