LEF1

Summary

LEF1 (lymphoid enhancer binding factor 1, HGNC:6551) is a protein-coding gene on chromosome 4q25, encoding Lymphoid enhancer-binding factor 1 (Q9UJU2). Transcription factor that binds DNA in a sequence-specific manner.

This gene encodes a transcription factor belonging to a family of proteins that share homology with the high mobility group protein-1. The protein encoded by this gene can bind to a functionally important site in the T-cell receptor-alpha enhancer, thereby conferring maximal enhancer activity. This transcription factor is involved in the Wnt signaling pathway, and it may function in hair cell differentiation and follicle morphogenesis. Mutations in this gene have been found in somatic sebaceous tumors. This gene has also been linked to other cancers, including androgen-independent prostate cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51176 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ectodermal dysplasia 17 with or without limb malformations (Strong, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 79 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Transcription factor: yes — 125 downstream targets (CollecTRI)
• MANE Select transcript: NM_016269

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6551
Approved symbol	LEF1
Name	lymphoid enhancer binding factor 1
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	TCF1ALPHA, TCF10, TCF7L3
Ensembl gene	ENSG00000138795
Ensembl biotype	protein_coding
OMIM	153245
Entrez	51176

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 11 protein_coding_CDS_not_defined, 10 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000265165, ENST00000379951, ENST00000438313, ENST00000503879, ENST00000504426, ENST00000504775, ENST00000504950, ENST00000505293, ENST00000505297, ENST00000505328, ENST00000505379, ENST00000506680, ENST00000507470, ENST00000509428, ENST00000510135, ENST00000510624, ENST00000510717, ENST00000512172, ENST00000512407, ENST00000514444, ENST00000515500, ENST00000890430, ENST00000890431, ENST00000948093, ENST00000948094

RefSeq mRNA: 4 — MANE Select: NM_016269 NM_001130713, NM_001130714, NM_001166119, NM_016269

CCDS: CCDS3679, CCDS47122, CCDS47123, CCDS54791

Canonical transcript exons

ENST00000265165 — 12 exons

Exon	Start	End
ENSE00001136349	108167555	108168932
ENSE00003468993	108081586	108081669
ENSE00003478404	108079492	108079614
ENSE00003510092	108063623	108063663
ENSE00003515141	108163568	108163701
ENSE00003530344	108064336	108064384
ENSE00003558404	108089125	108089257
ENSE00003604670	108078220	108078382
ENSE00003619569	108047548	108048751
ENSE00003638064	108165097	108165163
ENSE00003651348	108070663	108070770
ENSE00003663409	108083356	108083446

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 98.83.

FANTOM5 (CAGE): breadth broad, TPM avg 16.4789 / max 1136.8099, expressed in 889 samples.

FANTOM5 promoters (48 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53538	3.4046	124
53574	2.4312	330
53568	1.9601	450
53555	0.8444	365
53571	0.6932	259
53558	0.6419	395
53533	0.5208	187
53565	0.4558	116
53547	0.4370	88
53573	0.4165	150

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	98.83	gold quality
lymph node	UBERON:0000029	97.22	gold quality
tibia	UBERON:0000979	97.08	gold quality
oocyte	CL:0000023	96.14	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.49	gold quality
secondary oocyte	CL:0000655	95.32	gold quality
blood	UBERON:0000178	94.19	gold quality
vermiform appendix	UBERON:0001154	93.99	gold quality
buccal mucosa cell	CL:0002336	93.61	gold quality
granulocyte	CL:0000094	93.32	gold quality
right adrenal gland cortex	UBERON:0035827	91.65	gold quality
endometrium	UBERON:0001295	91.52	gold quality
adrenal tissue	UBERON:0018303	91.52	gold quality
caput epididymis	UBERON:0004358	91.34	gold quality
right adrenal gland	UBERON:0001233	91.24	gold quality
caecum	UBERON:0001153	90.65	gold quality
sperm	CL:0000019	90.45	gold quality
bone marrow	UBERON:0002371	90.34	gold quality
adrenal gland	UBERON:0002369	90.17	gold quality
right testis	UBERON:0004534	89.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.90	gold quality
adrenal cortex	UBERON:0001235	89.89	gold quality
left testis	UBERON:0004533	89.81	gold quality
left adrenal gland	UBERON:0001234	89.64	gold quality
testis	UBERON:0000473	89.56	gold quality
male germ cell	CL:0000015	89.10	gold quality
left adrenal gland cortex	UBERON:0035825	88.95	gold quality
bone marrow cell	CL:0002092	88.72	gold quality
germinal epithelium of ovary	UBERON:0001304	88.70	gold quality
periodontal ligament	UBERON:0008266	88.06	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	1003.88
E-GEOD-131882	yes	863.54
E-ANND-5	yes	607.20
E-CURD-89	yes	431.23
E-CURD-122	yes	281.96
E-HCAD-6	yes	182.90
E-HCAD-4	yes	106.73
E-CURD-88	yes	47.01
E-HCAD-8	yes	45.43
E-GEOD-109979	yes	38.60
E-HCAD-10	yes	23.32
E-HCAD-35	yes	21.25
E-ANND-3	yes	14.50
E-MTAB-9067	yes	13.76
E-CURD-112	yes	10.18

