LNX2

Summary

LNX2 (ligand of numb-protein X 2, HGNC:20421) is a protein-coding gene on chromosome 13q12.2, encoding Ligand of Numb protein X 2 (Q8N448).

Predicted to enable ubiquitin-protein transferase activity. Predicted to act upstream of or within neural precursor cell proliferation and neuron differentiation. Predicted to be located in plasma membrane.

Source: NCBI Gene 222484 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 111 total — 1 pathogenic
• MANE Select transcript: NM_153371

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20421
Approved symbol	LNX2
Name	ligand of numb-protein X 2
Location	13q12.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC46315
Ensembl gene	ENSG00000139517
Ensembl biotype	protein_coding
OMIM	609733
Entrez	222484

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000316334, ENST00000649248, ENST00000869675, ENST00000869676, ENST00000869677, ENST00000869678, ENST00000869679, ENST00000869680, ENST00000869681, ENST00000869682, ENST00000869683, ENST00000940589, ENST00000952571, ENST00000952572, ENST00000952573

RefSeq mRNA: 1 — MANE Select: NM_153371 NM_153371

CCDS: CCDS9323

Canonical transcript exons

ENST00000316334 — 10 exons

Exon	Start	End
ENSE00000938522	27569029	27569276
ENSE00000938523	27567640	27567839
ENSE00000938524	27562413	27562781
ENSE00000938525	27559842	27559985
ENSE00000938526	27556236	27556413
ENSE00000938527	27553208	27553439
ENSE00000938528	27550333	27550491
ENSE00001157716	27581297	27581803
ENSE00001255353	27620375	27620529
ENSE00001255376	27545913	27548470

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 95.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1760 / max 64.2658, expressed in 1616 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136497	5.4461	1589
136496	0.2768	114
136500	0.2225	108
136499	0.1991	120
136498	0.0315	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.97	gold quality
lower lobe of lung	UBERON:0008949	94.11	gold quality
epithelial cell of pancreas	CL:0000083	93.51	gold quality
ileal mucosa	UBERON:0000331	92.81	gold quality
amniotic fluid	UBERON:0000173	92.43	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.81	gold quality
nasal cavity epithelium	UBERON:0005384	91.73	silver quality
colonic mucosa	UBERON:0000317	91.60	gold quality
oral cavity	UBERON:0000167	91.23	gold quality
esophagus squamous epithelium	UBERON:0006920	91.20	gold quality
parotid gland	UBERON:0001831	91.08	silver quality
upper arm skin	UBERON:0004263	91.02	silver quality
left ventricle myocardium	UBERON:0006566	90.84	silver quality
kidney epithelium	UBERON:0004819	90.80	silver quality
palpebral conjunctiva	UBERON:0001812	90.67	gold quality
gingiva	UBERON:0001828	90.41	gold quality
gingival epithelium	UBERON:0001949	89.77	gold quality
jejunum	UBERON:0002115	89.58	gold quality
pancreatic ductal cell	CL:0002079	89.24	gold quality
heart right ventricle	UBERON:0002080	88.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.41	gold quality
pigmented layer of retina	UBERON:0001782	88.36	gold quality
corpus epididymis	UBERON:0004359	88.12	gold quality
duodenum	UBERON:0002114	87.97	gold quality
bronchial epithelial cell	CL:0002328	87.83	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.71	gold quality
caput epididymis	UBERON:0004358	87.59	gold quality
bronchus	UBERON:0002185	87.53	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.44	gold quality
nasal cavity mucosa	UBERON:0001826	87.10	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

149 targeting LNX2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-5680	99.91	69.83	3421

Literature-anchored findings (GeneRIF, showing 4)

