LCP2

Summary

LCP2 (lymphocyte cytosolic protein 2, HGNC:6529) is a protein-coding gene on chromosome 5q35.1, encoding Lymphocyte cytosolic protein 2 (Q13094). Adapter protein primarily involved in signaling pathways within T-cells, as well as other immune cells such as platelets, mast cells, and natural killer (NK) cells.

This gene encodes an adapter protein that acts as a substrate of the T cell antigen receptor (TCR)-activated protein tyrosine kinase pathway. The encoded protein associates with growth factor receptor bound protein 2, and is thought to play a role TCR-mediated intracellular signal transduction. A similar protein in mouse plays a role in normal T-cell development and activation. Mice lacking this gene show subcutaneous and intraperitoneal fetal hemorrhaging, dysfunctional platelets and impaired viability.

Source: NCBI Gene 3937 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 81 (Definitive, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 97 total — 1 pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_005565

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6529
Approved symbol	LCP2
Name	lymphocyte cytosolic protein 2
Location	5q35.1
Locus type	gene with protein product
Status	Approved
Aliases	SLP-76
Ensembl gene	ENSG00000043462
Ensembl biotype	protein_coding
OMIM	601603
Entrez	3937

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 retained_intron, 5 protein_coding

ENST00000046794, ENST00000519149, ENST00000519594, ENST00000520322, ENST00000520344, ENST00000521416, ENST00000522760, ENST00000522823, ENST00000523369, ENST00000968849, ENST00000968850

RefSeq mRNA: 1 — MANE Select: NM_005565 NM_005565

CCDS: CCDS47339

Canonical transcript exons

ENST00000046794 — 21 exons

Exon	Start	End
ENSE00000609392	170250730	170250885
ENSE00000769265	170252434	170252511
ENSE00000769273	170258037	170258166
ENSE00000769281	170266808	170266891
ENSE00000769283	170267009	170267075
ENSE00000769287	170268385	170268482
ENSE00000769288	170270719	170270917
ENSE00000812799	170253119	170253213
ENSE00000812800	170261107	170261137
ENSE00000812801	170262635	170262742
ENSE00001026289	170262967	170262992
ENSE00001026292	170262842	170262861
ENSE00002100375	170246233	170248819
ENSE00002138597	170297534	170297777
ENSE00002533832	170258866	170258878
ENSE00003568261	170293310	170293372
ENSE00003576005	170275320	170275351
ENSE00003583243	170274301	170274338
ENSE00003585965	170287970	170288016
ENSE00003620466	170275795	170275860
ENSE00003693412	170256526	170256575

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 98.87.

FANTOM5 (CAGE): breadth broad, TPM avg 47.4024 / max 3769.2009, expressed in 652 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64785	29.7135	630
64784	11.6594	471
64786	3.4118	382
64787	1.4698	235
64760	0.3890	153
64758	0.2619	115
64762	0.2270	78
64788	0.0974	53
64759	0.0773	40
64763	0.0584	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.87	gold quality
mononuclear cell	CL:0000842	98.75	gold quality
leukocyte	CL:0000738	98.74	gold quality
granulocyte	CL:0000094	98.28	gold quality
blood	UBERON:0000178	98.20	gold quality
bone marrow cell	CL:0002092	97.37	gold quality
spleen	UBERON:0002106	97.16	gold quality
vermiform appendix	UBERON:0001154	96.21	gold quality
lymph node	UBERON:0000029	96.20	gold quality
bone marrow	UBERON:0002371	95.91	gold quality
upper lobe of left lung	UBERON:0008952	95.08	gold quality
gall bladder	UBERON:0002110	94.87	gold quality
upper lobe of lung	UBERON:0008948	94.36	gold quality
thymus	UBERON:0002370	94.05	gold quality
right lung	UBERON:0002167	93.98	gold quality
colonic epithelium	UBERON:0000397	92.64	gold quality
omental fat pad	UBERON:0010414	92.56	gold quality
peritoneum	UBERON:0002358	92.48	gold quality
trabecular bone tissue	UBERON:0002483	91.47	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.39	gold quality
rectum	UBERON:0001052	91.28	gold quality
caecum	UBERON:0001153	91.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.83	gold quality
lung	UBERON:0002048	89.95	gold quality
small intestine	UBERON:0002108	89.24	gold quality
right coronary artery	UBERON:0001625	88.76	gold quality
lower lobe of lung	UBERON:0008949	88.53	gold quality
superficial temporal artery	UBERON:0001614	88.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.77	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.69	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	38.32
E-CURD-122	yes	35.96
E-CURD-112	yes	35.41
E-ANND-3	yes	28.50
E-MTAB-10287	yes	28.25
E-HCAD-6	yes	18.29
E-MTAB-9543	yes	15.03
E-MTAB-9388	yes	12.92
E-MTAB-9067	yes	11.45
E-MTAB-8498	yes	11.11
E-CURD-119	yes	6.06
E-MTAB-6379	no	513.53
E-MTAB-5061	no	3.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX1, SPI1