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

125 targets.

Target	Regulation
ADAM2	Repression
AP1
APP	Repression
AR	Unknown
ATP11C
AXIN1	Repression
BCL2	Activation
BGLAP	Repression
BIRC5	Unknown
BMP4	Activation
CACNA1G	Activation
CASP4	Repression
CCL7	Unknown
CCNA1
CCND1	Unknown
CD1D	Repression
CD4	Unknown
CDH1	Unknown
CDKN1A	Unknown
CDKN2A
CDX1	Activation
CDX4	Activation
CEBPA	Unknown
CEL
CELA2A	Activation
CHGA	Unknown
CLDN2	Activation
COL10A1
COL11A1	Activation
COL1A1	Repression

JASPAR motifs

Motif	Name	Family
MA0768.1	LEF1	TCF-7-related factors

JASPAR matrix evidence (PMIDs): PMID:19443739

Upstream regulators (CollecTRI, top): APP, BMP2, CTNNB1, ERG, FOXC1, LEF1, LMO2, MEF2C, NELFB, NFKB, NFYA, PAX5, PITX2, RUNX2, SATB2, SOX17, SOX2, SOX9, STAT5A, TCF4, TCF7, TCF7L2, TLE5, WNT1, WNT3A, YY1, ZBTB16

miRNA regulators (miRDB)

109 targeting LEF1, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
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-12136	99.98	72.81	5713
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-219A-5P	99.91	73.36	735

Literature-anchored findings (GeneRIF, showing 40)

