LAT2

Summary

LAT2 (linker for activation of T cells family member 2, HGNC:12749) is a protein-coding gene on chromosome 7q11.23, encoding Linker for activation of T-cells family member 2 (Q9GZY6). Involved in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells.

This gene is one of the contiguous genes at 7q11.23 commonly deleted in Williams syndrome, a multisystem developmental disorder. This gene consists of at least 14 exons, and its alternative splicing generates 3 transcript variants, all encoding the same protein.

Source: NCBI Gene 7462 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 58 total
• MANE Select transcript: NM_032464

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12749
Approved symbol	LAT2
Name	linker for activation of T cells family member 2
Location	7q11.23
Locus type	gene with protein product
Status	Approved
Aliases	WSCR5, HSPC046, LAB, NTAL
Ensembl gene	ENSG00000086730
Ensembl biotype	protein_coding
OMIM	605719
Entrez	7462

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000275635, ENST00000344995, ENST00000361082, ENST00000398475, ENST00000460943, ENST00000465116, ENST00000470709, ENST00000475494, ENST00000488266, ENST00000490586, ENST00000491595, ENST00000858502, ENST00000858503, ENST00000858504, ENST00000962406, ENST00000962407, ENST00000962408, ENST00000962409, ENST00000962410, ENST00000962411, ENST00000962412, ENST00000962413, ENST00000962414

RefSeq mRNA: 3 — MANE Select: NM_032464 NM_014146, NM_032463, NM_032464

CCDS: CCDS5566

Canonical transcript exons

ENST00000460943 — 14 exons

Exon	Start	End
ENSE00000551847	74216825	74216864
ENSE00000843226	74219744	74219787
ENSE00001215490	74214822	74215010
ENSE00001215627	74219960	74220008
ENSE00001385090	74220217	74220254
ENSE00001767944	74210006	74210088
ENSE00002180078	74215947	74216069
ENSE00003505528	74221637	74221692
ENSE00003546792	74224018	74224197
ENSE00003577523	74224639	74224760
ENSE00003589025	74223724	74223783
ENSE00003734067	74228944	74229834
ENSE00003784835	74220704	74220734
ENSE00003785286	74220584	74220619

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 98.34.

FANTOM5 (CAGE): breadth broad, TPM avg 16.1581 / max 515.3099, expressed in 587 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79082	12.3065	560
79081	2.6435	381
79080	1.0614	311
79079	0.1161	59
79083	0.0306	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.34	gold quality
mononuclear cell	CL:0000842	98.19	gold quality
leukocyte	CL:0000738	98.15	gold quality
granulocyte	CL:0000094	97.90	gold quality
blood	UBERON:0000178	97.50	gold quality
bone marrow	UBERON:0002371	94.50	gold quality
spleen	UBERON:0002106	93.62	gold quality
vermiform appendix	UBERON:0001154	93.06	gold quality
bone marrow cell	CL:0002092	92.42	gold quality
lymph node	UBERON:0000029	91.08	gold quality
trabecular bone tissue	UBERON:0002483	88.73	gold quality
caecum	UBERON:0001153	88.31	gold quality
superficial temporal artery	UBERON:0001614	87.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.64	gold quality
upper lobe of left lung	UBERON:0008952	85.98	gold quality
right lung	UBERON:0002167	85.83	gold quality
upper lobe of lung	UBERON:0008948	85.05	gold quality
spinal cord	UBERON:0002240	84.76	gold quality
buccal mucosa cell	CL:0002336	83.68	silver quality
periodontal ligament	UBERON:0008266	83.04	silver quality
pancreatic ductal cell	CL:0002079	82.57	gold quality
tonsil	UBERON:0002372	82.24	gold quality
lung	UBERON:0002048	81.74	gold quality
right coronary artery	UBERON:0001625	81.62	gold quality
gall bladder	UBERON:0002110	81.46	gold quality
right lobe of liver	UBERON:0001114	81.00	gold quality
small intestine Peyer’s patch	UBERON:0003454	80.17	gold quality
substantia nigra	UBERON:0002038	79.22	gold quality
rectum	UBERON:0001052	78.85	gold quality
small intestine	UBERON:0002108	78.37	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	62.42
E-CURD-122	yes	37.60
E-CURD-112	yes	21.34
E-ANND-3	yes	14.32
E-MTAB-8410	yes	9.01
E-MTAB-10042	yes	6.85
E-CURD-88	yes	4.54
E-HCAD-6	no	469.25
E-MTAB-5061	no	3.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX1, TBXT

miRNA regulators (miRDB)