• LNX1 and LNX2 interact with CD8alpha and promote its ubiquitylation and endocytosis (PMID:22045731)
• The authors found a high level of LNX1 and LNX2 mRNAs in endocarditis, the principal manifestation of chronic Q fever, but not in acute Q fever. (PMID:22066909)
• FOXC2 or its associated gene expression program may provide an effective target for anti-EMT-based therapies for the treatment of claudin-low/basal B breast tumors or other EMT-/CSC-enriched tumors (PMID:23319804)
• LNX2 involves in the role of ghrelin to promote the neuronal differentiation of adipose tissue-derived mesenchymal stem cells. (PMID:37237241)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lnx2a	ENSDARG00000029177
mus_musculus	Lnx2	ENSMUSG00000016520
rattus_norvegicus	Lnx2	ENSRNOG00000000955
caenorhabditis_elegans		WBGENE00001492
caenorhabditis_elegans		WBGENE00021406

Paralogs (5): LNX1 (ENSG00000072201), MPDZ (ENSG00000107186), PATJ (ENSG00000132849), STXBP4 (ENSG00000166263), FRMPD2 (ENSG00000170324)

Protein

Protein identifiers

Ligand of Numb protein X 2 — Q8N448 (reviewed: Q8N448)

Alternative names: Numb-binding protein 2, PDZ domain-containing RING finger protein 1

All UniProt accessions (1): Q8N448

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with the phosphotyrosine interaction domain of NUMB.

Domain organisation. The NPXY motif is required for the interaction with the PID domain of NUMB. It is however not sufficient.

RefSeq proteins (1): NP_699202* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR036034	PDZ_sf	Homologous_superfamily
IPR051342	PDZ_scaffold	Family

Pfam: PF00595, PF13923

UniProt features (34 total): strand 11, helix 8, turn 5, domain 4, region of interest 2, chain 1, zinc finger region 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5E1Y	X-RAY DIFFRACTION	1.01
5E21	X-RAY DIFFRACTION	1.01
2VWR	X-RAY DIFFRACTION	1.3
5E22	X-RAY DIFFRACTION	1.8
5E11	X-RAY DIFFRACTION	1.8
5DIN	X-RAY DIFFRACTION	1.86
7QCT	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N448-F1	74.97	0.35

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 127 (showing top): AREB6_01, GOBP_NEUROGENESIS, CAGCTG_AP4_Q5, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, MYOD_01, RYTTCCTG_ETS2_B, E12_Q6, ZHENG_BOUND_BY_FOXP3, ZHENG_FOXP3_TARGETS_IN_THYMUS_UP, E2F1_Q3_01, GOMF_ACYLTRANSFERASE_ACTIVITY, GOMF_AMINOACYLTRANSFERASE_ACTIVITY, RORA2_01, BRUINS_UVC_RESPONSE_EARLY_LATE, KOINUMA_TARGETS_OF_SMAD2_OR_SMAD3

GO Biological Process (3): neuron differentiation (GO:0030182), neural precursor cell proliferation (GO:0061351), nervous system development (GO:0007399)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), PDZ domain binding (GO:0030165), identical protein binding (GO:0042802), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	1
generation of neurons	1
cell population proliferation	1
system development	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein domain specific binding	1
protein binding	1
binding	1
cation binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LNX2	POLR1D	P0DPB6	900
LNX2	NUMB	P49757	878
LNX2	NUMBL	Q9Y6R0	873
LNX2	TCOF1	Q13428	762
LNX2	POLR1C	O15160	640
LNX2	MAGEB18	Q96M61	555
LNX2	SRGAP2	O75044	523
LNX2	SRGAP3	O43295	521
LNX2	FCHSD2	O94868	505
LNX2	IP6K2	Q9UHH9	474
LNX2	PDZD4	Q76G19	447
LNX2	ERBB2	P04626	444
LNX2	PDZRN4	Q6ZMN7	442
LNX2	PDZRN3	Q9UPQ7	432
LNX2	STX8	Q9UNK0	429

IntAct

1167 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
MYLIP	LNX2	psi-mi:“MI:0915”(physical association)	0.670
LNX2	MYLIP	psi-mi:“MI:0915”(physical association)	0.670
PEG10	LNX2	psi-mi:“MI:0915”(physical association)	0.670
MAPK9	LNX2	psi-mi:“MI:0915”(physical association)	0.670
IP6K2	LNX2	psi-mi:“MI:0915”(physical association)	0.670
MAP2K5	LNX2	psi-mi:“MI:0915”(physical association)	0.670
PTCD3	LNX2	psi-mi:“MI:0915”(physical association)	0.670
OPTN	LNX2	psi-mi:“MI:0915”(physical association)	0.670
SCLY	LNX2	psi-mi:“MI:0915”(physical association)	0.670
E	LNX2	psi-mi:“MI:0915”(physical association)	0.670
E	LNX2	psi-mi:“MI:0915”(physical association)	0.610
LNX2	LNX2	psi-mi:“MI:0915”(physical association)	0.590
E	LNX2	psi-mi:“MI:0915”(physical association)	0.590
LNX2	Hoxa1	psi-mi:“MI:0915”(physical association)	0.570
Hoxa1	LNX2	psi-mi:“MI:0915”(physical association)	0.570
LNX2	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
LNX2	TGFBR2	psi-mi:“MI:0915”(physical association)	0.560
LNX2	WFS1	psi-mi:“MI:0915”(physical association)	0.560
LNX2	KIF1B	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (149): LNX2 (Two-hybrid), LNX2 (Affinity Capture-RNA), LNX2 (PCA), Hoxa1 (Affinity Capture-Western), LNX2 (Two-hybrid), LNX2 (Two-hybrid), LNX2 (Two-hybrid), PEG10 (Two-hybrid), MSRB3 (Two-hybrid), MYLIP (Two-hybrid), IL16 (Two-hybrid), ATP5B (Two-hybrid), NMD3 (Two-hybrid), IP6K2 (Two-hybrid), SCLY (Two-hybrid)

ESM2 similar proteins: A0A0G2K2P5, A1A5G4, A8E0R9, G9CGD6, O08874, O54785, O70263, O88382, O97758, P15056, P28028, P34908, P39447, P53666, P53667, P53668, P53669, P53670, P53671, P97879, Q04982, Q07157, Q16513, Q32L23, Q5F488, Q5TCQ9, Q6ZWJ1, Q80T23, Q812E4, Q86UL8, Q8N448, Q8QFP8, Q8TBB1, Q8TDW5, Q8TEW8, Q91XL2, Q925T6, Q95168, Q96NE9, Q9C0E4

Diamond homologs: A0A1D5P556, A0A8C0TYJ0, A4D2P6, A5PKA5, A8MUH7, B7WN72, G5ECY0, O08774, O14745, O14924, O15085, O60879, P31007, P31016, P70175, P70441, P78352, P97879, Q09506, Q0D5P3, Q0QWG9, Q12959, Q13425, Q15599, Q15700, Q28619, Q28C55, Q3T0X8, Q3UHD6, Q4R6G4, Q5PYH5, Q5PYH6, Q5PYH7, Q5RCF7, Q5T2W1, Q5ZM14, Q61085, Q61235, Q62108, Q62696

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	LNX2	ubiquitination
LNX2	“down-regulates quantity by destabilization”	NUMB	ubiquitination
LNX2	“down-regulates quantity by destabilization”	NUMB	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
TNFR1-induced NF-kappa-B signaling pathway	5	26.7×	7e-04
PKR-mediated signaling	6	13.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	96
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
394462	GRCh37/hg19 13q12.11-34(chr13:19571503-115092510)	Pathogenic

SpliceAI

1842 predictions. Top by Δscore:

Variant	Effect	Δscore
13:27550331:A:AC	donor_gain	1.0000
13:27550332:C:CT	donor_gain	1.0000
13:27550341:T:TA	donor_gain	1.0000
13:27550487:GTGTG:G	acceptor_gain	1.0000
13:27550488:TGTG:T	acceptor_gain	1.0000
13:27550489:GTG:G	acceptor_gain	1.0000
13:27550490:TG:T	acceptor_gain	1.0000
13:27550492:C:CC	acceptor_gain	1.0000
13:27553257:A:AC	donor_gain	1.0000
13:27553258:C:CC	donor_gain	1.0000
13:27553261:A:AC	donor_gain	1.0000
13:27553261:ATTTT:A	donor_gain	1.0000
13:27553262:T:C	donor_gain	1.0000
13:27553439:CCTG:C	acceptor_loss	1.0000
13:27553441:T:A	acceptor_loss	1.0000
13:27556230:TCTTA:T	donor_loss	1.0000
13:27556231:CTTAC:C	donor_loss	1.0000
13:27556232:TTACC:T	donor_loss	1.0000
13:27556233:TA:T	donor_loss	1.0000
13:27556234:A:C	donor_loss	1.0000
13:27556235:CCT:C	donor_gain	1.0000
13:27556235:CCTCT:C	donor_gain	1.0000
13:27556409:AGATC:A	acceptor_gain	1.0000
13:27556410:GATC:G	acceptor_gain	1.0000
13:27556410:GATCC:G	acceptor_gain	1.0000
13:27556411:ATC:A	acceptor_gain	1.0000
13:27556411:ATCC:A	acceptor_gain	1.0000
13:27556412:TC:T	acceptor_gain	1.0000
13:27556412:TCC:T	acceptor_gain	1.0000
13:27556413:CC:C	acceptor_gain	1.0000

AlphaMissense

4537 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:27548369:A:G	L680P	1.000
13:27548396:A:G	L671S	1.000
13:27548465:C:T	G648D	1.000
13:27550336:A:G	L645S	1.000
13:27550378:T:A	K631I	1.000
13:27550432:A:G	F613S	1.000
13:27550436:C:G	G612R	1.000
13:27553233:A:G	W585R	1.000
13:27553233:A:T	W585R	1.000
13:27556334:A:T	V483D	1.000
13:27562417:A:T	I407N	1.000
13:27562426:G:T	A404D	1.000
13:27562429:G:T	A403D	1.000
13:27562573:A:G	L355S	1.000
13:27562702:A:G	L312P	1.000
13:27581364:A:G	C114R	1.000
13:27581454:A:G	C84R	1.000
13:27581487:A:G	C73R	1.000
13:27581494:G:C	C70W	1.000
13:27581496:A:G	C70R	1.000
13:27581545:G:C	C53W	1.000
13:27581547:A:G	C53R	1.000
13:27581554:G:C	C50W	1.000
13:27581555:C:T	C50Y	1.000
13:27581556:A:G	C50R	1.000
13:27548344:G:C	S688R	0.999
13:27548344:G:T	S688R	0.999
13:27548346:T:G	S688R	0.999
13:27548348:C:T	G687D	0.999
13:27548363:A:T	V682D	0.999

dbSNP variants (sampled 300 via entrez): RS1000086563 (13:27599191 A>G), RS1000128076 (13:27547808 A>G), RS1000148442 (13:27598666 T>C), RS1000158272 (13:27563365 T>C), RS1000210845 (13:27564851 T>C), RS1000237180 (13:27595334 A>G), RS1000248664 (13:27595007 C>G), RS1000325637 (13:27560596 G>A), RS1000390585 (13:27596621 A>C), RS1000392016 (13:27601857 C>A,G), RS1000405705 (13:27608793 G>C), RS1000469909 (13:27580047 CTTTG>C), RS1000576128 (13:27552542 A>G), RS1000578335 (13:27613928 T>A,C), RS1000644145 (13:27554131 A>C)

Disease associations

OMIM: gene MIM:609733 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001031_1	Large B-cell lymphoma	7.000000e-06
GCST002345_16	Response to cytadine analogues (cytosine arabinoside)	4.000000e-06
GCST003542_166	Night sleep phenotypes	5.000000e-06
GCST004599_199	Mean platelet volume	2.000000e-13
GCST004616_98	Platelet distribution width	1.000000e-10
GCST004904_169	Body mass index	2.000000e-10
GCST005951_4	Body mass index	2.000000e-08
GCST90000047_185	Age at first sexual intercourse	1.000000e-10
GCST90002395_150	Mean platelet volume	2.000000e-24
GCST90002401_54	Platelet distribution width	9.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004340	body mass index
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
Polychlorinated Biphenyls	affects expression	1
Quercetin	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	increases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Lactic Acid	increases expression	1
tert-Butylhydroperoxide	decreases methylation	1

Clinical trials (associated diseases)

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