MAML1

Summary

MAML1 (mastermind like transcriptional coactivator 1, HGNC:13632) is a protein-coding gene on chromosome 5q35.3, encoding Mastermind-like protein 1 (Q92585). Acts as a transcriptional coactivator for NOTCH proteins.

This protein is the human homolog of mastermind, a Drosophila protein that plays a role in the Notch signaling pathway involved in cell-fate determination. There is in vitro evidence that the human homolog forms a complex with the intracellular portion of human Notch receptors and can increase expression of a Notch-induced gene. This evidence supports its proposed function as a transcriptional co-activator in the Notch signaling pathway.

Source: NCBI Gene 9794 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 175 total
• MANE Select transcript: NM_014757

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13632
Approved symbol	MAML1
Name	mastermind like transcriptional coactivator 1
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0200, Mam-1
Ensembl gene	ENSG00000161021
Ensembl biotype	protein_coding
OMIM	605424
Entrez	9794

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

ENST00000292599, ENST00000507385, ENST00000511027, ENST00000933871

RefSeq mRNA: 1 — MANE Select: NM_014757 NM_014757

CCDS: CCDS34315

Canonical transcript exons

ENST00000292599 — 5 exons

Exon	Start	End
ENSE00001151658	179773895	179777283
ENSE00001258912	179732822	179733427
ENSE00003555501	179771147	179771243
ENSE00003574939	179768850	179769089
ENSE00003693353	179765326	179766741

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 92.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.5354 / max 174.5640, expressed in 1759 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60581	9.4406	1746
60580	0.3209	119
60583	0.2608	34
60589	0.2170	105
60582	0.2097	66
60584	0.0790	17
60585	0.0073	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	92.54	gold quality
ventricular zone	UBERON:0003053	90.03	gold quality
ganglionic eminence	UBERON:0004023	89.34	gold quality
gall bladder	UBERON:0002110	89.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.40	gold quality
cerebellar hemisphere	UBERON:0002245	88.35	gold quality
cerebellar cortex	UBERON:0002129	88.22	gold quality
cerebellum	UBERON:0002037	87.95	gold quality
mucosa of stomach	UBERON:0001199	87.13	gold quality
left uterine tube	UBERON:0001303	87.08	gold quality
rectum	UBERON:0001052	87.00	gold quality
left ovary	UBERON:0002119	86.98	gold quality
stromal cell of endometrium	CL:0002255	86.91	gold quality
right ovary	UBERON:0002118	86.70	gold quality
body of uterus	UBERON:0009853	86.65	gold quality
nerve	UBERON:0001021	86.63	gold quality
tibial nerve	UBERON:0001323	86.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.50	gold quality
lower esophagus	UBERON:0013473	86.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.36	gold quality
popliteal artery	UBERON:0002250	86.17	gold quality
tibial artery	UBERON:0007610	86.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.06	gold quality
lower esophagus mucosa	UBERON:0035834	86.00	gold quality
blood	UBERON:0000178	85.71	gold quality
gastrocnemius	UBERON:0001388	85.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.28	gold quality
ectocervix	UBERON:0012249	85.23	gold quality
aorta	UBERON:0000947	85.21	gold quality
descending thoracic aorta	UBERON:0002345	85.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.48

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
EGR1	Activation
HES1	Activation
HEY1	Repression
NOTCH1	Activation
TNFRSF12A	Repression

Upstream regulators (CollecTRI, top): BCL6, EGR1, HDAC7, HES1, KLF6, MEF2C, NFKB, PAX1, SNAI1, SP1, TP53

miRNA regulators (miRDB)

216 targeting MAML1, 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-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548AN	99.97	70.91	2817

Literature-anchored findings (GeneRIF, showing 40)

• Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex (PMID:12050117)
• requirement for cooperative assembly of the MAML1.ICN.CSL.DNA complex suggests that a primary function of ICN is to render CSL competent for MAML loading. (PMID:12644465)
• MAML1 recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. (PMID:15546612)
• Results report the crystal structure of a Notch transcriptional activation complex containing the ankyrin domain of human Notch1, the transcription factor CSL on cognate DNA, and a polypeptide from the coactivator Mastermind-like-1 (MAML-1). (PMID:16530044)
• MAML1 has a coactivator function for p53, independent of its function as a coactivator of Notch signaling pathway (PMID:17317671)
• Maml1 participates in the Wnt signaling by modulating the beta-catenin/TCF activity. Maml1 is recruited by beta-catenin on the cyclin D1 and c-Myc promoters. Maml1 functions in the Wnt/beta-catenin pathway independently of Notch signaling. (PMID:17875709)
• the RBP-Jkappa-associated domain of Notch increases the effective concentration of the ankyrin domain for its binding site on CSL, enabling docking of the ankyrin domain and subsequent recruitment of the Mastermind-like coactivator. (PMID:18155729)
• Studies indicate that MAML1 functions as a coactivator for the tumor suppressor p53, MEF2C, beta-catenin and Notch signaling. (PMID:19751190)
• Data support a model in which Notch-1 can activate the transcription of ERalpha-target genes via IKKalpha-dependent cooperative chromatin recruitment of Notch-CSL-MAML1 and ERalpha, which promotes the recruitment of p300. (PMID:19838210)
• SUMOylation of MAML1 is a mechanism for repressing MAML1 activity by influencing its interaction with HDAC7 (PMID:20203086)
• Data show no detectable difference in the DNA binding site preferences of CSL before and after loading of four different Notch receptors and MAML1 proteins. (PMID:21124806)
• To target Notch signaling using MAML1 treatment may present a novel method to control cell viability in cervical cancer cells. (PMID:21640102)
• Overexpression of MAML-1 and Twist1 were significantly associated with lymph node metastasis and the surgical staging of tumor (PMID:22006371)
• MAML1 increases Notch acetylation by potentiating p300 autoacetylation. (PMID:22100894)
• MAML1 is best known as the co-activator and effector of NOTCH-induced transcription, and BPV-1 E6 represses synthetic NOTCH-responsive promoters, endogenous NOTCH-responsive promoters, and is found in a complex with MAML1 in stably transformed cells (PMID:22249263)
• Association of CSL with NICD exerts remarkably little effect on the exchange kinetics of the ANK domain, whereas MAML1 binding greatly retards the exchange kinetics of ANK repeats 2-3. (PMID:22325781)
• This study demonstrated that targeting Maml1-induced tumor cell senescence and differentiation may alter the tumor microenvironment and cytokine and chemokine profiles and may also promote innate and adaptive immune cell infiltration and function. (PMID:22864395)
• Data indicate that EpCAM, CK19, and hMAM triple-marker-positive circulating tumor cells (CTCs) were detected in 86 of 98 (87.8 %) patients. (PMID:22990361)
• Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. (PMID:23029358)
• Authors report that human papillomavirus type 8 E6 subverts NOTCH activation during keratinocyte differentiation by inhibiting RBPJ/MAML1 transcriptional activator complexes at NOTCH target DNA. (PMID:23365452)
• Snail decreased transcription of Notch1 intracellular domain (NICD) target genes via competing with MAML1, co-activator, in NICD complex. (PMID:23454378)
• The impact of MAML1 genetic variants to heart rate was discovered. (PMID:24680774)
• In MCF-7 cells p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. (PMID:26033683)
• study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell (PMID:26225565)
• MMAL1 overexpression is associated with Esophageal Squamous Cell Carcinoma. (PMID:26294058)
• Notch signaling was altered in almost half of the clear-cell renal cell carcinoma patients and copy number variances in MAML1 and KAT2B were predominant changes. (PMID:26662507)
• The transcriptional coregulator MAML1 affects DNA methylation and gene expression patterns in human embryonic kidney cells. (PMID:26857655)
• MAML1 may play an important role in tumor progression of Hepatocellular Carcinoma. (PMID:27650617)
• Overexpression of Mastermind like1 was detected in 59% of tumor samples (PMID:28325367)
• Our results showed that MEIS1 may have a negative role in regulation of MAML1expression during the esophageal squamous cell carcinoma progression. (PMID:28462489)
• Authors report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. (PMID:28625977)
• The divergence of E6 proteins from either MAML1 or E6AP binding preference is a major event in papillomavirus evolution. (PMID:29281732)
• These new findings suggest an oncogenic role for concomitant expression of MAML1 and TWIST1 genes in head and neck squamous cell carcinoma invasion and metastasis (PMID:29333702)
• Knockdown of MAML1 inhibits proliferation and induces apoptosis of T-ALL cells through SP1-dependent inactivation of TRIM59. (PMID:30370525)
• Data indicated that MAML1 negatively regulates epithelial-mesenchymal transition markers expression in breast cancer cells. (PMID:30732857)
• MAML1 may be utilized for targeted therapy with a low side effect. (PMID:30992079)
• Neuron production in human cerebral cortex is coordinated by the MAML1. (PMID:31416089)
• ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway. (PMID:31874246)
• MAML1-Dependent Notch-Responsive Genes Exhibit Differing Cofactor Requirements for Transcriptional Activation. (PMID:32179552)
• MAML1 promotes ESCC aggressiveness through upregulation of EMT marker TWIST1. (PMID:32180088)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	maml1	ENSDARG00000076466
mus_musculus	Maml1	ENSMUSG00000050567
rattus_norvegicus	Maml1	ENSRNOG00000003268