34 targeting LAT2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-4684-5P	98.29	67.99	1650
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-585-5P	97.54	69.02	955
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-4714-5P	97.04	67.76	955
HSA-MIR-27A-5P	97.01	65.63	528
HSA-MIR-6085	96.57	64.11	621
HSA-MIR-345-5P	96.40	66.43	663

Literature-anchored findings (GeneRIF, showing 18)

• data show that NTAL (non-T cell activation linker) appears to be a structural and possibly also functional homologue of LAT (linker for activation of T cells)in non-T cells [non-T cell activation linker] (PMID:12486104)
• LAB links BCR engagement to downstream signaling pathways. (PMID:12514734)
• LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function (PMID:14722116)
• LAB resembled a LAT molecule unable to bind phospholipase C-gamma1. (PMID:15153499)
• The NTAL/LAB is expressed in a variety of immune cells. (PMID:15745852)
• NTAL acts as a negative regulator of TNF-alpha and IL-8 production after stimulation via TREM-1 (PMID:17277102)
• observations reported herein support the conclusion that NTAL may be differentially utilized by specific receptors for relaying alternative signals and this suggests a flexibility in the function of TRAPs not previously appreciated. (PMID:17993265)
• These data show that natural killer cell immunoreceptor tyrosine-based activation motifs preferentially use a signaling cassette regulated by interplay between LAT and LAB. (PMID:18645037)
• expression separates T lineage leukemias into two subgroups with good and poor prognostic outcome to prednisone therapy in acute lymphoblastic leukemia in children (PMID:19183565)
• LAT2 protein (NTAL) participates in the activation of the c-Met-Grb2-ERK-cPLA2 signalling cascade at early stages of H. pylori infection. (PMID:19879355)
• LAB has the ability to modulate signaling in virtually every type of leukocyte. (PMID:20643813)
• NTAL acts as a tumor suppressor that enhances the proximal signaling of leukemic blasts. The key downstream molecule responsible for the biological effect of TCR signaling is ERK. (PMID:22269118)
• LAT2 is an early mediator of the anti-leukemic activity of alkylphospholipids and arsenic trioxide. Thus, LAT2 may be used as a target for the design of drugs for cancer therapy. (PMID:23001822)
• The AML1/ETO target gene LAT2 interferes with differentiation of normal hematopoietic precursor cells. (PMID:24456692)
• Its overexpression represents a negative prognostic marker that has been linked to tumor grade, proliferating potential and angiogenesis and mediates intracellular transport of anticancer agents. (PMID:28815339)
• The lipid raft protein NTAL participates in AKT signaling in mantle cell lymphoma. (PMID:31060403)
• NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia. (PMID:32587277)
• Expression of Non-T Cell Activation Linker (NTAL) in Jurkat Cells Negatively Regulates TCR Signaling: Potential Role in Rheumatoid Arthritis. (PMID:36902005)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lat2	ENSMUSG00000040751
rattus_norvegicus	Lat2	ENSRNOG00000021856

Protein

Protein identifiers

Linker for activation of T-cells family member 2 — Q9GZY6 (reviewed: Q9GZY6)

Alternative names: Linker for activation of B-cells, Membrane-associated adapter molecule, Non-T-cell activation linker, Williams-Beuren syndrome chromosomal region 15 protein, Williams-Beuren syndrome chromosomal region 5 protein

All UniProt accessions (5): Q9GZY6, C9JA24, C9JDY7, C9JXP0, F8W947

UniProt curated annotations — full annotation on UniProt →

Function. Involved in FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. May also be involved in BCR (B-cell antigen receptor)-mediated signaling in B-cells and FCGR1 (high affinity immunoglobulin gamma Fc receptor I)-mediated signaling in myeloid cells. Couples activation of these receptors and their associated kinases with distal intracellular events through the recruitment of GRB2.

