SLC3A2

Summary

SLC3A2 (solute carrier family 3 member 2, HGNC:11026) is a protein-coding gene on chromosome 11q12.3, encoding Amino acid transporter heavy chain SLC3A2 (P08195). Acts as a chaperone that facilitates biogenesis and trafficking of functional transporters heterodimers to the plasma membrane. It is a selective cancer dependency (DepMap: 36.2% of cell lines).

This gene is a member of the solute carrier family and encodes a cell surface, transmembrane protein. The protein exists as the heavy chain of a heterodimer, covalently bound through di-sulfide bonds to one of several possible light chains. The encoded transporter plays a role in regulation of intracellular calcium levels and transports L-type amino acids. Alternatively spliced transcript variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 6520 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 74 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 36.2% of screened cell lines
• MANE Select transcript: NM_001013251

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11026
Approved symbol	SLC3A2
Name	solute carrier family 3 member 2
Location	11q12.3
Locus type	gene with protein product
Status	Approved
Aliases	4T2HC, 4F2, NACAE, CD98, CD98HC, 4F2HC
Ensembl gene	ENSG00000168003
Ensembl biotype	protein_coding
OMIM	158070
Entrez	6520

Gene structure

Transcript identifiers

Ensembl transcripts: 78 — 57 protein_coding, 12 retained_intron, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000338663, ENST00000377889, ENST00000377890, ENST00000377891, ENST00000457660, ENST00000535296, ENST00000535768, ENST00000536981, ENST00000537508, ENST00000537839, ENST00000538084, ENST00000538682, ENST00000539458, ENST00000539507, ENST00000539891, ENST00000541372, ENST00000541425, ENST00000541649, ENST00000542793, ENST00000542922, ENST00000544377, ENST00000546253, ENST00000546312, ENST00000679594, ENST00000679908, ENST00000680002, ENST00000680134, ENST00000680297, ENST00000680610, ENST00000680631, ENST00000680654, ENST00000680725, ENST00000680729, ENST00000681107, ENST00000681215, ENST00000681232, ENST00000681467, ENST00000681563, ENST00000681569, ENST00000681657, ENST00000700482, ENST00000908662, ENST00000908663, ENST00000908664, ENST00000908665, ENST00000908666, ENST00000908667, ENST00000908668, ENST00000926671, ENST00000926672, ENST00000926673, ENST00000926674, ENST00000926675, ENST00000926676, ENST00000926677, ENST00000926678, ENST00000926679, ENST00000926680, ENST00000926681, ENST00000926682, ENST00000926683, ENST00000926684, ENST00000926685, ENST00000926686, ENST00000926687, ENST00000926688, ENST00000926689, ENST00000926690, ENST00000926691, ENST00000926692, ENST00000926693, ENST00000926694, ENST00000926695, ENST00000971952, ENST00000971953, ENST00000971954, ENST00000971955, ENST00000971956

RefSeq mRNA: 4 — MANE Select: NM_001013251 NM_001012662, NM_001012664, NM_001013251, NM_002394

CCDS: CCDS31588, CCDS31589, CCDS31590, CCDS8039

Canonical transcript exons

ENST00000338663 — 9 exons

Exon	Start	End
ENSE00001374291	62880896	62881447
ENSE00002311625	62888331	62888860
ENSE00003490321	62885177	62885357
ENSE00003538765	62882908	62882999
ENSE00003608684	62884632	62884690
ENSE00003610068	62881893	62882066
ENSE00003659239	62888135	62888218
ENSE00003660800	62884457	62884525
ENSE00003661225	62885465	62885608

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 166.5013 / max 1392.0701, expressed in 1828 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114761	110.3379	1827
114763	18.5585	1794
114756	15.8517	1505
114760	5.9066	1729
114757	4.7842	1167
114766	2.6809	895
114762	1.9140	992
114767	1.5690	593
114765	0.8889	467
114771	0.7185	349