• Microphthalmia-associated transcription factor interacts with LEF-1, a mediator of Wnt signaling. (PMID:12032083)
• MITF-M transactivates its own promoter (M promoter) by interacting with LEF-1 (PMID:12048204)
• wnt3a-beta catenin signaling regulates LEF-1 gene expression (PMID:12052822)
• direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of epithelial-mesenchymal transformation (PMID:12095232)
• ZEB1 plays a role in repressing E-cadherin and MUC1 in epithelial cells [ZEB-1] (PMID:12161443)
• Nr-CAM is the gene most extensively induced by LEF1 (PMID:12183361)
• induction of Lef/Tcf-dependent transcription in human endothelial cells by fibroblast growth factor-2 (PMID:12235165)
• These results suggest that NLK phosphorylation on these sites contributes to the down-regulation of LEF-1/TCF transcriptional activity. (PMID:12556497)
• Tcf/LEF1 has a role in transcriptional induction of cyclin D1 (PMID:12589056)
• loss of expression of this transcription factor in a subset of peripheral t-cell lymphomas (PMID:12707037)
• Beta-catenin, Lef-1, Ets transcription factors, and the AP-1 protein c-Jun each weakly enhanced luciferase expression from an OPN promoter. (PMID:14990565)
• Lymphoid enhancer factor/T cell factor has a role in development of colorectal cancer [review] (PMID:15000148)
• Wnt regulation of the Lef-1 promoter at the WRE may play an important role during airway submucosal glandular bud formation. (PMID:15194563)
• a 110 bp Wnt/beta-catenin-responsive element, contained within a minimal 2.5 kb Lef-1 promoter, plays an important role in regulating mesenchymal, and potentially epithelial, expression during follicle development in mouse embryos. (PMID:15245424)
• LEF-1 expression is regulated through PITX2, LEF-1 and beta-catenin direct physical interactions (PMID:15728254)
• Smad-binding peptide aptamer LEF1 can be developed to selectively inhibit TGF-beta-induced gene expression. (PMID:15750622)
• Taken together, these data suggest that LEF-1 is abundantly expressed in human tumors and the ratio of the oncogenic and the dominant negative short isoform altered not only in carcinomas but also in leukemia. (PMID:15756419)
• LEF1 5’-untranslated region (UTR) mediates cap-independent translation; the 5’-UTR of full-length LEF1 mRNA contains a bona fide internal ribosome entry site (IRES). (PMID:16120831)
• LEF1, a downstream component of the Wnt signaling pathway, mediates breast cancer cell invasion, and may be regulated in part by estradiol (PMID:16142310)
• Involvement of LEF1 protein in the wingless type protein (WNT) signaling pathway not only regulates T cell development, but also peripheral T cell differentiation. (PMID:16424171)
• hAR is a direct target of LEF-1/TCF transcriptional regulation in PCa cells; expression of the hAR protein is suppressed by a degradation pathway regulated by cross-talk of Wnt, Akt, and PP2A (PMID:16474850)
• Sebaceous gland neoplasms harbor inactivating mutations in LEF1. (PMID:16565724)
• NARF functions as a novel ubiquitin-ligase to regulate ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (PMID:16714285)
• the biological outcome of aberrant LEF1 activation in colon cancer is directed by differential promoter activation and repression (PMID:16809766)
• LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with congenital neutropenia (PMID:17063141)
• Cooperates with SMAD4 to activate c-myc expression. (PMID:17132729)
• Additional prolactin (PRL) regulatory elements corresponding to LEF-l and AP-1 transcription factor binding sites appear important for PRL expression. (PMID:17240357)
• LEF-1 is a decisive transcription factor in neutrophil granulopoiesis [review] (PMID:17360796)
• This study demonstrates that the two consensus Lef/Tcf binding elements (TBE)reported in neoplastic cells are dispensable for c-Myc regulation in normal keratinocytes, which instead use a novel TBE sequence variant. (PMID:17466981)
• Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas (PMID:17585052)
• Re-expression of E-cadherin in HT29(US) cells restored the ability of caveolin-1 to down-regulate beta-catenin-Tcf/Lef-dependent transcription and survivin expression, as seen in HT29(ATCC) cells. (PMID:17785436)
• These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and beta-catenin. (PMID:17785445)
• Marked upregulation of lymphoid enhancer-binding factor 1 (LEF-1), a transcription factor in the Wnt pathway, was found in HBsAg-expressing cells (PMID:17947518)
• role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development (PMID:18316418)
• IL-4 stimulation possesses a negative effect on the expressions of LEF-1 and TCF-1 in primary T cells, suggesting a positive feedback effect of IL-4 on IL4 gene expression. (PMID:18579517)
• beta-catenin acts together with Lef-1 to influence DeltaNp63 promoter activity and protein expression (PMID:18615589)
• Dpr1 negatively modulates the basal activity of Wnt1/beta-catenin signaling in the nucleus by keeping LEF1 in the repressive state. (PMID:18936100)
• Id-1 is a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27(Kip1) phosphorylation (PMID:19079342)
• GnRH regulation of Jun transcription requires a functional interaction between TCF/LEF and beta-catenin. (PMID:19131506)
• By reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE(2)-induced signaling events linked to beta-catenin/Tcf/Lef-dependent transcription of tumor survival genes including cox-2 itself and survivin. (PMID:19244345)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lef1	ENSDARG00000031894
mus_musculus	Lef1	ENSMUSG00000027985
rattus_norvegicus	Lef1	ENSRNOG00000010121

Paralogs (3): TCF7 (ENSG00000081059), TCF7L2 (ENSG00000148737), TCF7L1 (ENSG00000152284)

Protein

Protein identifiers

Lymphoid enhancer-binding factor 1 — Q9UJU2 (reviewed: Q9UJU2)

Alternative names: T cell-specific transcription factor 1-alpha

All UniProt accessions (4): Q9UJU2, D6RAB1, D6RID7, D6RIV1

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that binds DNA in a sequence-specific manner. Participates in the Wnt signaling pathway. Activates transcription of target genes in the presence of CTNNB1 and EP300. PIAG antagonizes both Wnt-dependent and Wnt-independent activation by LEF1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by LEF1 and CTNNB1. Regulates T-cell receptor alpha enhancer function. Required for IL17A expressing gamma-delta T-cell maturation and development, via binding to regulator loci of BLK to modulate expression. Acts as a positive regulator of odontoblast differentiation during mesenchymal tooth germ formation, expression is repressed during the bell stage by MSX1-mediated inhibition of CTNNB1 signaling. May play a role in hair cell differentiation and follicle morphogenesis. Transcriptionally activates MYC and CCND1 expression and enhances proliferation of pancreatic tumor cells. Lacks the CTNNB1 interaction domain and may therefore be an antagonist for Wnt signaling. Transcriptionally activates the fibronectin promoter, binds to and represses transcription from the E-cadherin promoter in a CTNNB1-independent manner, and is involved in reducing cellular aggregation and increasing cell migration of pancreatic cancer cells.