Subunit / interactions. When phosphorylated, interacts with GRB2. May also interact with SOS1, GAB1 and CBL.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in spleen, peripheral blood lymphocytes, and germinal centers of lymph nodes. Also expressed in placenta, lung, pancreas and small intestine. Present in B-cells, NK cells and monocytes. Absent from T-cells (at protein level).

Post-translational modifications. Phosphorylated on tyrosines following cross-linking of BCR in B-cells, FCGR1 in myeloid cells, or FCER1 in mast cells; which induces the recruitment of GRB2. May be polyubiquitinated.

Disease relevance. LAT2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region. Haploinsufficiency of LAT2 may be the cause of certain cardiovascular and musculo-skeletal abnormalities observed in the disease.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9GZY6-1	1	yes
Q9GZY6-2	2

RefSeq proteins (3): NP_054865, NP_115852, NP_115853* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031428	LAT2	Family

Pfam: PF15703

UniProt features (27 total): mutagenesis site 8, modified residue 7, sequence conflict 4, topological domain 2, lipid moiety-binding region 2, chain 1, splice variant 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3MAZ	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZY6-F1	61.78	0.04

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 (9): 193, 233, 25, 28, 44, 58, 59, 92, 136

Mutagenesis-validated functional residues (8):

Position	Phenotype
58	no change in phosphorylation upon bcr activation.
84	no change in phosphorylation upon bcr activation.
95	slightly reduces phosphorylation upon bcr activation.
110	no change in phosphorylation upon bcr activation.
118	no change in phosphorylation upon bcr activation.
136	slightly reduces phosphorylation upon bcr activation.
193	reduces phosphorylation upon bcr activation.
233	strongly reduces phosphorylation upon bcr activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2730905	Role of LAT2/NTAL/LAB on calcium mobilization

MSigDB gene sets: 269 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MORI_IMMATURE_B_LYMPHOCYTE_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GNF2_LYN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOLDRATH_ANTIGEN_RESPONSE, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_MAST_CELL_ACTIVATION, GOBP_EXOCYTOSIS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, AMIT_EGF_RESPONSE_120_HELA, KOYAMA_SEMA3B_TARGETS_UP

GO Biological Process (8): adaptive immune response (GO:0002250), calcium-mediated signaling (GO:0019722), intracellular signal transduction (GO:0035556), B cell activation (GO:0042113), mast cell degranulation (GO:0043303), B cell receptor signaling pathway (GO:0050853), immune system process (GO:0002376), immune response-regulating signaling pathway (GO:0002764)

GO Molecular Function (2): SH2 domain binding (GO:0042169), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), membrane raft (GO:0045121), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Fc epsilon receptor (FCERI) signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
immune response	1
intracellular signaling cassette	1
intracellular anatomical structure	1
lymphocyte activation	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
antigen receptor-mediated signaling pathway	1
biological_process	1
regulation of immune response	1
protein domain specific binding	1
binding	1
membrane	1
cell periphery	1
membrane microdomain	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LAT2	LAT	O43561	916
LAT2	GRB2	P29354	872
LAT2	LCP2	Q13094	851
LAT2	PLCG1	P19174	816
LAT2	SYK	P43405	816
LAT2	LCT	P09848	716
LAT2	LYN	P07948	714
LAT2	GRAP2	O75791	711
LAT2	BLNK	Q8WV28	670
LAT2	PLCG2	P16885	668
LAT2	ZAP70	P43403	635
LAT2	LAX1	Q8IWV1	586
LAT2	LCK	P06239	578
LAT2	SOS1	Q07889	572
LAT2	SHC1	P29353	514

IntAct

2 interactions, top by confidence:

A	B	Type	Score
UBQLN4	LAT2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): LAT2 (Reconstituted Complex), LAT2 (Affinity Capture-MS), GRB2 (Affinity Capture-Western), PLCG1 (Affinity Capture-Western), PLCG2 (Affinity Capture-Western), LAT2 (Affinity Capture-RNA), LAT2 (Affinity Capture-RNA), LAT2 (Proximity Label-MS), LAT2 (Affinity Capture-RNA), LAT2 (Two-hybrid)

ESM2 similar proteins: A0A1B0GW64, A0A5F4BST2, A0PJX4, A8MVS5, A8MWV9, B0FP48, E5RIL1, E9PGG2, O14836, O60320, O95998, P09564, Q01113, Q01114, Q13477, Q2KI80, Q2T9R2, Q3TS39, Q3UPR0, Q3URD2, Q4V9L6, Q5FVJ4, Q5M869, Q6A044, Q6UWJ8, Q75VT8, Q864V4, Q8BRJ3, Q8BX43, Q8C503, Q8IVY1, Q8K5A9, Q8N112, Q8NC24, Q8NDY8, Q8QZT4, Q8R138, Q969Z4, Q9BUF7, Q9CQM1

Diamond homologs: Q5S7W5, Q8CGL2, Q9GZY6, Q9JHL0

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SYK	“up-regulates activity”	LAT2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1567 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:74216030:G:A	G19R	0.991
7:74216030:G:C	G19R	0.991
7:74216031:G:A	G19E	0.983
7:74223749:T:A	N138K	0.982
7:74223749:T:G	N138K	0.982
7:74216040:C:A	A22D	0.980
7:74223748:A:T	N138I	0.976
7:74216042:A:C	S23R	0.974
7:74216044:T:A	S23R	0.974
7:74216044:T:G	S23R	0.974
7:74224154:C:A	N195K	0.971
7:74224154:C:G	N195K	0.971
7:74224175:G:C	W202C	0.971
7:74224175:G:T	W202C	0.971
7:74216048:T:C	C25R	0.969
7:74216000:T:A	W9R	0.956
7:74216000:T:C	W9R	0.956
7:74224173:T:A	W202R	0.956
7:74224173:T:C	W202R	0.956
7:74224165:T:C	I199T	0.954
7:74216057:T:C	C28R	0.949
7:74223741:T:C	Y136H	0.947
7:74223741:T:G	Y136D	0.946
7:74223748:A:C	N138T	0.946
7:74220601:T:G	Y95D	0.943
7:74220611:T:C	F98S	0.939
7:74220236:T:C	F83L	0.938
7:74220238:C:A	F83L	0.938
7:74220238:C:G	F83L	0.938
7:74223751:T:A	V139E	0.938

dbSNP variants (sampled 300 via entrez): RS1000276920 (7:74218886 G>A), RS1000556086 (7:74212950 G>A), RS1000607875 (7:74217585 C>T), RS1000675249 (7:74212562 C>T), RS1000916879 (7:74229892 T>C), RS1000968528 (7:74229523 G>C), RS1001019513 (7:74229119 C>A,T), RS1001217464 (7:74223350 C>T), RS1001868886 (7:74225435 A>T), RS1002440071 (7:74208370 C>A,T), RS1002934331 (7:74226258 C>G,T), RS1003062443 (7:74211182 C>T), RS1003389646 (7:74209936 C>G), RS1003443775 (7:74209761 G>A,C,T), RS1003547321 (7:74215726 G>A)

Disease associations

OMIM: gene MIM:605719 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	decreases response to substance, decreases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
perifosine	increases expression, decreases response to substance, decreases expression, decreases reaction, increases cleavage	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
Tretinoin	decreases reaction, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
mivebresib	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	increases expression	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
2-bromopalmitate	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
pentanal	increases expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression, decreases reaction	1
methyl-beta-cyclodextrin	decreases expression, increases reaction	1
ICG 001	increases expression	1
abrine	increases expression	1
ixazomib	decreases expression, decreases reaction	1
3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid	increases expression	1
10-(octyloxy)decyl-2-(trimethylammonium)ethyl phosphate	decreases expression, decreases response to substance, increases reaction, affects cotreatment, decreases reaction (+1 more)	1
trametinib	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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