Paralogs (2): MAML2 (ENSG00000184384), MAML3 (ENSG00000196782)

Protein

Protein identifiers

Mastermind-like protein 1 — Q92585 (reviewed: Q92585)

All UniProt accessions (1): Q92585

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.

Subunit / interactions. Interacts (via N-terminus) with NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (via ankyrin repeat region). Interacts (via N-terminus) with p53 (via DNA-binding region). Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1. Also binds CREBBP/CBP and CDK8. Forms a complex with PRAG1, NOTCH1 and MAML1, in a MAML1-dependent manner.

Subcellular location. Nucleus speckle.

Tissue specificity. Widely expressed with highest levels in heart, pancreas, peripheral blood leukocytes and spleen.

Domain organisation. The C-terminal region is required for transcriptional activation.

Similarity. Belongs to the mastermind family.

RefSeq proteins (1): NP_055572* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019082	Mastermind-like_N	Domain
IPR046369	MAML1-3	Family
IPR046370	MAML_N_sf	Homologous_superfamily
IPR048455	MAML1_3_TAD2	Domain

Pfam: PF09596, PF20801

UniProt features (32 total): compositionally biased region 14, modified residue 7, region of interest 6, sequence variant 2, helix 2, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6SMV	X-RAY DIFFRACTION	2.14
2F8X	X-RAY DIFFRACTION	3.25
3NBN	X-RAY DIFFRACTION	3.45
3V79	X-RAY DIFFRACTION	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92585-F1	47.70	0.06

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 (7): 45, 120, 303, 314, 360, 822, 1015

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-210744	Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2197563	NOTCH2 intracellular domain regulates transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-8941856	RUNX3 regulates NOTCH signaling
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-186712	Regulation of beta-cell development
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-212436	Generic Transcription Pathway
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9012852	Signaling by NOTCH3
R-HSA-9013694	Signaling by NOTCH4

MSigDB gene sets: 251 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, MORF_MTA1, GOBP_POSITIVE_REGULATION_OF_MYOTUBE_DIFFERENTIATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, PAX4_01, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_POSITIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, SP3_Q3, MORF_RAD21, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AAAYRNCTG_UNKNOWN, GOBP_CARDIAC_CONDUCTION_SYSTEM_DEVELOPMENT