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	99.18	gold quality
ventricular zone	UBERON:0003053	98.97	gold quality
stromal cell of endometrium	CL:0002255	98.89	gold quality
right lobe of thyroid gland	UBERON:0001119	98.36	gold quality
left lobe of thyroid gland	UBERON:0001120	98.26	gold quality
ganglionic eminence	UBERON:0004023	98.25	gold quality
upper lobe of left lung	UBERON:0008952	98.11	gold quality
skin of abdomen	UBERON:0001416	98.08	gold quality
endocervix	UBERON:0000458	98.04	gold quality
skin of leg	UBERON:0001511	97.91	gold quality
ectocervix	UBERON:0012249	97.80	gold quality
minor salivary gland	UBERON:0001830	97.78	gold quality
adrenal tissue	UBERON:0018303	97.78	gold quality
body of uterus	UBERON:0009853	97.77	gold quality
metanephros cortex	UBERON:0010533	97.74	gold quality
mucosa of stomach	UBERON:0001199	97.71	gold quality
left uterine tube	UBERON:0001303	97.66	gold quality
tibial nerve	UBERON:0001323	97.66	gold quality
monocyte	CL:0000576	97.60	gold quality
body of pancreas	UBERON:0001150	97.59	gold quality
descending thoracic aorta	UBERON:0002345	97.54	gold quality
upper lobe of lung	UBERON:0008948	97.52	gold quality
right adrenal gland cortex	UBERON:0035827	97.52	gold quality
thyroid gland	UBERON:0002046	97.48	gold quality
left adrenal gland	UBERON:0001234	97.45	gold quality
right adrenal gland	UBERON:0001233	97.43	gold quality
left ovary	UBERON:0002119	97.43	gold quality
right lung	UBERON:0002167	97.41	gold quality
right ovary	UBERON:0002118	97.40	gold quality
gall bladder	UBERON:0002110	97.35	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	5305.84
E-MTAB-10662	yes	3203.42
E-MTAB-9154	yes	1433.13
E-GEOD-93593	yes	1123.27
E-HCAD-5	yes	896.63
E-MTAB-6075	yes	413.46
E-MTAB-6701	yes	44.86
E-GEOD-134144	yes	42.68
E-MTAB-9388	yes	12.66
E-MTAB-7606	no	1257.71
E-MTAB-8060	no	1009.55
E-GEOD-106540	no	804.38
E-MTAB-10485	no	640.16
E-CURD-95	no	598.61
E-MTAB-10290	no	504.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EZH2, GLI3, HR, KAT5, SP1, TXK