Subunit / interactions. Binds the armadillo repeat of CTNNB1 and forms a stable complex. Interacts with EP300, TLE1 and PIASG. Binds ALYREF/THOC4, MDFI and MDFIC. Interacts with NLK. Interacts with DAZAP2.

Subcellular location. Nucleus.

Tissue specificity. Detected in thymus. Not detected in normal colon, but highly expressed in colon cancer biopsies and colon cancer cell lines. Expressed in several pancreatic tumors and weakly expressed in normal pancreatic tissue. Isoforms 1 and 5 are detected in several pancreatic cell lines.

Post-translational modifications. Phosphorylated at Thr-155 and/or Ser-166 by NLK. Phosphorylation by NLK at these sites represses LEF1-mediated transcriptional activation of target genes of the canonical Wnt signaling pathway.

Disease relevance. Ectodermal dysplasia 17 with or without limb malformations (ECTD17) [MIM:621224] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures such as hair, teeth, nails and sweat glands, with or without any additional clinical sign. Each combination of clinical features represents a different type of ectodermal dysplasia. ECTD17 is an autosomal dominant form characterized by hypohidrosis, dry skin, hair and tooth anomalies, and slow nail growth. Some patients have limb abnormalities such as radial ray defects, polydactyly, syndactyly, and split hand/foot malformation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Proline-rich and acidic regions are implicated in the activation functions of RNA polymerase II transcription factors.

Miscellaneous. Produced by alternative promoter usage. Produced by alternative splicing of isoform 1. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Produced by alternative promoter usage. Acts as a dominant negative mutant. Produced by alternative splicing of isoform 3. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1.

Similarity. Belongs to the TCF/LEF family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9UJU2-1	1, A	yes
Q9UJU2-2	2, B, 8A
Q9UJU2-3	3, LEF-1-DN
Q9UJU2-4	4
Q9UJU2-5	5
Q9UJU2-6	6
Q9UJU2-7	7

RefSeq proteins (4): NP_001124185, NP_001124186, NP_001159591, NP_057353* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR013558	CTNNB1-bd_N	Domain
IPR024940	TCF/LEF	Family
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR036910	HMG_box_dom_sf	Homologous_superfamily

Pfam: PF00505, PF08347

UniProt features (28 total): splice variant 5, region of interest 5, compositionally biased region 4, sequence variant 4, modified residue 3, cross-link 2, mutagenesis site 2, chain 1, DNA-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJU2-F1	57.74	0.17

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 (5): 132, 155, 166, 27, 269

Mutagenesis-validated functional residues (2):

Position	Phenotype
155	reduced phosphorylation by nlk; when associated with a-166.
166	reduced phosphorylation by nlk; when associated with a-155.

Function

Pathways and Gene Ontology

Reactome pathways

30 pathways

ID	Pathway
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-4086398	Ca2+ pathway
R-HSA-4411364	Binding of TCF/LEF:CTNNB1 to target gene promoters
R-HSA-4641265	Repression of WNT target genes
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8951430	RUNX3 regulates WNT signaling
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9733709	Cardiogenesis
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9796292	Formation of axial mesoderm
R-HSA-9824272	Somitogenesis
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation
R-HSA-9825892	Regulation of MITF-M-dependent genes involved in cell cycle and proliferation
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-9909649	Regulation of PD-L1(CD274) transcription
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9758941	Gastrulation
R-HSA-9856651	MITF-M-dependent gene expression

MSigDB gene sets: 739 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_DENTATE_GYRUS_DEVELOPMENT, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, chr4q25, GOBP_HINDBRAIN_DEVELOPMENT, RRAGTTGT_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3