miRNA regulators (miRDB)

54 targeting LCP2, 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-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745

Literature-anchored findings (GeneRIF, showing 40)

• Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells (SLP-76) (PMID:12084069)
• SLP-76 is essential for NF-kappa B activation and lipid raft translocation of protein kinase C theta and the I kappa B kinase complex. (PMID:12496421)
• SLP-76 is required for intracellular calcium ion mobilization in response to SDF-1alpha/CXCL12-induced prolonged activation of extracellular signal-related protein kinase in Jurkat T cells. (PMID:12817019)
• SLP-76 is necessary for T cell receptor stimulation-induced polarization of the T cell’s microtubule-organizing center, as it moves toward the interface of the T cell and antigen-presenting cell. (PMID:12847255)
• Study provides the first data to address the mechanisms controlling SLP-76 transcription by providing evidence for several key cis-regulatory elements in the promoter region. (PMID:14662865)
• the proline-rich domain in SLP-76 has a role in subcellular localization and T cell function (PMID:14722089)
• Data suggest that SLP-76 may play a role in signaling pathways by interacting with the p85 subunit of phosphoinositide 3-kinase (PI3K). (PMID:15388330)
• SLP-76 need not interact with SH3(PLC) to activate PLC-gamma1, and the P-I region of SLP-76 serves a structural role that is sequence-independent and is not directly related to protein-protein interactions (PMID:15623534)
• Data show that the adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation. (PMID:15699071)
• TCR-induced association of Vav3 with SLP-76 is required for its membrane/IS localization and function (PMID:15708849)
• the Lck binding region of SLP-76 is essential for T cell antigen receptor signaling and normal T cell development and function (PMID:16354835)
• In T cells all SLP-76 proteins are in a approximately 400 kDa complex with the small adaptor protein Grb2-like adaptor protein Gads. (PMID:16356554)
• findings show that retinoic acid(RA) induced the expression of SLP-76, which when co-expressed with an RA-induced receptor, c-FMS, enhanced RA-induced cell differentiation and G0 cell cycle arrest (PMID:16439309)
• The costimulatory effect of CD6 is mediated through phosphorylation-dependent binding of a specific tyrosine residue, 662Y, in its cytoplasmic region to the adaptor SLP-76. (PMID:16914752)
• The P-I region deletion disrupted Vav association and reduced SLP-76-associated kinase activity. (PMID:17148460)
• The integrity of T-cell receptor signaling in vivo is sustained both by strong selection of SLP-76 for the Gads C-SH3 domain and by a capacity to buffer intrinsic crossreactivity. (PMID:17235283)
• phosphorylation of the adaptor molecule SLP-76 is essential for recruitment of the exchange factor Vav leading to Ca(2+) flux and IL-2 production (PMID:17237383)
• Required for activation of IL-2-inducible T cell kinase (ITK); furthermore, an ongoing physical interaction between SLP-76 and ITK is required to maintain ITK in an active conformation. (PMID:17420479)
• study reports that T cell costimulation by the integrin VLA-4 (alpha4beta1) required SLP-76 domains implicated in microcluster assembly (PMID:18549800)
• SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells. (PMID:19667077)
• SLP76 is differentially required for T cell receptor- compared to chemokine C-X-C receptor 4-mediated inside-out signaling pathways regulating T cell adhesion and migration in Jurkat T cells. (PMID:19812192)
• The results show that Bcr-Abl regulates the actin cytoskeleton and non-apoptotic membrane blebbing via a GADS/Slp-76/Nck1 adaptor protein pathway. (PMID:20079431)
• T-cell receptor (TCR)-induced association between ITK and SLP-76, recruitment and transphosphorylation of ITK, actin polarization at the T-cell contact site, and expression of Th2 cytokines (PMID:20457812)
• findings reconfigure the TCR signaling pathway by showing SLP-76 back-regulation of ZAP-70, an event that could ensure that signaling components are in balance for optimal T cell activation (PMID:20534575)
• Results define the composition, stoichiometry and specificity of interactions in the SLP-76, Nck and VAV1 complex, which is crucial for regulation of the actin machinery after T-cell activation. (PMID:20562827)
• LAT recruits Src homology 2 domain-containing leukocyte 76 kDa protein (SLP-76) following T-cell receptor ligation and membrane translocation of Akt and phosphatidylinositol 3-kinase (PI3K)phosphorylation in Jurkat cells, activating Akt signaling. (PMID:21282515)
• findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo (PMID:21469089)
• These data suggest a sequential mechanism whereby ZAP-70-dependent priming of SLP-76 at three N-terminal sites triggers reciprocal regulatory interactions between Itk and SLP-76, which are ultimately required to couple active Itk to PLC-gamma1. (PMID:21725281)
• The spatial correlation between kinase ZAP70 and adaptor SLP76 microclusters (MC) at the cell periphery and the effects of F-actin on MC assembly, were analysed. (PMID:21887278)
• Combining regulated deletion of endogenous SLP-76 with transgenic expression of a SLP-76 SH2 domain mutant demonstrates that the SLP-76 SH2 domain is required for peripheral T cell activation and positive selection of thymocytes. (PMID:21949020)
• our studies demonstrate a novel role for the adaptor molecule SLP-76 in regulating HIV-1 infection in T cells (PMID:22323535)
• both T cell activation and the association between SLP-76 and Nck. After T cell receptor stimulation, SLP-76 was phosphorylated, which enabled the binding of Nck. (PMID:22534133)
• Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells. (PMID:22786724)
• Nef employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 (PMID:22802418)
• These findings reveal a novel role for SLP-76 in CXCR4-mediated T lymphocyte trafficking. (PMID:22806433)
• a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling. (PMID:22902619)
• Unique modes of regulation of positive and negative feedback pathways in T cells by SLP-76. (PMID:23071622)
• Data indicate that the intracellular signaling of ITK-SYK requires both SLP-76 and the adapter function of SYK/ZAP-70 kinases. (PMID:23293025)
• analysis of a costimulatory mechanism by which CXCL12 and antigen converge at SLP-76 microcluster formation to enhance T cell responses (PMID:23901140)
• Data indicate a role for the SAM domain in mediating SLP-76 self-association for T-cell function. (PMID:23935094)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lcp2b	ENSDARG00000036215
danio_rerio	lcp2a	ENSDARG00000055955
danio_rerio		ENSDARG00000091321
mus_musculus	Lcp2	ENSMUSG00000002699
rattus_norvegicus	Lcp2	ENSRNOG00000005620

Paralogs (3): BLNK (ENSG00000095585), CLNK (ENSG00000109684), SH2D6 (ENSG00000152292)

Protein

Protein identifiers

Lymphocyte cytosolic protein 2 — Q13094 (reviewed: Q13094)

Alternative names: SH2 domain-containing leukocyte protein of 76 kDa, SLP-76 tyrosine phosphoprotein

All UniProt accessions (3): E5RKA2, E7ESF6, Q13094

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein primarily involved in signaling pathways within T-cells, as well as other immune cells such as platelets, mast cells, and natural killer (NK) cells. Plays a crucial role for transducing signal from the T-cell receptor (TCR) after antigen recognition leading to T-cell activation. Mechanistically, once phosphorylated by the kinase ZAP70, mediates interactions with the guanine-nucleotide exchange factor VAV1, the adapter protein NCK and the kinase ITK. In turn, stimulates the activation of PKC-theta/PRKCQ and NF-kappa-B transcriptional activity in response to CD3 and CD28 costimulation. Also plays an essential role in AGER-induced signaling pathways including p38 MAPK and ERK1/2 activation leading to cytokine release and pro-inflammatory responses.

Subunit / interactions. Interacts with SLA. Interacts with CBLB. Interacts with GRB2. Interacts with SHB. Interacts with PRAM1. Interacts (via SH2 domain) with CD6 (via tyrosine phosphorylated C-terminus). Interacts with FYB1 and the phosphorylated form of FYB2. Interacts with 14-3-3 adapter/YWHAZ; this phosphorylation leads to YWHAZ proteolytic degradation. Interacts with VAV1; this interaction plays a role in TCR-mediated cytokine production. Interacts with AGER; this interaction plays an important role in AGER-mediated pro-inflammatory responses and cytokine release.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in spleen, thymus and peripheral blood leukocytes. Highly expressed also in T-cell and monocytic cell lines, expressed at lower level in B-cell lines. Not detected in fibroblast or neuroblastoma cell lines.

Post-translational modifications. Phosphorylated after T-cell receptor activation by ZAP70, ITK and TXK, which leads to the up-regulation of Th1 preferred cytokine IL-2. SYK-dependent phosphorylation is required for recruitment of PI3K signaling components.

Disease relevance. Immunodeficiency 81 (IMD81) [MIM:619374] An autosomal recessive disorder characterized by recurrent infections, including fungal infections, associated with T cell, neutrophil, and NK cell dysfunction. B cells may also show maturation abnormalities. Other features include autoimmune hemolytic anemia and abnormal platelet aggregation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The SH2 domain mediates interaction with phosphorylated CD6. The SH2 domain mediates interaction with SHB. Possesses an N-terminal acidic domain containing three tyrosine phosphorylation motifs, a central proline-rich region, and a C-terminal SH2 domain.

RefSeq proteins (1): NP_005556* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR051751	Immunoreceptor_sig_adapters	Family

Pfam: PF00017, PF07647

UniProt features (25 total): helix 7, compositionally biased region 5, modified residue 4, domain 2, turn 2, chain 1, sequence variant 1, sequence conflict 1, strand 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6ZCJ	X-RAY DIFFRACTION	1.53
1YWO	X-RAY DIFFRACTION	1.81
1H3H	SOLUTION NMR
2EAP	SOLUTION NMR
2ROR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13094-F1	63.50	0.21

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 (4): 207, 376, 410, 23

Function

Pathways and Gene Ontology

Reactome pathways

13 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-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-109582	Hemostasis
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-202403	TCR signaling
R-HSA-2172127	DAP12 interactions
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling
R-HSA-76002	Platelet activation, signaling and aggregation

MSigDB gene sets: 435 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, HNF3ALPHA_Q6, MCLACHLAN_DENTAL_CARIES_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, GNF2_CASP8, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ZHAN_MULTIPLE_MYELOMA_MF_UP, MODULE_45, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, MODULE_16

GO Biological Process (7): immune response (GO:0006955), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), intracellular signal transduction (GO:0035556), mast cell activation (GO:0045576), positive regulation of protein kinase activity (GO:0045860), T cell receptor signaling pathway (GO:0050852), immune system process (GO:0002376)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): cytosol (GO:0005829), cell-cell junction (GO:0005911), TCR signalosome (GO:0036398), plasma membrane raft (GO:0044853), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-8 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
immune system process	1
response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
signal transduction	1
myeloid leukocyte activation	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
biological_process	1
binding	1
cytoplasm	1
anchoring junction	1
protein-containing complex	1
T cell receptor complex	1
plasma membrane	1
membrane raft	1
plasma membrane region	1

Protein interactions and networks

STRING

3226 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LCP2	GRAP2	O75791	999
LCP2	ZAP70	P43403	999
LCP2	FYB1	O15117	998
LCP2	LAT	O43561	998
LCP2	VAV1	P15498	998
LCP2	SYK	P43405	998
LCP2	GRB2	P29354	997
LCP2	ITK	Q08881	996
LCP2	LCK	P06239	995
LCP2	NCK1	P16333	995
LCP2	VAV3	Q9UKW4	994
LCP2	PLCG1	P19174	989
LCP2	PLCG2	P16885	983
LCP2	BTK	Q06187	983
LCP2	FYN	P06241	981

IntAct

213 interactions, top by confidence:

A	B	Type	Score
LCP2	GRAP2	psi-mi:“MI:0915”(physical association)	0.980
GRAP2	LCP2	psi-mi:“MI:0915”(physical association)	0.980
LCP2	GRAP2	psi-mi:“MI:2364”(proximity)	0.980

BioGRID (122): LCP2 (Two-hybrid), LCP2 (Two-hybrid), NCK2 (Two-hybrid), GRAP2 (Two-hybrid), FXR2 (Two-hybrid), STAM2 (Two-hybrid), LCP2 (Two-hybrid), GRAP2 (Two-hybrid), LCP2 (Two-hybrid), GRAP2 (Two-hybrid), FXR2 (Two-hybrid), LCP2 (PCA), LCP2 (Affinity Capture-Luminescence), LCP2 (Reconstituted Complex), LCP2 (Affinity Capture-Western)

ESM2 similar proteins: A1X283, A2AAY5, A5D7F8, A5GFW5, A6ND36, D3ZIE4, D3ZUI5, E2RP94, M0R4F8, O15117, O35601, O54967, O75128, O89032, Q04584, Q06649, Q07912, Q13094, Q13625, Q15942, Q17R10, Q17R13, Q1LYG0, Q32LQ1, Q3TC93, Q3UH68, Q498M5, Q4KM52, Q5DTU0, Q5JV73, Q5NBX1, Q5TCZ1, Q5U2X5, Q62523, Q6IQ23, Q6TXD4, Q80TI1, Q8BI17, Q8BZI0, Q8CG79

Diamond homologs: O55033, P08487, P10686, P19174, Q13094, Q4KM52, Q60787, Q62077, Q7Z4S9, Q7Z7G1, Q9D413, Q9QUN3, Q9QZE2, Q9YGC1, Q8WV28, A6QLK6, P23727, P26450, P27986, P35235, P41499, Q06124, Q5R685, Q63787, Q90687, P24604, P42680, P16885, O00459, O08908, O46404, P23726, P29349, P53356, Q24708, Q63788, Q63789, Q64143, Q92569, Q9CX99

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
ZAP70	“up-regulates activity”	LCP2	phosphorylation
MAP4K1	up-regulates	LCP2	phosphorylation
TXK	“up-regulates activity”	LCP2	phosphorylation
MAP4K1	“down-regulates activity”	LCP2	phosphorylation
ZAP70	up-regulates	LCP2	phosphorylation
TXK	up-regulates	LCP2	phosphorylation
FYN	down-regulates	LCP2	phosphorylation
LCK	unknown	LCP2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
InlB-mediated entry of Listeria monocytogenes into host cell	5	112.0×	2e-08
Constitutive Signaling by EGFRvIII	5	105.0×	3e-08
Regulation of KIT signaling	5	88.4×	6e-08
Regulation of signaling by CBL	6	87.6×	3e-09
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	84.0×	7e-08
Negative regulation of MET activity	5	76.3×	1e-07
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	76.3×	1e-07
DAP12 signaling	7	75.8×	5e-10

GO biological processes:

GO term	Partners	Fold	FDR
T cell costimulation	5	49.3×	1e-05
T cell activation	6	40.9×	2e-06
epidermal growth factor receptor signaling pathway	5	32.6×	3e-05
T cell receptor signaling pathway	7	28.0×	2e-06
integrin-mediated signaling pathway	5	21.1×	2e-04
adaptive immune response	5	11.1×	2e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	10.3×	3e-03
intracellular signal transduction	9	9.0×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	61
Likely benign	12
Benign	15

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1172796	NM_005565.5(LCP2):c.957+1G>A	Pathogenic

SpliceAI

2741 predictions. Top by Δscore:

Variant	Effect	Δscore
5:170250724:CCTTA:C	donor_loss	1.0000
5:170250725:CTTAC:C	donor_loss	1.0000
5:170250726:TTACC:T	donor_loss	1.0000
5:170250727:TACC:T	donor_loss	1.0000
5:170250728:A:AC	donor_gain	1.0000
5:170250728:ACCTC:A	donor_loss	1.0000
5:170250729:C:A	donor_loss	1.0000
5:170250729:C:CC	donor_gain	1.0000
5:170250729:CCT:C	donor_gain	1.0000
5:170250773:T:A	donor_gain	1.0000
5:170250881:CCATC:C	acceptor_gain	1.0000
5:170250882:CATC:C	acceptor_gain	1.0000
5:170250882:CATCC:C	acceptor_gain	1.0000
5:170250884:TC:T	acceptor_gain	1.0000
5:170250884:TCC:T	acceptor_loss	1.0000
5:170250885:CC:C	acceptor_gain	1.0000
5:170250886:C:CC	acceptor_gain	1.0000
5:170250886:CTAAA:C	acceptor_loss	1.0000
5:170250887:T:A	acceptor_loss	1.0000
5:170262633:A:AC	donor_gain	1.0000
5:170262634:C:CC	donor_gain	1.0000
5:170262635:TTTGG:T	donor_gain	1.0000
5:170262636:TTGGC:T	donor_gain	1.0000
5:170262654:T:TA	donor_gain	1.0000
5:170262655:C:A	donor_gain	1.0000
5:170270781:T:TA	donor_gain	1.0000
5:170275793:A:AC	donor_gain	1.0000
5:170275794:C:CC	donor_gain	1.0000
5:170275794:CTTG:C	donor_gain	1.0000
5:170275859:TC:T	acceptor_gain	1.0000

AlphaMissense

3510 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:170248722:A:G	L526S	1.000
5:170248764:A:G	L512P	1.000
5:170250796:G:C	N471K	1.000
5:170250796:G:T	N471K	1.000
5:170250827:A:G	L461P	1.000
5:170250827:A:T	L461H	1.000
5:170250865:T:A	R448S	1.000
5:170250865:T:G	R448S	1.000
5:170250866:C:G	R448T	1.000
5:170250869:A:T	V447D	1.000
5:170250872:A:G	L446P	1.000
5:170250874:A:C	F445L	1.000
5:170250874:A:T	F445L	1.000
5:170250876:A:G	F445L	1.000
5:170252450:A:T	L436H	1.000
5:170248764:A:T	L512H	0.999
5:170248770:A:G	L510P	0.999
5:170248770:A:T	L510H	0.999
5:170248814:A:C	F495L	0.999
5:170248814:A:T	F495L	0.999
5:170248816:A:G	F495L	0.999
5:170250752:C:A	G486V	0.999
5:170250752:C:T	G486E	0.999
5:170250753:C:G	G486R	0.999
5:170250753:C:T	G486R	0.999
5:170250755:A:G	L485S	0.999
5:170250762:A:C	Y483D	0.999
5:170250785:C:G	R475P	0.999
5:170250788:A:C	I474S	0.999
5:170250788:A:G	I474T	0.999

dbSNP variants (sampled 300 via entrez): RS1000012215 (5:170259719 C>A), RS1000043646 (5:170260007 A>C), RS1000255388 (5:170282537 C>T), RS1000288004 (5:170282852 G>A), RS1000439422 (5:170277494 T>A), RS1000441242 (5:170272116 C>A,T), RS1000458118 (5:170298924 G>A), RS1000479576 (5:170282418 C>T), RS1000485431 (5:170294292 T>C), RS1000517618 (5:170253630 G>T), RS1000530145 (5:170254651 C>T), RS1000574461 (5:170246360 T>C), RS1000676004 (5:170259996 T>C), RS1000708904 (5:170247749 A>G), RS1000923274 (5:170276241 G>T)

Disease associations

OMIM: gene MIM:601603 | disease phenotypes: MIM:619374

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 81	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 81	Definitive	AR

Mondo (1): immunodeficiency 81 (MONDO:0030302)

Orphanet (0):

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000967	Petechiae
HP:0000988	Skin rash
HP:0001890	Autoimmune hemolytic anemia
HP:0002719	Recurrent infections
HP:0002721	Immunodeficiency
HP:0003203	Decreased neutrophil oxidative burst
HP:0008320	Impaired collagen-induced platelet aggregation
HP:0012177	Abnormal natural killer cell physiology
HP:0025615	Abscess
HP:0030388	Decreased class-switched memory B cell proportion
HP:0031402	Reduced antigen-specific T cell proliferation
HP:0031545	Abnormally low T cell receptor excision circle level
HP:0032218	Decreased CD4+ T cell proportion
HP:0040238	Impaired neutrophil chemotaxis
HP:0100838	Recurrent cutaneous abscess formation

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002481_3	Acne (severe)	3.000000e-06
GCST003830_42	Response to bronchodilator in chronic obstructive pulmonary disease (change in FEV1)	6.000000e-07
GCST005859_3	Liver transplant-free survival in primary sclerosing cholangitis (time to event)	7.000000e-08
GCST012190_6	Body mass index and diastolic blood pressure (bivariate analysis)	5.000000e-06
GCST90002381_403	Eosinophil count	5.000000e-14
GCST90002382_137	Eosinophil percentage of white cells	3.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005921	FEV change measurement
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196086 (SINGLE PROTEIN)

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

ChEMBL bioactivities

35 potent at pChembl≥5 of 35 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	IC50	9	nM	CHEMBL6133969
7.89	IC50	13	nM	CHEMBL6152052
7.77	IC50	17	nM	CHEMBL5860476
7.70	IC50	20	nM	CHEMBL6150979
7.50	IC50	32	nM	CHEMBL6160518
7.47	IC50	34	nM	CHEMBL5877890
7.43	IC50	37	nM	CHEMBL5969973
7.33	IC50	47	nM	CHEMBL5755922
7.33	IC50	47	nM	CHEMBL6144164
7.32	IC50	48	nM	CHEMBL6132870
7.28	IC50	52	nM	CHEMBL5826036
7.28	IC50	53	nM	CHEMBL5856381
7.28	IC50	53	nM	CHEMBL5842777
7.18	IC50	66	nM	CHEMBL6146353
7.16	IC50	70	nM	CHEMBL5848065
7.11	IC50	77	nM	CHEMBL6132909
7.09	IC50	81	nM	CHEMBL5936007
7.09	IC50	82	nM	CHEMBL6147087
7.06	IC50	87	nM	CHEMBL5902160
7.01	IC50	98	nM	CHEMBL6144058
6.95	IC50	112	nM	CHEMBL5759430
6.94	IC50	115	nM	CHEMBL6102709
6.92	IC50	121	nM	CHEMBL5897911
6.86	IC50	139	nM	CHEMBL6149797
6.81	IC50	155	nM	CHEMBL6148235
6.77	IC50	170	nM	CHEMBL6171777
6.70	IC50	198	nM	CHEMBL6133655
6.65	IC50	222	nM	CHEMBL6147154
6.42	IC50	383	nM	CHEMBL6108993
6.28	IC50	520	nM	CHEMBL6144977
5.98	IC50	1040	nM	CHEMBL5419358
5.97	IC50	1077	nM	CHEMBL6150317
5.97	IC50	1074	nM	CHEMBL6091907
5.92	IC50	1200	nM	CHEMBL6167391

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
Tretinoin	decreases reaction, increases expression, affects cotreatment, increases reaction, increases phosphorylation	3
Valproic Acid	affects cotreatment, increases expression	3
Nickel	increases expression	2
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
zomepirac glucuronide	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
tolmetin glucuronide	increases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Curcumin	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
T-2 Toxin	decreases expression	1
Vincristine	increases expression	1
Isotretinoin	increases expression	1
Aflatoxin B1	increases methylation	1
Paclitaxel	increases expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6081514	Binding	Inhibition of SLP76 phosphorylation at Ser376 in human Jurkat cells incubated for 30 mins by HTRF assay	Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer. — J Med Chem

Clinical trials (associated diseases)

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