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 36.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Data show that, in vitro, under physiological conditions, CD98 is constitutively associated with beta1 integrins regardless of activation status. (PMID:12181350)
• the interaction of CD98/LAT2 with ICAM-1, found to be expressed to the basolateral domain, and the potential of such interaction on intracellular signal activation in Caco2-BBE cell monolayers (PMID:12716892)
• Involved in process of cell fusion necessary for syncytiotrophoblast formation. During this physiologically important event, amino acid transport activity is also regulated through expression of this membrane protein. (PMID:12740424)
• The heavy chain of the cell surface antigen 4F2 is induced by lysophosphatidylcholine, oxLDL and many oxidation products. It mediates increased cytokine production by endothelial cells. (PMID:15178563)
• results explain how high expression of CD98hc antigen in human cancers contributes to transformation (PMID:15485886)
• iRNA-induced reduction in CD98 expression suppresses cell fusion during syncytialization of placental cell line. (PMID:15556631)
• CD98hc is an integrin-associated protein that mediates integrin-dependent signals, which promote tumorigenesis. (PMID:15625115)
• CD98 is a scaffolding protein that interacts with basolaterally expressed amino acid transporters and beta1 integrins and can alter amino acid transport and cell adhesion, migration and branching morphogenesis (PMID:15713750)
• The 15 carboxy-terminal residues of 4F2hc are required for the transport function of the heterodimer. Mutation of the conserved residue leucine 523 to glutamine in the carboxy terminus reduced the Vmax of arginine and leucine uptake. (PMID:16785209)
• Results demonstrated that a reduction of Sp1 or NF-kappaB expression reduced CD98 protein expression. (PMID:17023546)
• data suggest N-glycosylation of CD98 & subsequent interaction with galectin 3 is critical for aspects of placental cell biology, & provides rationale for observation that in mice truncation of CD98hc extracellular domain leads to early embryonic lethality (PMID:17451431)
• CD98hc is a bridge between multidrug resistance phenotype and tumor metastasis (PMID:17611393)
• The structure of human 4F2HC ectodomain provides a model for homodimerization and electrostatic interaction with plasma membrane. (PMID:17724034)
• The transmembrane domain of CD98 heavy chain has an essential role in the stimulation of alpha(v)beta(3) integrin for cell adhesion and motility. (PMID:18032696)
• Altogether, our results support a model whereby CyPB induces integrin-mediated adhesion via interaction with a multimolecular unit formed by the association between CD147, CD98 and beta1 integrins. (PMID:18054915)
• interaction between SLC3A2 and SAT1 suggests that these proteins may facilitate excretion of acetylated polyamines. (PMID:18660501)
• Inhibition of system L (LAT1/CD98hc) reduces the growth of cultured human breast cancer cells. (PMID:18813831)
• CD98 expression in primary and metastatic neoplasms is reported. (PMID:19018776)
• CD98 was phosphorylated in vitro by ecto-protein kinases from Jurkat cells and by the commercial casein kinase 2 (CK2). (PMID:19065266)
• over expression of CD98 is a pathological factor to predict the prognosis in patients with resectable stage I pulmonary adenocarcinoma (PMID:19171406)
• We conclude that arginine transport in human erythroid cells is due to both system y(+) (CAT1 transporter) and system y(+)L (4F2hc/y(+)LAT2 isoform), which mainly contribute, respectively, to the influx and to the efflux of the cationic amino acid. (PMID:19562367)
• High CD98 expression is associated with non-small-cell lung cancer with lymph node metastases. (PMID:19777189)
• 4F2hc genes may play important roles in leiomyoma cell proliferation and regulate leiomyoma growth. (PMID:19808856)
• CD98 expression is down-regulated in thyroid papillary carcinoma; this may relate to the better prognosis associated with many of these tumours. (PMID:19922591)
• High expression of 4F2HC is associated with high-grade gliomas. (PMID:20091333)
• CD98 expression was associated with the grade of malignancy and cell cycle control, and was useful for predicting poor outcome in thymic epithelial tumors (PMID:20811665)
• Taken together, these observations indicate that 4F2hc is likely to be involved in GLUT1 stabilization and to contribute to the regulation of not only amino acid but also glucose metabolism. (PMID:21270293)
• CD98hc is involved in integrin trafficking and by consequence, in keratinocyte adhesion and differentiation. (PMID:21282044)
• Folding seems to be directed by the initial formation of hydrophobic clusters within the first strands of the beta-barrel of domain A followed by additional hydrophobic interactions in domain C. (PMID:21352957)
• Compared with the adult cerebral cortex, mRNAs encoding OATP1A2, OATP1C1, OATP3A1 variant 2, OATP4A1, LAT2 and CD98 were reduced in fetal cortex at different gestational ages, whilst mRNAs encoding MCT8, MCT10, OATP3A1 variant 1 and LAT1 were similar. (PMID:21486766)
• The integrin-binding domain of the CD98 heavy chain transgene is required for antigen-driven T cell clonal expansion in the pathogenesis of an autoimmune disease such as experimental type 1 diabetes. mellitus. (PMID:21670318)
• Results suggest that 4F2hc may play a significant role in tumor progression, hypoxic conditions and poor outcome in patients with pulmonary NE tumors. (PMID:21750865)
• study revealed that LAT1 and CD98 expression are positively correlated with breast cancer proliferation and negatively correlated with ER and PgR status; show that LAT1 and CD98 expression are prognostic factors in triple negative breast cancer (PMID:22077314)
• Strategies targeting transgenic CD98 heavy-chain demonstrate clinical application for treating type 1 diabetes and other T cell-mediated autoimmune diseases. (PMID:22291182)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• [REVIEW] Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. (PMID:22499670)
• The interaction of galectin 3 and CD98 can induce Eos to release chemical mediators that contributes to the initiation of the intestinal inflammation. (PMID:23272174)
• These findings demonstrate the importance of the extracellular loop of CD98 in the innate host defense response to intestinal infection by attaching and effacing (A/E) pathogens. (PMID:23297381)
• Although extracellular galectin-3 accumulates due to the decrease in MMP-2 activity, galectin-3 signaling events are blocked due to an impaired interaction with 4F2hc, inducing an increased degradation of beta-catenin. (PMID:23651923)
• heteromerization of y+LAT1 and 4F2hc within the cell is not disrupted by any of the tested LPI mutations (PMID:23940088)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc3a2a	ENSDARG00000036427
danio_rerio	slc3a2b	ENSDARG00000037012
danio_rerio	zgc:158423	ENSDARG00000055791
mus_musculus	Slc3a2	ENSMUSG00000010095
rattus_norvegicus	Slc3a2	ENSRNOG00000018487
drosophila_melanogaster	Amy-d	FBGN0000078
drosophila_melanogaster	Amy-p	FBGN0000079
drosophila_melanogaster	Mal-A2	FBGN0002569
drosophila_melanogaster	Mal-A3	FBGN0002571
drosophila_melanogaster	Amyrel	FBGN0020506
drosophila_melanogaster	Mal-B1	FBGN0032381
drosophila_melanogaster	Mal-B2	FBGN0032382
drosophila_melanogaster	Mal-A4	FBGN0033294
drosophila_melanogaster	Mal-A7	FBGN0033296
drosophila_melanogaster	Mal-A8	FBGN0033297
drosophila_melanogaster	Mal-A6	FBGN0050360
caenorhabditis_elegans		WBGENE00008220