GO Biological Process (9): atrioventricular node development (GO:0003162), protein phosphorylation (GO:0006468), Notch signaling pathway (GO:0007219), positive regulation of transcription of Notch receptor target (GO:0007221), positive regulation of myotube differentiation (GO:0010831), myoblast differentiation (GO:0045445), positive regulation of transcription by RNA polymerase II (GO:0045944), atrioventricular node cell development (GO:0060928), positive regulation of muscle cell differentiation (GO:0051149)

GO Molecular Function (4): transcription coactivator activity (GO:0003713), protein kinase binding (GO:0019901), peptide antigen binding (GO:0042605), protein binding (GO:0005515)

GO Cellular Component (4): MAML1-RBP-Jkappa- ICN1 complex (GO:0002193), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by NOTCH	3
Pre-NOTCH Expression and Processing	1
Regulation of beta-cell development	1
Signaling by NOTCH1	1
Signaling by NOTCH2	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX3	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Gastrulation	1
Differentiation of T cells	1
Signal Transduction	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
cardiac conduction system development	1
cardiac muscle tissue development	1
phosphorylation	1
protein modification process	1
cell surface receptor signaling pathway	1
Notch signaling pathway	1
positive regulation of transcription by RNA polymerase II	1
regulation of myotube differentiation	1
myotube differentiation	1
positive regulation of striated muscle cell differentiation	1
cell differentiation	1
muscle structure development	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
atrioventricular node cell differentiation	1
cardiac pacemaker cell development	1
muscle cell differentiation	1
positive regulation of cell differentiation	1
regulation of muscle cell differentiation	1
transcription coregulator activity	1
kinase binding	1
antigen binding	1
peptide binding	1
binding	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAML1	RBPJ	Q06330	999
MAML1	NOTCH1	P46531	998
MAML1	EP300	Q09472	970
MAML1	NOTCH4	Q99466	896
MAML1	NOTCH2	Q04721	885
MAML1	ANK1	P16157	878
MAML1	JAG1	P78504	874
MAML1	ANK3	Q12955	868
MAML1	ANK2	Q01484	868
MAML1	DES	P17661	855
MAML1	NOTCH3	Q9UM47	842
MAML1	GNLY	P09325	832
MAML1	RBPJL	Q9UBG7	758
MAML1	HEY1	Q9Y5J3	752
MAML1	MEF2C	Q06413	750

IntAct

61 interactions, top by confidence:

A	B	Type	Score
NOTCH1	MAML1	psi-mi:“MI:0915”(physical association)	0.950
MAML1	NOTCH1	psi-mi:“MI:0914”(association)	0.950
MAML1	NOTCH1	psi-mi:“MI:0915”(physical association)	0.950
MAML1	NOTCH1	psi-mi:“MI:0407”(direct interaction)	0.950
RBPJ	NOTCH1	psi-mi:“MI:0914”(association)	0.910
NOTCH1	RBPJ	psi-mi:“MI:0914”(association)	0.740
NOTCH1	KDM1A	psi-mi:“MI:0914”(association)	0.560
KDM1A	NOTCH1	psi-mi:“MI:0914”(association)	0.560
RMND5A	DDX5	psi-mi:“MI:0914”(association)	0.510
NOTCH1	HIF1A	psi-mi:“MI:0914”(association)	0.500
E6	EP300	psi-mi:“MI:0914”(association)	0.460
Nipbl	BRAT1	psi-mi:“MI:0914”(association)	0.350
HUWE1	NCOA4	psi-mi:“MI:0914”(association)	0.350
RBPJ	CLPTM1	psi-mi:“MI:0914”(association)	0.350
RBPJ	SAMD1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
E6	TRAFD1	psi-mi:“MI:0914”(association)	0.350
EGLN3	FAM168B	psi-mi:“MI:0914”(association)	0.350
NOTCH1	CNOT1	psi-mi:“MI:0914”(association)	0.350
MAML1	KDM1A	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (126): MAML1 (Affinity Capture-MS), EP300 (Reconstituted Complex), CDK8 (Reconstituted Complex), MAML1 (Proximity Label-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-Western), RND3 (Affinity Capture-Western), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS), MAML1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IBL7, A3RK74, A4L7N3, A5D7F6, B2RWS6, B5DE09, E1BPQ1, G3V7R4, O00512, O43524, P11420, P45481, P78364, Q09472, Q12778, Q13227, Q14686, Q15596, Q17BA4, Q61026, Q64028, Q66JJ0, Q67FY2, Q6AI39, Q6JHU9, Q6T264, Q7ZUK7, Q810W5, Q86UU0, Q8CHH5, Q8CHP6, Q8IXK0, Q8IZL2, Q921N8, Q924H2, Q92585, Q92793, Q961D9, Q96JK9, Q96RN5