GO Biological Process (69): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in blood vessel morphogenesis (GO:0001569), osteoblast differentiation (GO:0001649), somitogenesis (GO:0001756), epithelial to mesenchymal transition (GO:0001837), sprouting angiogenesis (GO:0002040), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), positive regulation of gene expression (GO:0010628), positive regulation of epithelial to mesenchymal transition (GO:0010718), dentate gyrus development (GO:0021542), forebrain radial glial cell differentiation (GO:0021861), forebrain neuroblast division (GO:0021873), formation of radial glial scaffolds (GO:0021943), positive regulation of Wnt signaling pathway (GO:0030177), neutrophil differentiation (GO:0030223), embryonic limb morphogenesis (GO:0030326), positive regulation of cell migration (GO:0030335), BMP signaling pathway (GO:0030509), positive regulation of granulocyte differentiation (GO:0030854), mammary gland development (GO:0030879), negative regulation of interleukin-13 production (GO:0032696), negative regulation of interleukin-4 production (GO:0032713), negative regulation of interleukin-5 production (GO:0032714), T cell receptor V(D)J recombination (GO:0033153), B cell proliferation (GO:0042100), odontogenesis of dentin-containing tooth (GO:0042475), negative regulation of apoptotic process (GO:0043066), negative regulation of DNA binding (GO:0043392), tongue development (GO:0043586), host-mediated activation of viral transcription (GO:0043923), T-helper 1 cell differentiation (GO:0045063), positive regulation of gamma-delta T cell differentiation (GO:0045588), positive regulation of cell differentiation (GO:0045597), negative regulation of striated muscle tissue development (GO:0045843), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), paraxial mesoderm formation (GO:0048341), regulation of neurogenesis (GO:0050767)

GO Molecular Function (22): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription corepressor binding (GO:0001222), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), DNA binding, bending (GO:0008301), nuclear estrogen receptor binding (GO:0030331), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), gamma-catenin binding (GO:0045295), armadillo repeat domain binding (GO:0070016), C2H2 zinc finger domain binding (GO:0070742), transcription regulator inhibitor activity (GO:0140416), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), cis-regulatory region sequence-specific DNA binding (GO:0000987), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), protein-DNA complex (GO:0032993), beta-catenin-TCF complex (GO:1990907), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Gastrulation	3
TCF dependent signaling in response to WNT	2
Developmental Biology	2
MITF-M-dependent gene expression	2
Beta-catenin independent WNT signaling	1
Formation of the beta-catenin:TCF transactivating complex	1
Degradation of beta-catenin by the destruction complex	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX3	1
Formation of paraxial mesoderm	1
MITF-M-regulated melanocyte development	1
Regulation of PD-L1(CD274) expression	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
angiogenesis	2
regulation of DNA-templated transcription	2
regulation of gene expression	2
forebrain generation of neurons	2
granulocyte differentiation	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
transcription regulator activity	2
protein binding	2
DNA binding	2
protein domain specific binding	2
protein-containing complex	2
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
ossification	1
cell differentiation	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
mesenchymal cell differentiation	1
DNA-templated transcription	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
hippocampus development	1
anatomical structure development	1
radial glial cell differentiation	1
neuroblast division	1
cell morphogenesis	1
hindbrain radial glia guided cell migration	1

Protein interactions and networks

STRING

3982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LEF1	CTNNB1	P35222	999
LEF1	HNF4A	P41235	999
LEF1	SMAD4	Q13485	989
LEF1	FHL2	Q14192	988
LEF1	SMAD2	Q15796	952
LEF1	SMAD3	P84022	951
LEF1	RUNX1	Q01196	925
LEF1	HDAC1	Q13547	905
LEF1	PYGO2	Q9BRQ0	891
LEF1	AXIN1	O15169	881
LEF1	AXIN2	Q9Y2T1	880
LEF1	CCND1	P24385	862
LEF1	WNT3A	P56704	848
LEF1	BMP4	P12644	832
LEF1	RUNX2	Q13950	823

IntAct

46 interactions, top by confidence:

A	B	Type	Score
CTNNB1	AXIN1	psi-mi:“MI:0914”(association)	0.940
CTNNB1	TCF4	psi-mi:“MI:0914”(association)	0.940
LEF1	CTNNB1	psi-mi:“MI:0914”(association)	0.890
CTNNB1	LEF1	psi-mi:“MI:0407”(direct interaction)	0.890
CTNNB1	LEF1	psi-mi:“MI:0915”(physical association)	0.890
LEF1	PRMT6	psi-mi:“MI:0915”(physical association)	0.640
IGF1R	LEF1	psi-mi:“MI:0915”(physical association)	0.580
LEF1	IGF1R	psi-mi:“MI:0915”(physical association)	0.580
NFE2L2	LEF1	psi-mi:“MI:0915”(physical association)	0.510
LEF1	FHIT	psi-mi:“MI:0915”(physical association)	0.500
IGF1R	CTNNB1	psi-mi:“MI:0914”(association)	0.500
LEF1	TLE1	psi-mi:“MI:0407”(direct interaction)	0.440
LEF1	Nrarp	psi-mi:“MI:0915”(physical association)	0.400
LEF1	nrarp	psi-mi:“MI:0915”(physical association)	0.400
	LEF1	psi-mi:“MI:0915”(physical association)	0.400
	MLLT11	psi-mi:“MI:0915”(physical association)	0.400
LEF1	Hdac1	psi-mi:“MI:0915”(physical association)	0.400
JUP	LEF1	psi-mi:“MI:0915”(physical association)	0.400
MLLT11	LEF1	psi-mi:“MI:0915”(physical association)	0.370
TNFSF4	LEF1	psi-mi:“MI:0915”(physical association)	0.370
LEF1	ZBTB3	psi-mi:“MI:0915”(physical association)	0.370
LEF1	DPYSL2	psi-mi:“MI:0915”(physical association)	0.370
LEF1	AURKA	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (136): RNF138 (Affinity Capture-Western), LEF1 (Biochemical Activity), LEF1 (Affinity Capture-Western), LEF1 (Affinity Capture-Western), LEF1 (Affinity Capture-Western), LEF1 (Affinity Capture-Western), NLK (Co-localization), NARF (Co-localization), STAT5A (Co-localization), PRMT6 (Affinity Capture-MS), LEF1 (Affinity Capture-Western), LEF1 (Affinity Capture-Western), LEF1 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), LEF1 (Affinity Capture-MS)

ESM2 similar proteins: A0JC51, A5ABV9, O08656, O09100, O18896, O57311, O60481, O73689, O95409, P09022, P10070, P19544, P22561, P23769, P23770, P23771, P23772, P23824, P25932, P46684, P49639, P49952, P54655, P55878, P70062, P70063, Q08DV0, Q0VGT2, Q15915, Q62520, Q62521, Q6DJQ6, Q6VVD7, Q6XP49, Q7TQ40, Q800Q5, Q8JJC0, Q91689, Q924A0, Q924Y4

Diamond homologs: A0A0G2JTZ2, A2TED3, A8WWH5, B1H349, B3DM43, O94993, O95416, P27782, P35711, P35712, P36389, P36390, P36393, P36394, P36396, P36402, P40645, P40647, P40656, P57073, P57074, P61259, P70062, P70063, P70064, P91943, Q00417, Q03256, Q04886, Q04892, Q05738, Q10666, Q28447, Q2PG84, Q32PP9, Q5RCU4, Q62563, Q62565, Q67EX7, Q69FB1

SIGNOR signaling

38 interactions.

A	Effect	B	Mechanism
CTNNB1	“up-regulates activity”	LEF1	binding
CSNK1D	down-regulates	LEF1	phosphorylation
CSNK1E	down-regulates	LEF1	phosphorylation
CSNK2A1	up-regulates	LEF1	phosphorylation
LEF1	“up-regulates quantity by expression”	MYF5	“transcriptional regulation”
PAX3	“up-regulates activity”	LEF1	binding
TLE2	down-regulates	LEF1	binding
LEF1	“up-regulates quantity by expression”	PITX2	“transcriptional regulation”
SMAD3/SMAD4	up-regulates	LEF1	“transcriptional regulation”
SMAD3	“up-regulates activity”	LEF1
SMAD4	“up-regulates activity”	LEF1
LEF1	up-regulates	Proliferation
LEF1	up-regulates	Survival
LEF1	up-regulates	Differentiation
LEF1	“up-regulates quantity by expression”	MYC	“transcriptional regulation”
LEF1	“down-regulates quantity by repression”	DSG4	“transcriptional regulation”
LEF1	“down-regulates quantity by repression”	IL4	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	ELANE	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	CEBPA	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	OCA2	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	CCND1	“transcriptional regulation”
RNF138	“down-regulates quantity by destabilization”	LEF1	polyubiquitination
NLK	“down-regulates quantity”	LEF1	phosphorylation
LEF1	“up-regulates quantity by expression”	CDH2	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	VIM	“transcriptional regulation”
LEF1	“up-regulates quantity by expression”	SNAI1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 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
Transcriptional Regulation by TP53	5	13.5×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
canonical Wnt signaling pathway	5	29.5×	2e-04
negative regulation of canonical Wnt signaling pathway	6	27.2×	4e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — HCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	47
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1319981	NM_016269.5(LEF1):c.66GAT[3] (p.Met23dup)	Pathogenic
1322007	NM_016269.5(LEF1):c.1042TAT[1] (p.Tyr349del)	Pathogenic
1322008	NM_016269.5(LEF1):c.544del (p.Gln182fs)	Pathogenic
3901232	NM_016269.5(LEF1):c.856del (p.His286fs)	Pathogenic
3377105	NM_016269.5(LEF1):c.513del (p.Ser172fs)	Likely pathogenic
4531918	NM_016269.5(LEF1):c.469dup (p.Leu157fs)	Likely pathogenic
4819819	NM_016269.5(LEF1):c.976dup (p.Ser326fs)	Likely pathogenic

SpliceAI

2510 predictions. Top by Δscore:

Variant	Effect	Δscore
4:108048755:A:T	acceptor_gain	1.0000
4:108064330:GCCTA:G	donor_loss	1.0000
4:108064331:CCTAC:C	donor_loss	1.0000
4:108064332:CTACC:C	donor_loss	1.0000
4:108064333:TA:T	donor_loss	1.0000
4:108064334:A:C	donor_loss	1.0000
4:108070661:A:AC	donor_gain	1.0000
4:108070662:C:CC	donor_gain	1.0000
4:108070766:TGCCA:T	acceptor_gain	1.0000
4:108070771:C:CC	acceptor_gain	1.0000
4:108079486:ACTT:A	donor_loss	1.0000
4:108079487:CTTA:C	donor_loss	1.0000
4:108079489:TACAC:T	donor_loss	1.0000
4:108079490:A:AC	donor_gain	1.0000
4:108079491:C:CC	donor_gain	1.0000
4:108079491:CA:C	donor_gain	1.0000
4:108079491:CACG:C	donor_gain	1.0000
4:108079491:CACGT:C	donor_gain	1.0000
4:108083442:CATGC:C	acceptor_gain	1.0000
4:108083445:GCC:G	acceptor_loss	1.0000
4:108083447:C:CG	acceptor_loss	1.0000
4:108163559:GTTAC:G	donor_loss	1.0000
4:108163560:TTACT:T	donor_loss	1.0000
4:108163561:TAC:T	donor_loss	1.0000
4:108163562:ACTTA:A	donor_loss	1.0000
4:108163563:CT:C	donor_loss	1.0000
4:108163563:CTTA:C	donor_gain	1.0000
4:108163564:TT:T	donor_loss	1.0000
4:108163565:TA:T	donor_loss	1.0000
4:108163566:A:AC	donor_gain	1.0000

AlphaMissense

2627 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:108064367:C:A	R378S	1.000
4:108064367:C:G	R378S	1.000
4:108070665:A:G	Y372H	1.000
4:108070666:A:C	N371K	1.000
4:108070666:A:T	N371K	1.000
4:108070668:T:C	N371D	1.000
4:108070672:T:A	R369S	1.000
4:108070672:T:G	R369S	1.000
4:108070673:C:A	R369I	1.000
4:108070673:C:G	R369T	1.000
4:108070676:G:T	A368E	1.000
4:108070680:A:G	S367P	1.000
4:108070681:C:A	W366C	1.000
4:108070681:C:G	W366C	1.000
4:108070682:C:A	W366L	1.000
4:108070682:C:G	W366S	1.000
4:108070683:A:G	W366R	1.000
4:108070683:A:T	W366R	1.000
4:108070692:A:C	Y363D	1.000
4:108070694:A:G	L362P	1.000
4:108070697:T:G	Q361P	1.000
4:108070702:A:C	H359Q	1.000
4:108070702:A:T	H359Q	1.000
4:108070703:T:A	H359L	1.000
4:108070703:T:C	H359R	1.000
4:108070703:T:G	H359P	1.000
4:108070704:G:A	H359Y	1.000
4:108070704:G:C	H359D	1.000
4:108070704:G:T	H359N	1.000
4:108070706:A:G	L358P	1.000

dbSNP variants (sampled 300 via entrez): RS1000016381 (4:108167435 A>G), RS1000027770 (4:108103837 G>A), RS1000032067 (4:108148933 T>C), RS1000039102 (4:108156209 G>A), RS1000055728 (4:108075165 G>A), RS1000069385 (4:108068220 T>A), RS1000070884 (4:108109316 G>A), RS1000161834 (4:108104290 G>A,C), RS1000206106 (4:108160293 A>G), RS1000228444 (4:108113976 T>C), RS1000238501 (4:108051519 G>A), RS1000289568 (4:108107178 T>C), RS1000297037 (4:108062140 T>A), RS1000375647 (4:108089725 A>C), RS1000411215 (4:108168992 T>C)

Disease associations

OMIM: gene MIM:153245 | disease phenotypes: MIM:129810, MIM:183600, MIM:621224

GenCC curated gene-disease

Disease	Classification	Inheritance
ectodermal dysplasia 17 with or without limb malformations	Strong	Autosomal dominant

Mondo (3): ectrodactyly and ectodermal dysplasia without cleft lip/palate (MONDO:0007516), split hand-foot malformation (MONDO:0016576), ectodermal dysplasia 17 with or without limb malformations (MONDO:0979228)

Orphanet (2): Isolated split hand-split foot malformation (Orphanet:2440), Ectrodactyly-ectodermal dysplasia without clefting syndrome (Orphanet:1888)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000653	Sparse eyelashes
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000691	Microdontia
HP:0000704	Periodontitis
HP:0000767	Pectus excavatum
HP:0000853	Goiter
HP:0000870	Increased circulating prolactin concentration
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0000966	Hypohidrosis
HP:0001159	Syndactyly
HP:0001171	Split hand
HP:0001177	Preaxial hand polydactyly
HP:0001245	Small thenar eminence
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001385	Hip dysplasia
HP:0001480	Freckling
HP:0001510	Growth delay
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001770	Toe syndactyly
HP:0001807	Ridged nail

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000292_10	Metabolic traits	3.000000e-11
GCST001384_2	Systemic lupus erythematosus	2.000000e-06
GCST001621_23	Airflow obstruction	1.000000e-06
GCST002073_5	Chronic lymphocytic leukemia	4.000000e-10
GCST003468_4	Chronic lymphocytic leukemia	1.000000e-07
GCST004146_7	Chronic lymphocytic leukemia	6.000000e-09
GCST005390_1	Tooth agenesis (mandibular second premolars)	6.000000e-10
GCST006988_25	Blond vs. brown/black hair color	3.000000e-15
GCST006988_6	Blond vs. brown/black hair color	2.000000e-09
GCST007094_113	Diastolic blood pressure	6.000000e-08
GCST007095_48	Systolic blood pressure	5.000000e-06
GCST007099_6	Systolic blood pressure	1.000000e-08
GCST007267_271	Systolic blood pressure	2.000000e-08
GCST007929_101	Medication use (calcium channel blockers)	5.000000e-08
GCST009597_332	Multiple sclerosis	2.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0003924	hair color
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0009930	Calcium channel blocker use measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565065	Ectrodactyly and Ectodermal Dysplasia without Cleft Lip-Palate (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3217392 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.82	IC50	150	nM	CHEMBL3222139
5.21	IC50	6200	nM	CHEMBL3222138

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, affects expression, increases expression, affects binding, decreases reaction (+1 more)	5
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	4
Valproic Acid	affects cotreatment, increases expression, decreases methylation	3
butylbenzyl phthalate	affects binding, increases reaction, increases expression, decreases reaction	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Ascorbic Acid	affects binding, affects cotreatment, increases expression, decreases expression	2
Cadmium	decreases expression, decreases reaction, increases abundance	2
Nickel	increases expression	2
Cadmium Chloride	decreases expression, decreases reaction, increases abundance	2
aristolochic acid I	decreases expression	1
thymoquinone	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
quercitrin	affects expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
methylparaben	increases expression	1
tobacco tar	decreases reaction, increases expression	1
benzo(e)pyrene	increases methylation	1
diallyl disulfide	decreases reaction, increases expression	1
cupric chloride	increases expression	1
loliolide	decreases reaction, increases expression	1
hydroquinone	affects binding, decreases reaction, decreases expression	1
butylparaben	increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
3-deazaneplanocin	affects expression, affects cotreatment	1
evodiamine	affects expression	1
casticin	decreases expression	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
CHEMBL3223402	Binding	Inhibition of LEF-1-mediated gene transcription in HEK293 cells after 48 hrs by luciferase reporter gene assay	Small-molecule inhibitors of dimeric transcription factors: Antagonism of proteinprotein and proteinDNA interactions — Medchemcomm

Cellosaurus cell lines

7 cell lines: 3 embryonic stem cell, 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A3T8	SEES3-1V human LEF1, clone1	Embryonic stem cell	Male
CVCL_A3T9	SEES3-1V human LEF1, clone2	Embryonic stem cell	Male
CVCL_A3U0	SEES3-1V human LEF1, clone3	Embryonic stem cell	Male
CVCL_B7VB	Abcam Jurkat LEF1 KO	Cancer cell line	Male
CVCL_D9IH	Ubigene HEK293 LEF1 KO	Transformed cell line	Female
CVCL_SV44	HAP1 LEF1 (-) 1	Cancer cell line	Male
CVCL_XQ10	HAP1 LEF1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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