Paralogs (7): GBE1 (ENSG00000114480), SLC3A1 (ENSG00000138079), AMY1B (ENSG00000174876), AMY1C (ENSG00000187733), AMY1A (ENSG00000237763), AMY2B (ENSG00000240038), AMY2A (ENSG00000243480)

Protein

Protein identifiers

Amino acid transporter heavy chain SLC3A2 — P08195 (reviewed: P08195)

Alternative names: 4F2 cell-surface antigen heavy chain, 4F2 heavy chain antigen, Lymphocyte activation antigen 4F2 large subunit, Solute carrier family 3 member 2

All UniProt accessions (20): A0A7P0T853, A0A7P0T8F1, A0A7P0T8U7, A0A7P0T9F7, A0A7P0TAN7, A0A7P0TAS6, A0A7P0TAT7, A0A7P0TBF8, A0A7P0Z4A0, A0A7P0Z4P5, P08195, F5GZI0, F5GZR9, F5GZS6, F5H056, F5H0E2, F5H867, H0YFS2, H0YFX4, H0YH36

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a chaperone that facilitates biogenesis and trafficking of functional transporters heterodimers to the plasma membrane. Forms heterodimer with SLC7 family transporters (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 and SLC7A11), a group of amino-acid antiporters. Heterodimers function as amino acids exchangers, the specificity of the substrate depending on the SLC7A subunit. Heterodimers SLC3A2/SLC7A6 or SLC3A2/SLC7A7 mediate the uptake of dibasic amino acids. Heterodimer SLC3A2/SLC7A11 functions as an antiporter by mediating the exchange of extracellular anionic L-cystine and intracellular L-glutamate across the cellular plasma membrane. SLC3A2/SLC7A10 translocates small neutral L- and D-amino acids across the plasma membrane. SLC3A2/SLC75 or SLC3A2/SLC7A8 translocates neutral amino acids with broad specificity, thyroid hormones and L-DOPA. SLC3A2 is essential for plasma membrane localization, stability, and the transport activity of SLC7A5 and SLC7A8. When associated with LAPTM4B, the heterodimer SLC7A5 is recruited to lysosomes to promote leucine uptake into these organelles, and thereby mediates mTORC1 activation. Modulates integrin-related signaling and is essential for integrin-dependent cell spreading, migration and tumor progression. (Microbial infection) In case of hepatitis C virus/HCV infection, the complex formed by SLC3A2 and SLC7A5/LAT1 plays a role in HCV propagation by facilitating viral entry into host cell and increasing L-leucine uptake-mediated mTORC1 signaling activation, thereby contributing to HCV-mediated pathogenesis. (Microbial infection) Acts as a receptor for malaria parasite Plasmodium vivax (Thai isolate) in immature red blood cells.

Subunit / interactions. Disulfide-linked heterodimer with a non-glycosylated catalytic light subunit (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10 or SLC7A11). Interacts with TLCD3A/CT120. Interacts with ICAM1. Constitutively and specifically associates with beta-1 integrins (alpha-2/beta-1, alpha-3/beta-1, alpha-5/beta-1 and alpha-6/beta-1), but minimally with alpha-4/beta-1. Interacts with LAPTM4B; recruits SLC3A2 and SLC7A5/LAT1 to lysosomes to promote leucine uptake into these organelles and is required for mTORC1 activation. (Microbial infection) Interacts with hepatitis C virus/HCV envelope glycoprotein E2; the interaction may facilitate viral entry into host cell.

Subcellular location. Apical cell membrane. Cell membrane. Cell junction. Lysosome membrane. Melanosome. Basolateral cell membrane.

Tissue specificity. Expressed ubiquitously in all tissues tested with highest levels detected in kidney, placenta and testis and weakest level in thymus. During gestation, expression in the placenta was significantly stronger at full-term than at the mid-trimester stage. Expressed in HUVECS and at low levels in resting peripheral blood T-lymphocytes and quiescent fibroblasts. Also expressed in fetal liver and in the astrocytic process of primary astrocytic gliomas. Expressed in retinal endothelial cells and in the intestinal epithelial cell line C2BBe1.

Post-translational modifications. N-glycosylated; N-glycosylation is crucial for trafficking and stability of SLC3A2 to the plasma membrane. Phosphorylation on Ser-305; Ser-307 or Ser-309 and on Ser-426 or Ser-430 by ecto-protein kinases favors heterotypic cell-cell interactions.

Induction. Expression is induced in resting peripheral blood T-lymphocytes following PHA stimulation. Expression increases at the time of maximal DNA synthesis, in fibroblasts stimulated to divide. Expression and the uptake of leucine is stimulated in mononuclear, cytotrophoblast-like choriocarcinoma cells by combined treatment with PMA and calcium ionophore. Up-regulated in response to hydrogen peroxide. Highly expressed in various cancer types. (Microbial infection) Up-regulated upon hepatitis C virus/HCV infection via NS3-A4 viral protein complex; the up-regulation is mediated by oxidative stress. Up-regulation of the complex formed by SLC3A2 and SLC7A5/LAT1 upon hepatitis C virus/HCV infection.

Similarity. Belongs to the SLC3A transporter family.

Isoforms (4)

UniProt ID	Names	Canonical?
P08195-2	2	yes
P08195-1	1
P08195-3	3
P08195-5	5

RefSeq proteins (4): NP_001012680, NP_001012682, NP_001013269, NP_002385 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006047	GH13_cat_dom	Domain
IPR013780	Glyco_hydro_b	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR031984	SLC3A2_N	Domain
IPR042280	SLC3A2	Family

Pfam: PF00128, PF16028

UniProt features (111 total): strand 30, helix 29, sequence conflict 12, modified residue 11, mutagenesis site 9, glycosylation site 4, turn 4, splice variant 3, topological domain 2, cross-link 2, initiator methionine 1, chain 1, disulfide bond 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

43 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6S8V	X-RAY DIFFRACTION	1.8
2DH2	X-RAY DIFFRACTION	2.1
8G0M	X-RAY DIFFRACTION	2.25
9KJU	ELECTRON MICROSCOPY	2.7
2DH3	X-RAY DIFFRACTION	2.8
7DF1	X-RAY DIFFRACTION	2.81
7CMI	ELECTRON MICROSCOPY	2.9
7DSK	ELECTRON MICROSCOPY	2.9
7DSL	ELECTRON MICROSCOPY	2.9
8YLP	ELECTRON MICROSCOPY	2.9
7DSN	ELECTRON MICROSCOPY	3.1
8X0W	ELECTRON MICROSCOPY	3.1
8A6L	ELECTRON MICROSCOPY	3.18
8IDA	ELECTRON MICROSCOPY	3.2
6IRS	ELECTRON MICROSCOPY	3.3
8XPU	ELECTRON MICROSCOPY	3.3
6JMQ	ELECTRON MICROSCOPY	3.31
7CMH	ELECTRON MICROSCOPY	3.4
7DSQ	ELECTRON MICROSCOPY	3.4
7EPZ	ELECTRON MICROSCOPY	3.4
7P9V	ELECTRON MICROSCOPY	3.4
8WNS	ELECTRON MICROSCOPY	3.42
8WNT	ELECTRON MICROSCOPY	3.42
6IRT	ELECTRON MICROSCOPY	3.5
8WNY	ELECTRON MICROSCOPY	3.5
8J8L	ELECTRON MICROSCOPY	3.56
8J8M	ELECTRON MICROSCOPY	3.58
8KDI	ELECTRON MICROSCOPY	3.58
9LDR	ELECTRON MICROSCOPY	3.58
9KY5	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08195-F1	80.01	0.65

Antibody-complex structures (SAbDab): 4 — 7DF1, 8KDD, 8KDG, 8KDI

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 64, 305, 1, 307, 309, 426, 430, 46, 65, 2, 2, 5, 33

Disulfide bonds (1): 109

Glycosylation sites (4): 264, 280, 323, 405

Mutagenesis-validated functional residues (9):

Position	Phenotype
81	strongly decreased leucine transport activity.
109	abolishes dimerization, leucine uptake and interaction with beta-1 integrins.
133–529	nearly abolishes leucine transport activity.
264	impairs both the stability and the trafficking of slc3a2 to the plasma membrane; when associated with q-280; q-323 and q
280	impairs both the stability and the trafficking of slc3a2 to the plasma membrane; when associated with q-264; q-323 and q
323	impairs both the stability and the trafficking of slc3a2 to the plasma membrane; when associated with q-264 q-280 and q-
330	no effect on dimerization, leucine uptake or interaction with beta-1 integrins.
405	impairs both the stability and the trafficking of slc3a2 to the plasma membrane; when associated with q-264 q-280 and q-
431	strongly decreased leucine transport activity.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-210991	Basigin interactions
R-HSA-352230	Amino acid transport across the plasma membrane
R-HSA-5660862	Defective amino acid transport by SLC7A7 causes lysinuric protein intolerance (LPI)
R-HSA-71240	Tryptophan catabolism
R-HSA-109582	Hemostasis
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 402 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, TSENG_IRS1_TARGETS_UP, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOCC_VACUOLAR_MEMBRANE, ENK_UV_RESPONSE_KERATINOCYTE_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, REACTOME_TRYPTOPHAN_CATABOLISM, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_HORMONE_TRANSPORT, CAFFAREL_RESPONSE_TO_THC_UP, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT

GO Biological Process (19): carbohydrate metabolic process (GO:0005975), calcium ion transport (GO:0006816), amino acid transport (GO:0006865), isoleucine transport (GO:0015818), L-leucine transport (GO:0015820), methionine transport (GO:0015821), phenylalanine transport (GO:0015823), proline transport (GO:0015824), tryptophan transport (GO:0015827), tyrosine transport (GO:0015828), valine transport (GO:0015829), response to exogenous dsRNA (GO:0043330), symbiont entry into host cell (GO:0046718), thyroid hormone transport (GO:0070327), L-histidine transport (GO:1902024), L-leucine import across plasma membrane (GO:1903801), L-alanine import across plasma membrane (GO:1904273), obsolete organic cation transport (GO:0015695), carboxylic acid transport (GO:0046942)

GO Molecular Function (12): virus receptor activity (GO:0001618), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), aromatic amino acid transmembrane transporter activity (GO:0015173), neutral L-amino acid transmembrane transporter activity (GO:0015175), L-alanine transmembrane transporter activity (GO:0015180), L-leucine transmembrane transporter activity (GO:0015190), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), protein heterodimerization activity (GO:0046982), exogenous protein binding (GO:0140272), protein binding (GO:0005515)

GO Cellular Component (16): nucleoplasm (GO:0005654), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), basal plasma membrane (GO:0009925), cell surface (GO:0009986), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), melanosome (GO:0042470), apical pole of neuron (GO:0044225), synapse (GO:0045202), extracellular exosome (GO:0070062), anchoring junction (GO:0070161), amino acid transport complex (GO:1990184), lysosome (GO:0005764), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Cell surface interactions at the vascular wall	1
SLC-mediated transport of amino acids	1
SLC transporter disorders	1
Metabolism of amino acids and derivatives	1
Hemostasis	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neutral amino acid transport	5
L-amino acid transport	4
aromatic amino acid transport	4
branched-chain amino acid transport	3
cellular anatomical structure	3
plasma membrane region	3
amino acid transport	2
amino acid import across plasma membrane	2
L-amino acid transmembrane transporter activity	2
protein dimerization activity	2
cell junction	2
primary metabolic process	1
metal ion transport	1
transport	1
sulfur amino acid transport	1
carboxylic acid transport	1
nitrogen compound transport	1
response to dsRNA	1
viral life cycle	1
symbiont entry into host	1
hormone transport	1
basic amino acid transport	1
L-leucine transport	1
L-alpha-amino acid transmembrane transport	1
L-alanine transmembrane transport	1
organic acid transport	1
symbiont entry into host cell	1
exogenous protein binding	1
nucleic acid binding	1
RNA binding	1
carboxylic acid transmembrane transporter activity	1
amino acid transmembrane transporter activity	1
L-alanine transport	1
alanine transmembrane transporter activity	1
neutral L-amino acid transmembrane transporter activity	1
branched-chain amino acid transmembrane transporter activity	1
identical protein binding	1
cell adhesion molecule binding	1
protein binding	1
binding	1

Protein interactions and networks

STRING

3170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC3A2	SLC7A5	Q01650	999
SLC3A2	SLC7A11	Q9UPY5	999
SLC3A2	SLC7A8	Q9UHI5	999
SLC3A2	SLC7A6	Q92536	999
SLC3A2	SLC7A7	Q9UM01	999
SLC3A2	SLC7A10	Q9NS82	974
SLC3A2	SLC43A1	O75387	937
SLC3A2	SLC1A5	Q15758	865
SLC3A2	BSG	P35613	862
SLC3A2	SLC7A9	P82251	824
SLC3A2	TLCD3A	Q8TBR7	796
SLC3A2	SLC43A2	Q8N370	777
SLC3A2	LGALS3	P17931	769
SLC3A2	SLC3A1	Q07837	745
SLC3A2	ASNS	P08184	737

IntAct

222 interactions, top by confidence:

A	B	Type	Score
ATP1A1	ATP1B1	psi-mi:“MI:0914”(association)	0.910
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
EGFR	GAPDH	psi-mi:“MI:0914”(association)	0.790
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
SLC3A2	SLC7A5	psi-mi:“MI:0407”(direct interaction)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
SLC3A2	sepZ	psi-mi:“MI:0915”(physical association)	0.590
SLC3A2	sepZ	psi-mi:“MI:0403”(colocalization)	0.590
GPR37	SLC3A2	psi-mi:“MI:0915”(physical association)	0.580
SLC3A2	GPR37	psi-mi:“MI:0915”(physical association)	0.580
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
SLC7A7	SLC3A2	psi-mi:“MI:0915”(physical association)	0.560
SLC3A2	SLC7A11	psi-mi:“MI:0407”(direct interaction)	0.550
CD81	C2orf72	psi-mi:“MI:0914”(association)	0.530

BioGRID (560): SLC3A2 (Affinity Capture-MS), SLC3A2 (Affinity Capture-MS), SLC3A2 (Affinity Capture-MS), SLC3A2 (Affinity Capture-MS), SLC3A2 (Affinity Capture-MS), BSG (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Co-fractionation), SLC3A2 (Affinity Capture-MS)

ESM2 similar proteins: A4D0V7, B2GUY2, G5E872, O08773, O19011, O35465, O43566, P01137, P04202, P07200, P08195, P09533, P10852, P18341, P50414, P50555, P50747, P54831, P97492, Q0VCT3, Q14318, Q27J81, Q3B7U9, Q3TAA7, Q496Y0, Q4R4I0, Q5E9Y6, Q5E9Z9, Q5EAN7, Q5STE3, Q6AYG3, Q6MZW2, Q6YGZ1, Q71RP1, Q794F9, Q7YQK3, Q86TP1, Q8C190, Q8HXH0, Q8IYL2

Diamond homologs: A0R6E0, A4TQV2, A7FNX5, B0XAA1, L8B068, O05242, O06458, O06994, O14154, O16098, O16099, O30565, O34364, O86956, P07190, P07191, P07192, P07265, P08195, P0CW40, P0CW41, P10852, P13080, P14898, P21332, P27036, P28904, P29093, P29094, P31746, P31797, P38158, P39795, P40884, P43473, P53051, P53341, P72235, P95867, P9WQ18

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MARCHF8	“down-regulates quantity by destabilization”	SLC3A2	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 202 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by EGFRvIII	5	26.4×	2e-04
Signaling by ERBB2 ECD mutants	5	24.9×	2e-04
Basigin interactions	7	22.8×	1e-05
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	21.1×	3e-04
Signaling by ERBB2 TMD/JMD mutants	5	17.6×	6e-04
Signaling by ERBB2 KD Mutants	5	15.7×	7e-04
Downstream signal transduction	5	14.1×	1e-03
Amino acid transport across the plasma membrane	6	13.4×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
amino acid transmembrane transport	5	22.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

74 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1697 predictions. Top by Δscore:

Variant	Effect	Δscore
11:62856377:CTCAG:C	donor_loss	1.0000
11:62856378:TCAGG:T	donor_loss	1.0000
11:62856379:CAGG:C	donor_loss	1.0000
11:62856380:AGGT:A	donor_loss	1.0000
11:62856381:GG:G	donor_loss	1.0000
11:62856382:GT:G	donor_loss	1.0000
11:62856383:T:G	donor_loss	1.0000
11:62881443:GGCGG:G	donor_gain	1.0000
11:62881444:GCGGG:G	donor_gain	1.0000
11:62881888:TTCA:T	acceptor_loss	1.0000
11:62881891:AGGTC:A	acceptor_loss	1.0000
11:62882027:G:GT	donor_gain	1.0000
11:62882027:G:T	donor_gain	1.0000
11:62882028:A:T	donor_gain	1.0000
11:62882062:AAAGA:A	donor_gain	1.0000
11:62882063:AAGA:A	donor_gain	1.0000
11:62882064:AGA:A	donor_gain	1.0000
11:62882065:GA:G	donor_gain	1.0000
11:62882065:GAG:G	donor_gain	1.0000
11:62882067:G:GG	donor_gain	1.0000
11:62882897:C:CA	acceptor_gain	1.0000
11:62882900:T:TA	acceptor_gain	1.0000
11:62882906:A:AG	acceptor_gain	1.0000
11:62882906:AG:A	acceptor_gain	1.0000
11:62882907:G:A	acceptor_loss	1.0000
11:62882907:G:GT	acceptor_gain	1.0000
11:62882907:GG:G	acceptor_gain	1.0000
11:62882907:GGC:G	acceptor_gain	1.0000
11:62883000:GTG:G	donor_loss	1.0000
11:62884445:T:A	acceptor_gain	1.0000

AlphaMissense

3440 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:62881226:T:C	L169P	0.998
11:62881297:T:A	W193R	0.998
11:62881297:T:C	W193R	0.998
11:62881201:T:C	F161L	0.997
11:62881203:C:A	F161L	0.997
11:62881203:C:G	F161L	0.997
11:62881218:G:C	K166N	0.997
11:62881218:G:T	K166N	0.997
11:62881254:G:C	W178C	0.997
11:62881254:G:T	W178C	0.997
11:62881288:T:A	W190R	0.997
11:62881288:T:C	W190R	0.997
11:62881307:T:A	M196K	0.995
11:62881307:T:G	M196R	0.995
11:62881285:T:C	F189L	0.994
11:62881287:C:A	F189L	0.994
11:62881287:C:G	F189L	0.994
11:62881295:G:A	G192D	0.994
11:62881310:T:A	L197H	0.994
11:62881328:T:A	I203K	0.994
11:62881294:G:C	G192R	0.993
11:62881303:G:C	G195R	0.993
11:62881304:G:A	G195D	0.993
11:62881252:T:A	W178R	0.992
11:62881252:T:C	W178R	0.992
11:62888471:G:C	W557C	0.992
11:62888471:G:T	W557C	0.992
11:62881202:T:G	F161C	0.991
11:62881226:T:A	L169Q	0.990
11:62881319:C:A	A200D	0.990

dbSNP variants (sampled 300 via entrez): RS1000055291 (11:62855272 T>G), RS1000139662 (11:62860697 T>A), RS1000222769 (11:62866855 C>A,T), RS1000243041 (11:62880349 G>T), RS1000272936 (11:62867230 G>A), RS1000281707 (11:62887100 C>T), RS1000298180 (11:62873496 A>G), RS1000336929 (11:62886991 G>C,T), RS1000431895 (11:62880809 TG>T,TGG), RS1000570723 (11:62879970 T>C), RS1000661059 (11:62855896 C>A,G,T), RS1000682595 (11:62886543 G>A), RS1000793318 (11:62859826 C>T), RS1000940240 (11:62868023 G>A), RS1000988950 (11:62855843 T>A,C)

Disease associations

OMIM: gene MIM:158070 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90020025_949	Waist-to-hip ratio adjusted for BMI	1.000000e-09
GCST90020027_1481	Waist-hip index	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066973 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC3 family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
IGN523	Binding	8.89	pKd

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.46	Kd	346.9	nM	CHEMBL5653589
6.44	ED50	362.3	nM	CHEMBL5653589
5.27	Kd	5333	nM	CHEMBL3752910
5.25	ED50	5569	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149427: Binding affinity to human SLC3A2 incubated for 45 mins by Kinobead based pull down assay	kd	0.3469	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149427: Binding affinity to human SLC3A2 incubated for 45 mins by Kinobead based pull down assay	kd	5.3328	uM

CTD chemical–gene interactions

216 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	8
Tetrachlorodibenzodioxin	decreases reaction, increases expression	7
bisphenol A	affects methylation, affects cotreatment, decreases methylation, decreases expression, increases expression (+1 more)	6
Benzo(a)pyrene	decreases expression, increases expression	6
Tobacco Smoke Pollution	affects expression, increases expression	6
Valproic Acid	increases expression, affects expression, affects cotreatment	6
sodium arsenite	increases expression, affects cotreatment, increases abundance	5
Estradiol	increases expression, increases reaction, affects cotreatment, decreases expression	5
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression, increases expression	4
Cisplatin	affects expression, affects cotreatment, decreases expression, increases expression	4
perfluorooctane sulfonic acid	increases expression	3
Arsenic	decreases ubiquitination, increases expression, affects cotreatment, increases abundance	3
Cadmium	decreases expression, increases response to substance, increases abundance, increases expression	3
Tunicamycin	increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
Genistein	increases expression, increases reaction	3
Particulate Matter	increases abundance, increases expression, affects cotreatment	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
cobaltous chloride	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
monomethylarsonous acid	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction, increases expression	2
Zoledronic Acid	decreases expression	2
Dexamethasone	decreases expression, affects cotreatment	2
Ethinyl Estradiol	affects expression, increases expression	2
Indomethacin	decreases expression, increases expression, affects cotreatment	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Paraquat	increases expression	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652469	Binding	Binding affinity to human SLC3A2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2G8	Abcam HeLa SLC3A2 KO	Cancer cell line	Female
CVCL_D4NV	HCT116-SLC3A2-KO-c6	Cancer cell line	Male
CVCL_D8AJ	Ubigene A-549 SLC3A2 KO	Cancer cell line	Male
CVCL_D8VE	Ubigene HCT 116 SLC3A2 KO	Cancer cell line	Male
CVCL_D9S1	Ubigene HEK293 SLC3A2 KO	Transformed cell line	Female
CVCL_E0NZ	Ubigene HeLa SLC3A2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.