Diamond homologs: Q6T264, Q8IZL2, Q92585, Q96JK9

SIGNOR signaling

22 interactions.

A	Effect	B	Mechanism
MAML1	up-regulates	CCNC	relocalization
MAML1	up-regulates	CCNT1	relocalization
MAML1	up-regulates	CDK8	binding
MAML1	up-regulates	CDK8	relocalization
MAML1	up-regulates	MEF2C	binding
MAML1	up-regulates	EP300	binding
EP300	up-regulates	MAML1	acetylation
MAML1	“down-regulates activity”	H3C1	acetylation
MAML1	“down-regulates activity”	H4C1	acetylation
MAML1	up-regulates	CTNNB1	binding
MAML1	up-regulates	TP53	binding
MAML1	up-regulates	EP300	relocalization
GSK3B	down-regulates	MAML1	phosphorylation
MAML1	“down-regulates activity”	“Histone H3”	acetylation
MAML1	up-regulates	NOTCH	binding
MAML1	up-regulates	NOTCH1	binding
MAML1	up-regulates	NOTCH2	binding
MAML1	up-regulates	NOTCH3	binding
MAML1	up-regulates	NOTCH4	binding
MAML1	up-regulates	RBPJ	binding
MAML1	“up-regulates quantity by expression”	NOTCH1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
NOTCH1 Intracellular Domain Regulates Transcription	5	28.3×	2e-04
Transcriptional regulation of white adipocyte differentiation	5	15.4×	1e-03
Signaling by WNT	5	13.3×	2e-03
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	5	9.8×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to hypoxia	5	11.0×	3e-03
transcription by RNA polymerase II	6	7.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	156
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1180 predictions. Top by Δscore:

Variant	Effect	Δscore
5:179763190:G:GT	donor_gain	1.0000
5:179763191:A:T	donor_gain	1.0000
5:179765324:A:AG	acceptor_gain	1.0000
5:179765325:G:GG	acceptor_gain	1.0000
5:179765325:GC:G	acceptor_gain	1.0000
5:179765325:GCAT:G	acceptor_gain	1.0000
5:179766737:GCCAG:G	donor_gain	1.0000
5:179766739:CAGGT:C	donor_loss	1.0000
5:179766740:AGGTA:A	donor_loss	1.0000
5:179766742:G:GG	donor_gain	1.0000
5:179733425:ACGG:A	donor_loss	0.9900
5:179733427:GGT:G	donor_loss	0.9900
5:179733428:G:GA	donor_loss	0.9900
5:179733428:G:GG	donor_gain	0.9900
5:179733429:TGA:T	donor_loss	0.9900
5:179733430:GAG:G	donor_loss	0.9900
5:179733768:G:GT	donor_gain	0.9900
5:179765322:TCA:T	acceptor_loss	0.9900
5:179765323:CA:C	acceptor_loss	0.9900
5:179765323:CAGCA:C	acceptor_gain	0.9900
5:179765324:A:G	acceptor_loss	0.9900
5:179765325:G:GT	acceptor_loss	0.9900
5:179765325:GCA:G	acceptor_gain	0.9900
5:179765325:GCATC:G	acceptor_gain	0.9900
5:179766738:CCAG:C	donor_gain	0.9900
5:179766739:CAG:C	donor_gain	0.9900
5:179766740:AG:A	donor_gain	0.9900
5:179766741:GG:G	donor_gain	0.9900
5:179769085:AACAG:A	donor_loss	0.9900
5:179769086:ACAGG:A	donor_loss	0.9900

