LAT

Summary

LAT (linker for activation of T cells, HGNC:18874) is a protein-coding gene on chromosome 16p11.2, encoding Linker for activation of T-cells family member 1 (O43561). Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development.

The protein encoded by this gene is phosphorylated by ZAP-70/Syk protein tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction pathway. This transmembrane protein localizes to lipid rafts and acts as a docking site for SH2 domain-containing proteins. Upon phosphorylation, this protein recruits multiple adaptor proteins and downstream signaling molecules into multimolecular signaling complexes located near the site of TCR engagement. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 27040 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe combined immunodeficiency due to LAT deficiency (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 241 total — 12 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001014987

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18874
Approved symbol	LAT
Name	linker for activation of T cells
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	LAT1
Ensembl gene	ENSG00000213658
Ensembl biotype	protein_coding
OMIM	602354
Entrez	27040

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 9 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000360872, ENST00000395456, ENST00000395461, ENST00000454369, ENST00000562472, ENST00000562701, ENST00000563964, ENST00000564277, ENST00000564447, ENST00000566177, ENST00000566270, ENST00000566415, ENST00000568440, ENST00000568899, ENST00000570232, ENST00000697038, ENST00000966550, ENST00000966551

RefSeq mRNA: 4 — MANE Select: NM_001014987 NM_001014987, NM_001014988, NM_001014989, NM_014387

CCDS: CCDS10647, CCDS32425, CCDS45455, CCDS53999

Canonical transcript exons

ENST00000395456 — 12 exons

Exon	Start	End
ENSE00000000138	28990189	28990784
ENSE00001909261	28985052	28985517
ENSE00003500367	28989933	28990019
ENSE00003524112	28986382	28986446
ENSE00003569904	28986540	28986569
ENSE00003604781	28986657	28986714
ENSE00003703931	28989774	28989839
ENSE00003706434	28989527	28989589
ENSE00003710609	28986799	28986893
ENSE00003729460	28985713	28985740
ENSE00003731545	28985854	28985888
ENSE00003736446	28986135	28986216

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.49.

FANTOM5 (CAGE): breadth broad, TPM avg 18.2763 / max 594.9906, expressed in 528 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153449	7.3325	338
153448	4.7739	327
153446	3.9507	392
153447	1.0466	266
153445	0.7256	204
153451	0.2453	66
153450	0.1598	73
153452	0.0418	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.49	gold quality
lymph node	UBERON:0000029	97.39	gold quality
blood	UBERON:0000178	94.68	gold quality
vermiform appendix	UBERON:0001154	94.12	gold quality
right coronary artery	UBERON:0001625	92.94	gold quality
spleen	UBERON:0002106	92.38	gold quality
popliteal artery	UBERON:0002250	91.89	gold quality
tibial artery	UBERON:0007610	91.87	gold quality
leukocyte	CL:0000738	91.63	gold quality
monocyte	CL:0000576	91.09	gold quality
descending thoracic aorta	UBERON:0002345	90.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.64	gold quality
thoracic aorta	UBERON:0001515	89.37	gold quality
ascending aorta	UBERON:0001496	89.34	gold quality
left coronary artery	UBERON:0001626	89.04	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.62	gold quality
mucosa of stomach	UBERON:0001199	88.29	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.96	gold quality
lower esophagus	UBERON:0013473	87.95	gold quality
small intestine	UBERON:0002108	87.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.65	gold quality
lower esophagus mucosa	UBERON:0035834	87.23	gold quality
body of uterus	UBERON:0009853	87.14	gold quality
pituitary gland	UBERON:0000007	87.13	gold quality
right lobe of thyroid gland	UBERON:0001119	87.08	gold quality
myometrium	UBERON:0001296	87.02	gold quality
mucosa of transverse colon	UBERON:0004991	87.01	gold quality
fundus of stomach	UBERON:0001160	86.78	gold quality
right uterine tube	UBERON:0001302	86.73	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	43.92
E-HCAD-4	yes	35.57
E-CURD-112	yes	34.89
E-MTAB-8410	yes	21.21
E-HCAD-1	yes	18.74
E-HCAD-10	yes	18.10
E-MTAB-8142	yes	17.94
E-MTAB-9067	yes	12.66
E-ANND-3	yes	6.90
E-MTAB-9801	yes	5.99
E-MTAB-8207	no	546.28
E-GEOD-70580	no	503.77
E-CURD-77	no	402.44
E-CURD-120	no	5.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting LAT, 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-8485	100.00	77.57	4731
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-18A-5P	99.29	71.05	806
HSA-MIR-18B-5P	99.29	71.05	806
HSA-MIR-4735-3P	99.14	69.85	777
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-1225-3P	97.29	64.60	876

Literature-anchored findings (GeneRIF, showing 40)

• LAT displacement from lipid rafts is a molecular mechanism by which PUFAs inhibit T cell signaling (PMID:12029091)
• Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. (PMID:12186560)
• LAT has a role in signal transduction for T cell activation and is stably associated with plasma membrane rafts (PMID:12515827)
• interaction with open-active form of Lck in lipid rafts reveals a new mechanism for the regulation of Lck in T cells (PMID:12570875)
• examination of synergistic assembly in T cell plasma membrane domains (PMID:12646565)
• The T cell adapter molecule LAT is required for correct orientation of the microtubule-organizing center, as it moves toward the interface of the T cell and antigen-presenting cell. (PMID:12847255)
• Results reveal the basis for preferential recognition of specific LAT sites by Gads. (PMID:15029250)
• CD3/T cell receptor complex signaling to beta 1 integrins is defective in LAT-deficient Jurkat T cells, and can be restored with expression of wild-type LAT. (PMID:15100278)
• LAB resembled a LAT molecule unable to bind phospholipase C-gamma1. (PMID:15153499)
• A variable reduction in LAT expression was observed in almost all the inflammatory and neoplastic skin conditions investigated, irrespective of the particular disease. (PMID:15449076)
• Data show that the adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation. (PMID:15699071)
• The loss LAT in mast cells is associated with a defective effector response. (PMID:15745852)
• identify a novel post-translational modification of LAT by ubiquitination that is likely to influence LAT protein stability, intracellular localisation and/or recycling (PMID:16236370)
• human LAT mutant lacking palmitoylation became unstable when the extracellular portion was swapped for that from mouse, indicating that both palmitoylation and the extracellular portion regulate the stability of LAT. (PMID:16460687)
• mapped the transcriptional start sites for the LAT gene and localized the 5’ and 3’ boundaries of the proximal promoter (PMID:16464244)
• In T cells, the SH2 domain of GRB2 binds phosphorylated tyrosines on the adaptor protein LAT and the GRB2 SH3 domains associate with the proline-rich regions of SOS1 and CBL. (PMID:16906159)
• LAT, ZAP-70, and DNMT1 protein levels in CD4(+) T cells can be associated with systemic lupus erythematosus. (PMID:17492476)
• These data indicate that following the rapid formation of signaling complexes upon T cell receptor stimulation, c-Cbl activity is involved in the internalization and possible downregulation of a subset of activated signaling molecules. (PMID:17938199)
• PLSCR1 is a novel amplifier of FcepsilonRI signaling that acts selectively on the Lyn-initiated LAT/phospholipase Cgamma1/calcium axis, resulting in potentiation of a selected set of mast cell responses (PMID:18579528)
• 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)
• A significant decrease of mRNA expression of LAT gene in T cells of asthmatic patients may be due to the up-regulation of its upstream regulatory factors Lck and ZAP-70. (PMID:18683785)
• while Vav-1 and LAT preferentially bound to Syk, phospholipase C-gamma1 bound to both Syk and ZAP-70 (PMID:19018007)
• Elevated expression of LAT1 is associated with squamous cell carcinoma of the lung. (PMID:19068093)
• In addition to its essential role in pre-T cell receptor (TCR)-mediated signaling, LAT plays an important role in TCR signaling in double-positive (DP)thymocytes and is required during thymocyte differentiation from DP to single-positive. (PMID:19380807)
• the formation of LAT-mediated complexes do not appear to depend on PI3K activity, whereas the optimal downstream function of these complexes requires the catalytic function of PI3K. (PMID:19427038)
• PECAM-1-mediated inhibition of GPVI-dependent platelet responses result from recruitment of SHP-2-p85 complexes to tyrosine-phosphorylated PECAM-1, which diminishes the association of PI3K with activatory signaling molecules Gab1 and LAT (PMID:20723025)
• Studies indicate that LAT is present in membrane rafts and involved in signalling through a number of receptors other than the T cell receptor. (PMID:20875087)
• The adaptor LAT contains several conserved serine-based motifs, which are essential for proper signal transduction through the TCR. (PMID:20940326)
• Results indicate for the first time that LAT promotes TCR signal initiation and suggest that this adaptor may contribute to maintain active Lck in proximity of their substrates. (PMID:21152094)
• These results reveal a novel role of HSP90 as a positive regulator for expression of LAT gene in activated T cells. (PMID:21251717)
• LAT recruits Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) following T-cell receptor ligation and Akt kinase phosphorylation in Jurkat cells, activating the phosphoinositide 3-hydroxykinase (PI3K) signaling cascade. (PMID:21282515)
• LAT ubiquitylation is a molecular checkpoint for attenuation of T-cell signaling. (PMID:21282648)
• Data show that MAL regulates membrane order and the distribution of microtubule and transport vesicle docking machinery at the IS and, by doing so, ensures correct protein sorting of Lck and LAT to the cSMAC. (PMID:21508261)
• Activation of T cell antigen receptors resulted in the recruitment and phosphorylation of linker for activation of T cells (Lat) from subsynaptic vesicles. Studies of Lat mutants confirmed that recruitment preceded Lat phosphorylation. (PMID:21642986)
• Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCRalpha gene expression. (PMID:21966541)
• the segment comprising residues 112-126 of human LAT is required for its interaction with Lck. (PMID:22034845)
• Modeling and simulation of aggregation of membrane protein LAT with molecular variability in the number of binding sites for cytosolic Grb2-SOS1-Grb2 (PMID:22396725)
• Nef employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 (PMID:22802418)
• Expression of constitutively active Raf transgene enhances lymphoproliferation, indicating a role for the Ras-MAPK pathway in LAT-mediated autoimmune hyperproliferation. (PMID:22984075)
• LAT is required to maintain calcium homeostasis in T cells. (PMID:22998346)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lat	ENSMUSG00000030742
rattus_norvegicus	Lat	ENSRNOG00000017429

Protein

Protein identifiers

Linker for activation of T-cells family member 1 — O43561 (reviewed: O43561)

Alternative names: 36 kDa phosphotyrosine adapter protein, p36-38

All UniProt accessions (3): C7C5T5, O43561, H3BQD8

UniProt curated annotations — full annotation on UniProt →

Function. Required for TCR (T-cell antigen receptor)- and pre-TCR-mediated signaling, both in mature T-cells and during their development. Involved in FCGR3 (low affinity immunoglobulin gamma Fc region receptor III)-mediated signaling in natural killer cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells. Couples activation of these receptors and their associated kinases with distal intracellular events such as mobilization of intracellular calcium stores, PKC activation, MAPK activation or cytoskeletal reorganization through the recruitment of PLCG1, GRB2, GRAP2, and other signaling molecules.

Subunit / interactions. When phosphorylated, interacts directly with the PIK3R1 subunit of phosphoinositide 3-kinase and the SH2 domains of GRB2, GRAP, GRAP2, PLCG1 and PLCG2. Interacts indirectly with CBL, SOS, VAV, and LCP2. Interacts with SHB, SKAP2 and CLNK. Interacts with FCGR1A. Interacts with GRB2, PLCG1 and THEMIS upon TCR activation in thymocytes. Interacts with THEMIS2. (Microbial infection) Interacts with herpes virus 1/HHV-1 protein US3; this interaction prevents the interaction between LAT and TRAF6.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in thymus, T-cells, NK cells, mast cells and, at lower levels, in spleen. Present in T-cells but not B-cells (at protein level).

Post-translational modifications. Phosphorylated on tyrosines by ZAP70 upon TCR activation, or by SYK upon other immunoreceptor activation; which leads to the recruitment of multiple signaling molecules. Is one of the most prominently tyrosine-phosphorylated proteins detected following TCR engagement. May be dephosphorylated by PTPRJ. Phosphorylated by ITK leading to the recruitment of VAV1 to LAT-containing complexes. Palmitoylation of Cys-26 and Cys-29 is required for raft targeting and efficient phosphorylation. ‘Lys-63’-linked ubiquitinated by TRAF6.

Disease relevance. Immunodeficiency 52 (IMD52) [MIM:617514] An autosomal recessive primary immunodeficiency characterized by T-cell abnormalities, resulting in severe combined immunodeficiency, autoimmune disease, progressive lymphopenia and hypogammaglobulinemia, and lymphoproliferation with splenomegaly. Patients develop severe recurrent infections from infancy. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Engagement of killer inhibitory receptors (KIR) disrupts the interaction of PLCG1 with LAT and blocks target cell-induced activation of PLC, maybe by inducing the dephosphorylation of LAT.

Isoforms (5)

UniProt ID	Names	Canonical?
O43561-1	1, Long	yes
O43561-2	2, Short
O43561-3	3
O43561-4	4
O43561-5	5

RefSeq proteins (4): NP_001014987, NP_001014988, NP_001014989, NP_055202 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008359	Linker_for_activat_Tcells_prot	Family

Pfam: PF15234

UniProt features (37 total): modified residue 17, mutagenesis site 5, region of interest 5, splice variant 3, topological domain 2, lipid moiety-binding region 2, chain 1, transmembrane region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43561-F1	59.77	0.05

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 (19): 39, 40, 41, 43, 84, 101, 106, 109, 110, 156, 161, 200, 220, 224, 240, 241, 255, 26, 29

Mutagenesis-validated functional residues (5):

Position	Phenotype
26	reduces palmitoylation; abolishes localization to lipid rafts.
29	reduces palmitoylation; impairs localization to lipid rafts.
161	abolishes interaction with plcg1.
200	abolishes interaction with grb2 and pik3r1; when associated with f-220.
220	abolishes interaction with grb2 and pik3r1; when associated with f-200.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-202433	Generation of second messenger molecules
R-HSA-2424491	DAP12 signaling
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-109582	Hemostasis
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-202403	TCR signaling
R-HSA-76002	Platelet activation, signaling and aggregation

MSigDB gene sets: 325 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, MODULE_64, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, AP4_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MEMBRANE_RAFT_ORGANIZATION

GO Biological Process (19): adaptive immune response (GO:0002250), lymphocyte homeostasis (GO:0002260), inflammatory response (GO:0006954), immune response (GO:0006955), integrin-mediated signaling pathway (GO:0007229), Ras protein signal transduction (GO:0007265), gene expression (GO:0010467), calcium-mediated signaling (GO:0019722), membrane raft distribution (GO:0031580), intracellular signal transduction (GO:0035556), T cell activation (GO:0042110), mast cell degranulation (GO:0043303), positive regulation of MAPK cascade (GO:0043410), positive regulation of protein kinase activity (GO:0045860), T cell receptor signaling pathway (GO:0050852), regulation of T cell activation (GO:0050863), immune system process (GO:0002376), signal transduction (GO:0007165), homeostasis of number of cells (GO:0048872)

GO Molecular Function (5): protein kinase binding (GO:0019901), signaling receptor complex adaptor activity (GO:0030159), signaling adaptor activity (GO:0035591), molecular condensate scaffold activity (GO:0140693), protein binding (GO:0005515)

GO Cellular Component (8): immunological synapse (GO:0001772), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), COP9 signalosome (GO:0008180), membrane (GO:0016020), TCR signalosome (GO:0036398), membrane raft (GO:0045121)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Fc epsilon receptor (FCERI) signaling	2
Platelet activation, signaling and aggregation	1
TCR signaling	1
DAP12 interactions	1
Innate Immune System	1
MAPK1/MAPK3 signaling	1
Immune System	1
Adaptive Immune System	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein-macromolecule adaptor activity	2
cellular anatomical structure	2
immune response	1
leukocyte homeostasis	1
defense response	1
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway	1
small GTPase-mediated signal transduction	1
macromolecule biosynthetic process	1
intracellular signaling cassette	1
membrane raft organization	1
membrane raft localization	1
intracellular anatomical structure	1
signal transduction	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
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
positive regulation of protein phosphorylation	1
protein kinase activity	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
antigen receptor-mediated signaling pathway	1
T cell activation	1
regulation of lymphocyte activation	1
biological_process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
multicellular organismal-level homeostasis	1
kinase binding	1
signaling receptor binding	1

Protein interactions and networks

STRING

770 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LAT	LCP2	Q13094	998
LAT	GRB2	P29354	995
LAT	PLCG1	P19174	992
LAT	ZAP70	P43403	989
LAT	GRAP2	O75791	980
LAT	VAV1	P15498	929
LAT	LAT2	Q9GZY6	916
LAT	SYK	P43405	904
LAT	LCK	P06239	866
LAT	BLNK	Q8WV28	841
LAT	CLNK	Q7Z7G1	788
LAT	LYN	P07948	772
LAT	GRAP	Q13588	734
LAT	ITK	Q08881	713
LAT	CD247	P20963	694

IntAct

47 interactions, top by confidence:

A	B	Type	Score
PLCG1	LAT	psi-mi:“MI:0407”(direct interaction)	0.810
PLCG1	LAT	psi-mi:“MI:0915”(physical association)	0.810
PLCG1	LAT	psi-mi:“MI:0914”(association)	0.810
GRB2	LAT	psi-mi:“MI:0915”(physical association)	0.710
GRB2	LAT	psi-mi:“MI:0914”(association)	0.710
LAT	EGFR	psi-mi:“MI:0915”(physical association)	0.630
EGFR	LAT	psi-mi:“MI:0915”(physical association)	0.630
PTPN1	LAT	psi-mi:“MI:0403”(colocalization)	0.590
PTPN1	LAT	psi-mi:“MI:0203”(dephosphorylation reaction)	0.590
PTPN1	LAT	psi-mi:“MI:0915”(physical association)	0.590
SGTA	LAT	psi-mi:“MI:0915”(physical association)	0.560
LAT	SGTA	psi-mi:“MI:0915”(physical association)	0.560
LCK	LAT	psi-mi:“MI:0217”(phosphorylation reaction)	0.520
LAT	LCK	psi-mi:“MI:0914”(association)	0.520
THEMIS	LAT	psi-mi:“MI:0914”(association)	0.460
PIK3R1	LAT	psi-mi:“MI:0914”(association)	0.460

BioGRID (160): LAT (Co-fractionation), LAT (Two-hybrid), LAT (Two-hybrid), LAT (Two-hybrid), LAT (PCA), LAT (Affinity Capture-Luminescence), LAT (Proximity Label-MS), TRAF6 (Affinity Capture-Western), US3 (Affinity Capture-Western), PLCG1 (Affinity Capture-Western), PLCG1 (FRET), PLCG2 (FRET), PLCG2 (Affinity Capture-Western), LAT (Affinity Capture-Western), PTPN6 (Affinity Capture-Western)

ESM2 similar proteins: A2A7Y5, A2VE02, A5D7K1, A6NKC9, O43561, O54957, O70601, O88834, P14784, P15391, P16382, P24394, P25917, P25918, Q13651, Q13796, Q2NL68, Q38J84, Q38J85, Q3KP66, Q3LRP3, Q3SYS8, Q3U1F9, Q3UU41, Q58CT8, Q5BK39, Q5FVQ5, Q5JTC6, Q5SX79, Q64322, Q6RFH4, Q6WG24, Q7M4L6, Q7TN12, Q7Z591, Q863Z5, Q86WR7, Q8BHB3, Q8BI17, Q8C708

Diamond homologs: O43561, O54957, O70601

SIGNOR signaling

29 interactions.

A	Effect	B	Mechanism
PTPN1	down-regulates	LAT	dephosphorylation
PTPRJ	down-regulates	LAT	dephosphorylation
MAPK3	down-regulates	LAT	phosphorylation
MAPK8	down-regulates	LAT	phosphorylation
FYN	up-regulates	LAT	phosphorylation
LCK	up-regulates	LAT	phosphorylation
LAT	“up-regulates activity”	VAV1	binding
LAT	“up-regulates activity”	PIK3R1	binding
LAT	“up-regulates activity”	PIK3R2	binding
LAT	“up-regulates activity”	PLCG1	binding
LAT	“up-regulates activity”	PIK3CA	binding
ZAP70	“up-regulates activity”	LAT	phosphorylation
PTPN1	“down-regulates activity”	LAT	dephosphorylation
PTPRJ	“down-regulates activity”	LAT	dephosphorylation
LAT	up-regulates	GRB2	binding
LAT	“up-regulates activity”	PI3K	binding
TRAF6	“up-regulates activity”	LAT	ubiquitination
STK25	“up-regulates activity”	LAT	phosphorylation
STK4	“up-regulates activity”	LAT	phosphorylation
NUAK2	“down-regulates activity”	LAT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 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
DAP12 signaling	7	151.7×	3e-12
GPVI-mediated activation cascade	6	108.9×	1e-09
FCERI mediated Ca+2 mobilization	5	105.0×	6e-08
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	5	105.0×	6e-08
Constitutive Signaling by Aberrant PI3K in Cancer	5	37.3×	4e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	28.5×	1e-05
PIP3 activates AKT signaling	5	19.6×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
T cell receptor signaling pathway	7	53.1×	1e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	1
Uncertain significance	78
Likely benign	124
Benign	14

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1341176	GRCh37/hg19 16p11.2(chr16:28485883-29416001)x1	Pathogenic
1997125	NM_001014987.2(LAT):c.475C>T (p.Arg159Ter)	Pathogenic
2423470	NC_000016.9:g.(?28996697)(29001658_?)del	Pathogenic
2751748	NM_001014987.2(LAT):c.125_128del (p.Asp42fs)	Pathogenic
2856535	NM_001014987.2(LAT):c.286dup (p.Ser96fs)	Pathogenic
427750	NM_001014987.2(LAT):c.268_269del (p.Gly90fs)	Pathogenic
427751	NM_001014987.2(LAT):c.44dup (p.Leu16fs)	Pathogenic
442244	GRCh37/hg19 16p12.2-11.2(chr16:21596299-30399167)x1	Pathogenic
4717457	NM_001014987.2(LAT):c.279del (p.Thr94fs)	Pathogenic
4733323	NM_001014987.2(LAT):c.586C>T (p.Gln196Ter)	Pathogenic
523253	GRCh37/hg19 16p11.2(chr16:28861531-29031059)	Pathogenic
832035	NC_000016.10:g.(?28985376)(29038755_?)del	Pathogenic
636650	NM_001014987.2(LAT):c.78_81del (p.Val27fs)	Likely pathogenic

SpliceAI

1232 predictions. Top by Δscore:

Variant	Effect	Δscore
16:28985516:AGGTG:A	donor_loss	1.0000
16:28986708:GC:G	donor_gain	1.0000
16:28986710:TACCT:T	donor_gain	1.0000
16:28986712:CCT:C	donor_gain	1.0000
16:28986713:CT:C	donor_gain	1.0000
16:28986714:TG:T	donor_loss	1.0000
16:28986715:G:GG	donor_gain	1.0000
16:28986715:GT:G	donor_loss	1.0000
16:28986716:TGAGT:T	donor_loss	1.0000
16:28986717:GAGTG:G	donor_loss	1.0000
16:28986797:AG:A	acceptor_gain	1.0000
16:28986797:AGGGT:A	acceptor_gain	1.0000
16:28986798:G:A	acceptor_gain	1.0000
16:28986798:GGGT:G	acceptor_gain	1.0000
16:28986798:GGGTG:G	acceptor_gain	1.0000
16:28986894:G:GG	donor_gain	1.0000
16:28989588:GG:G	donor_gain	1.0000
16:28989589:GG:G	donor_gain	1.0000
16:28989589:GGT:G	donor_loss	1.0000
16:28989590:G:GG	donor_gain	1.0000
16:28989590:GTGA:G	donor_loss	1.0000
16:28989591:T:A	donor_loss	1.0000
16:28989824:GC:G	donor_gain	1.0000
16:28989825:C:G	donor_gain	1.0000
16:28989835:GCCTG:G	donor_gain	1.0000
16:28989931:A:AG	acceptor_gain	1.0000
16:28989932:G:GG	acceptor_gain	1.0000
16:28989932:GCC:G	acceptor_gain	1.0000
16:28985513:GCCAG:G	donor_gain	0.9900
16:28985519:T:A	donor_loss	0.9900

AlphaMissense

1504 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:28989788:T:C	Y220H	0.983
16:28989789:A:G	Y220C	0.980
16:28986554:A:C	S109R	0.969
16:28986556:C:A	S109R	0.969
16:28986556:C:G	S109R	0.969
16:28989789:A:C	Y220S	0.967
16:28989796:T:A	N222K	0.962
16:28989796:T:G	N222K	0.962
16:28985467:C:G	P17R	0.944
16:28989994:T:A	N257K	0.944
16:28989994:T:G	N257K	0.944
16:28989552:C:A	N202K	0.942
16:28989552:C:G	N202K	0.942
16:28989788:T:G	Y220D	0.940
16:28986213:T:C	I81T	0.937
16:28989779:A:C	S217R	0.936
16:28989781:C:A	S217R	0.936
16:28989781:C:G	S217R	0.936
16:28986565:C:A	N112K	0.929
16:28986565:C:G	N112K	0.929
16:28986887:T:C	F192L	0.925
16:28986889:C:A	F192L	0.925
16:28986889:C:G	F192L	0.925
16:28986545:A:C	S106R	0.919
16:28986547:T:A	S106R	0.919
16:28986547:T:G	S106R	0.919
16:28989788:T:A	Y220N	0.918
16:28989986:T:C	Y255H	0.917
16:28986564:A:T	N112I	0.907
16:28985467:C:A	P17H	0.902

dbSNP variants (sampled 300 via entrez): RS1000209393 (16:28985500 A>C,G), RS1000528284 (16:28986367 A>C), RS1001024532 (16:28991225 T>C), RS1001129876 (16:28985089 G>A,T), RS1002367394 (16:28985588 C>T), RS1002565579 (16:28988212 G>A), RS1002569820 (16:28989367 C>T), RS1002679816 (16:28984504 G>A), RS1003036509 (16:28988423 C>T), RS1003654262 (16:28983438 T>C), RS1003918451 (16:28988794 G>A,T), RS1003922482 (16:28983061 C>A,T), RS1004483202 (16:28985757 C>A,T), RS1004522387 (16:28988472 A>T), RS1005167574 (16:28985248 G>A)

Disease associations

OMIM: gene MIM:602354 | disease phenotypes: MIM:617514

GenCC curated gene-disease

Disease	Classification	Inheritance
severe combined immunodeficiency due to LAT deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
severe combined immunodeficiency due to LAT deficiency	Definitive	AR

Mondo (1): severe combined immunodeficiency due to LAT deficiency (MONDO:0044721)

Orphanet (1): Severe combined immunodeficiency due to LAT deficiency (Orphanet:504523)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000879_2	Crohn’s disease	2.000000e-11
GCST002598_62	Educational attainment	1.000000e-06
GCST007732_19	Allergic disease (asthma, hay fever or eczema)	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5779 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	3
Cisplatin	increases expression, affects cotreatment	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
beauvericin	decreases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
convulxin	decreases reaction, increases phosphorylation	1
cupric oxide	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
bisperoxovanadium	increases expression, affects reaction	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL968354	Binding	Increase in LAT phosphorylation in anti-CD3-coated microbeads-stimulated CD45 deficient human J45.01 cells after 3 days	Lateral compartmentalization of T cell receptor versus CD45 by galectin-N-glycan binding and microfilaments coordinate basal and activation signaling. — J Biol Chem

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DR61	J.CaM2.5	Cancer cell line	Male
CVCL_R862	J.CaM2	Cancer cell line	Male
CVCL_SV32	HAP1 LAT (-) 1	Cancer cell line	Male
CVCL_XQ07	HAP1 LAT (-) 2	Cancer cell line	Male
CVCL_XQ08	HAP1 LAT (-) 3	Cancer cell line	Male
CVCL_XQ09	HAP1 LAT (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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