AlphaMissense

6667 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:179733180:T:C	L23P	1.000
5:179765761:T:A	W251R	1.000
5:179765761:T:C	W251R	1.000
5:179765771:T:C	L254P	1.000
5:179733180:T:A	L23H	0.999
5:179733183:G:C	R24P	0.999
5:179733188:C:A	R26S	0.999
5:179733189:G:C	R26P	0.999
5:179733192:T:A	I27N	0.999
5:179733204:G:C	R31P	0.999
5:179733270:G:C	R53P	0.999
5:179733288:T:C	L59P	0.999
5:179765763:G:C	W251C	0.999
5:179765763:G:T	W251C	0.999
5:179765783:T:C	L258P	0.999
5:179733182:C:A	R24S	0.998
5:179733186:G:C	R25P	0.998
5:179733192:T:G	I27S	0.998
5:179733209:C:G	H33D	0.998
5:179733297:G:C	R62P	0.998
5:179771177:C:A	R668S	0.998
5:179774839:T:A	W1005R	0.998
5:179774839:T:C	W1005R	0.998
5:179774841:G:C	W1005C	0.998
5:179774841:G:T	W1005C	0.998
5:179733176:C:A	R22S	0.997
5:179733177:G:C	R22P	0.997
5:179733198:T:C	L29P	0.997
5:179733200:T:C	C30R	0.997
5:179733207:G:C	R32P	0.997

dbSNP variants (sampled 300 via entrez): RS1000069534 (5:179756308 C>T), RS1000156048 (5:179733399 A>T), RS1000177524 (5:179772603 A>C), RS1000178089 (5:179762397 G>A), RS1000391970 (5:179772117 A>G), RS1000437488 (5:179734115 C>A,G), RS1000541833 (5:179774348 A>C,G), RS1000543646 (5:179734510 C>G,T), RS1000738159 (5:179732247 A>G), RS1000769217 (5:179732539 G>C), RS1000781861 (5:179770849 T>C), RS1000965415 (5:179776933 A>C), RS1001036202 (5:179743830 A>T), RS1001124696 (5:179761843 C>T), RS1001132322 (5:179770502 A>G)

Disease associations

OMIM: gene MIM:605424 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002398_2	Resting heart rate	1.000000e-08
GCST004608_20	Granulocyte percentage of myeloid white cells	8.000000e-25
GCST004609_59	Monocyte percentage of white cells	1.000000e-23
GCST004613_136	Sum neutrophil eosinophil counts	4.000000e-12
GCST004614_86	Granulocyte count	6.000000e-12
GCST004620_149	Sum basophil neutrophil counts	5.000000e-12
GCST004629_73	Neutrophil count	6.000000e-12
GCST009269_7	Dental caries (decayed and filled deciduous teeth)	3.000000e-06
GCST012489_145	Heel bone mineral density x serum urate levels interaction	3.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	2
FR900359	affects phosphorylation	1
napabucasin	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
HT-2 toxin	increases expression	1
arsenite	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
enzalutamide	affects expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Glyphosate	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Carcinogens	decreases expression	1
Lead	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	affects expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7U1	Ubigene A-549 MAML1 KO	Cancer cell line	Male
CVCL_D8PQ	Ubigene HCT 116 MAML1 KO	Cancer cell line	Male
CVCL_E0GY	Ubigene HeLa MAML1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer