MTMR4

Summary

MTMR4 (myotubularin related protein 4, HGNC:7452) is a protein-coding gene on chromosome 17q22, encoding Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR4 (Q9NYA4). Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate.

Enables several functions, including R-SMAD binding activity; phosphatidylinositol phosphate phosphatase activity; and protein phosphatase binding activity. Involved in several processes, including midbody abscission; negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway; and phosphatidylinositol dephosphorylation. Located in early endosome membrane; late endosome membrane; and recycling endosome membrane. Is active in early phagosome membrane and endosome membrane.

Source: NCBI Gene 9110 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 152 total
• MANE Select transcript: NM_001378067

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7452
Approved symbol	MTMR4
Name	myotubularin related protein 4
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0647, ZFYVE11
Ensembl gene	ENSG00000108389
Ensembl biotype	protein_coding
OMIM	603559
Entrez	9110

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000323456, ENST00000578259, ENST00000579921, ENST00000579925, ENST00000580983, ENST00000582390, ENST00000582663, ENST00000583243, ENST00000583966, ENST00000682306, ENST00000938934, ENST00000955804

RefSeq mRNA: 3 — MANE Select: NM_001378067 NM_001378066, NM_001378067, NM_004687

CCDS: CCDS11608, CCDS92367

Canonical transcript exons

ENST00000682306 — 18 exons

Exon	Start	End
ENSE00000739534	58507123	58507319
ENSE00000739536	58506743	58506871
ENSE00000739543	58504303	58504488
ENSE00000739547	58503744	58503898
ENSE00000739549	58494932	58496330
ENSE00000739554	58492511	58492599
ENSE00000925170	58492842	58492952
ENSE00000925173	58504050	58504220
ENSE00000925175	58504779	58504974
ENSE00000925176	58505472	58505583
ENSE00001112852	58508161	58508274
ENSE00001112860	58489537	58491840
ENSE00003614883	58511429	58511511
ENSE00003615371	58512390	58512506
ENSE00003615678	58512852	58512941
ENSE00003645609	58508681	58508841
ENSE00003788766	58508468	58508564
ENSE00003918170	58514363	58514638

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3127 / max 133.8733, expressed in 1791 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167279	6.9368	1652
167277	3.2110	1347
167276	2.8082	1403
167275	0.8269	509
167274	0.4745	268
167272	0.0358	5
167273	0.0196	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	97.78	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.43	gold quality
endothelial cell	CL:0000115	96.97	gold quality
pons	UBERON:0000988	96.31	gold quality
cortical plate	UBERON:0005343	94.97	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.50	gold quality
cerebellar cortex	UBERON:0002129	93.81	gold quality
cerebellar hemisphere	UBERON:0002245	93.80	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.69	gold quality
cerebellum	UBERON:0002037	93.65	gold quality
medial globus pallidus	UBERON:0002477	93.52	gold quality
right lobe of liver	UBERON:0001114	93.40	gold quality
adrenal tissue	UBERON:0018303	93.09	gold quality
primary visual cortex	UBERON:0002436	92.99	gold quality
cerebellar vermis	UBERON:0004720	92.81	gold quality
secondary oocyte	CL:0000655	92.35	gold quality
paraflocculus	UBERON:0005351	92.30	gold quality
globus pallidus	UBERON:0001875	92.27	gold quality
occipital lobe	UBERON:0002021	92.20	gold quality
visceral pleura	UBERON:0002401	92.09	gold quality
liver	UBERON:0002107	91.84	gold quality
nephron tubule	UBERON:0001231	91.81	gold quality
ganglionic eminence	UBERON:0004023	91.73	gold quality
superior vestibular nucleus	UBERON:0007227	91.68	gold quality
jejunal mucosa	UBERON:0000399	91.62	gold quality
pleura	UBERON:0000977	91.60	gold quality
parietal pleura	UBERON:0002400	91.54	gold quality
substantia nigra pars compacta	UBERON:0001965	91.50	gold quality
corpus callosum	UBERON:0002336	91.36	gold quality
tibia	UBERON:0000979	91.35	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.17
E-MTAB-6386	no	244.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

245 targeting MTMR4, 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-3646	100.00	73.56	5283
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372

Literature-anchored findings (GeneRIF, showing 9)

• Data found that hMTMR4 (human MTMR4) and Nedd4 co-immunoprecipitated and co-localized to late endosomes. (PMID:19125695)
• MTMR4 plays an important role in preventing the overactivation of TGFbeta signaling by dephosphorylating activated R-Smads that have been trafficked to early endosomes (PMID:20061380)
• MTMR4 localizes at the interface of early and recycling endosomes to regulate trafficking. (PMID:20736309)
• MTMR4 is a necessary negative modulator for the homeostasis of BMP/Dpp signaling (PMID:23150675)
• the PH-GRAM domain of human MTMR4 was cloned, overexpressed in Escherichia coli, purified and crystallized by the vapour-diffusion method (PMID:25195910)
• myotubularin-related protein 3 and myotubularin-related protein 4 may act as a bridge between CEP55 and polo-like kinase 1, ensuring proper CEP55 phosphorylation and regulating CEP55 recruitment to the midbody. (PMID:25659891)
• Here the authors demonstrate that green fluorescent protein-tagged MTMR4 is recruited to the Salmonella-containing vacuole and infection of cells depleted of endogenous MTMR4 results in a decrease in viable intracellular Salmonella. (PMID:27625994)
• MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes. (PMID:32173736)
• MTMR4 belongs to the myotubularin family of phosphoinositides phosphatases (PMID:9736772)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mtmr4	ENSMUSG00000018401
rattus_norvegicus	Mtmr4	ENSRNOG00000007496
drosophila_melanogaster	mtm	FBGN0025742
drosophila_melanogaster	Sbf	FBGN0025802
drosophila_melanogaster	Mtmr6	FBGN0028497
drosophila_melanogaster	CG14411	FBGN0030582
drosophila_melanogaster	CG3632	FBGN0030735
drosophila_melanogaster	CG5026	FBGN0035945
caenorhabditis_elegans	mtm-1	WBGENE00003475
caenorhabditis_elegans		WBGENE00003476
caenorhabditis_elegans		WBGENE00003477
caenorhabditis_elegans		WBGENE00003478
caenorhabditis_elegans		WBGENE00003479
caenorhabditis_elegans	mtm-10	WBGENE00021683

Paralogs (13): MTMR7 (ENSG00000003987), MTMR11 (ENSG00000014914), MTMR1 (ENSG00000063601), MTMR2 (ENSG00000087053), SBF1 (ENSG00000100241), MTMR3 (ENSG00000100330), MTMR8 (ENSG00000102043), MTMR9 (ENSG00000104643), SBF2 (ENSG00000133812), MTMR6 (ENSG00000139505), MTMR12 (ENSG00000150712), MTMR10 (ENSG00000166912), MTM1 (ENSG00000171100)

Protein

Protein identifiers

Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR4 — Q9NYA4 (reviewed: Q9NYA4)

Alternative names: FYVE domain-containing dual specificity protein phosphatase 2, Myotubularin-related protein 4, Phosphatidylinositol-3,5-bisphosphate 3-phosphatase, Zinc finger FYVE domain-containing protein 11

All UniProt accessions (6): A0A804HJV7, Q9NYA4, J3KT95, J3QKV8, J3QR65, J3QRJ2

UniProt curated annotations — full annotation on UniProt →

Function. Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate. Decreases the levels of phosphatidylinositol 3-phosphate, a phospholipid found in cell membranes where it acts as key regulator of both cell signaling and intracellular membrane traffic, in a subset of endosomal membranes to negatively regulate both endocytic recycling and trafficking and/or maturation of endosomes toward lysosomes. Through phosphatidylinositol 3-phosphate turnover in phagosome membranes regulates phagocytosis and phagosome maturation. By decreasing phosphatidylinositol 3-monophosphate (PI3P) levels in immune cells it can also regulate the innate immune response. Beside its lipid phosphatase activity, can also function as a molecular adapter to regulate midbody abscission during mitotic cytokinesis. Can also negatively regulate TGF-beta and BMP signaling through Smad proteins dephosphorylation and retention in endosomes.

Subunit / interactions. Homooligomeric. Forms MTMR3:MTMR4 heterooligomers; regulates the localization of both proteins. The MTMR3:MTMR4 heterooligomer can also recruit both CEP55 and PLK1; occurs during early mitosis, regulates the phosphorylation of CEP55 by PLK1 and its recruitment to the midbody where it can mediate cell abscission. Interacts with SMAD2 and SMAD3; negatively regulates TGF-beta signaling through SMAD2 and SMAD3 dephosphorylation and retention in endosomes. Interacts with SMAD1; negatively regulates BMP signaling through SMAD1 dephosphorylation and retention in endosomes.

Subcellular location. Early endosome membrane. Recycling endosome membrane. Late endosome membrane. Cytoplasmic vesicle. Phagosome membrane.

Tissue specificity. Expressed in brain, heart, kidney, spleen, liver, colon, testis, muscle, placenta, thyroid gland, pancreas, ovary, prostate, skin, peripheral blood, and bone marrow.

Post-translational modifications. Ubiquitinated. Ubiquitination by NEDD4 probably leads to proteasomal degradation. Phosphorylated by CDK1 during mitosis.

Activity regulation. The phosphatidylinositol-3-phosphate phosphatase activity is inhibited by vanadate.

Domain organisation. The coiled coil domain mediates the interaction between MTMR3 and MTMR4. It is essential to bring together CEP55 and PLK1 during mitotic abscission.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.

RefSeq proteins (3): NP_001364995, NP_001364996, NP_004678 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR000387	Tyr_Pase_dom	Domain
IPR010569	Myotubularin-like_Pase_dom	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR016130	Tyr_Pase_AS	Active_site
IPR017455	Znf_FYVE-rel	Domain
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR030564	Myotubularin	Family
IPR030590	MTMR4_PTP	Domain
IPR035997	MTMR4_PH-GRAM	Domain
IPR046978	MTMR4_FYVE	Domain

Pfam: PF01363, PF06602

Catalyzed reactions (Rhea), 4 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (RHEA:12316)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + phosphate (RHEA:39019)
• 1,2-dioctanoyl-sn-glycero-3-phospho-(1-D-myo-inositol-3-phosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (RHEA:42328)
• 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + phosphate (RHEA:45632)

UniProt features (52 total): binding site 29, mutagenesis site 5, compositionally biased region 3, region of interest 3, modified residue 3, sequence variant 3, chain 1, domain 1, active site 1, zinc finger region 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYA4-F1	67.20	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 407 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (29): 320; 320; 345; 345; 346; 346; 408; 408; 409; 409; 410; 410 …

Post-translational modifications (3): 8, 610, 629

Mutagenesis-validated functional residues (5):

Position	Phenotype
11	loss of function in mitotic abscission. decreased interaction with cep55.
407	loss of phosphatase activity. dominant negative.
407	no effect on function in mitotic abscission.
1006	loss of interaction with nedd4. loss of ubiquitination.
1169	loss of localization to early endosome membranes. no effect on function in mitotic abscission.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1660516	Synthesis of PIPs at the early endosome membrane
R-HSA-1660517	Synthesis of PIPs at the late endosome membrane
R-HSA-2173788	Downregulation of TGF-beta receptor signaling
R-HSA-1430728	Metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-2173789	TGF-beta receptor signaling activates SMADs
R-HSA-556833	Metabolism of lipids
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 377 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_MITOTIC_CYTOKINESIS, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_LIPID_MODIFICATION, GCM_MAP4K4, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, YAGI_AML_WITH_INV_16_TRANSLOCATION, CCAWYNNGAAR_UNKNOWN, GCM_GSPT1

GO Biological Process (9): phosphatidylinositol biosynthetic process (GO:0006661), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of BMP signaling pathway (GO:0030514), phosphatidylinositol dephosphorylation (GO:0046856), midbody abscission (GO:0061952), phagosome maturation (GO:0090382), negative regulation of endocytic recycling (GO:2001136), response to denervation involved in regulation of muscle adaptation (GO:0014894), dephosphorylation (GO:0016311)

GO Molecular Function (11): phosphatidylinositol-3-phosphate phosphatase activity (GO:0004438), protein serine/threonine phosphatase activity (GO:0004722), zinc ion binding (GO:0008270), protein phosphatase binding (GO:0019903), phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity (GO:0052629), molecular adaptor activity (GO:0060090), R-SMAD binding (GO:0070412), protein tyrosine phosphatase activity (GO:0004725), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (13): obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), cytosol (GO:0005829), endosome membrane (GO:0010008), membrane (GO:0016020), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), early phagosome membrane (GO:0036186), recycling endosome membrane (GO:0055038), endosome (GO:0005768), endomembrane system (GO:0012505), phagocytic vesicle membrane (GO:0030670), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
PI Metabolism	2
TGF-beta receptor signaling activates SMADs	1
Phospholipid metabolism	1
Metabolism of lipids	1
Signaling by TGFB family members	1
Signaling by TGF-beta Receptor Complex	1
Metabolism	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endosome membrane	3
phosphatidylinositol metabolic process	2
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
phosphoprotein phosphatase activity	2
binding	2
cytoplasm	2
biosynthetic process	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
phospholipid dephosphorylation	1
membrane organization	1
mitotic cytokinetic process	1
phagolysosome assembly	1
exocytosis	1
organelle organization	1
negative regulation of intracellular transport	1
endocytic recycling	1
regulation of endocytic recycling	1
response to muscle inactivity	1
regulation of muscle adaptation	1
phosphate-containing compound metabolic process	1
phosphatidylinositol monophosphate phosphatase activity	1
transition metal ion binding	1
phosphatase binding	1
phosphatidylinositol-3,5-bisphosphate phosphatase activity	1
molecular_function	1
SMAD binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
early endosome	1
late endosome	1
phagocytic vesicle membrane	1

Protein interactions and networks

STRING

1092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTMR4	SSMEM1	Q8WWF3	529
MTMR4	RNGTT	O60942	523
MTMR4	MTMR14	Q8NCE2	513
MTMR4	PIK3C3	Q8NEB9	501
MTMR4	SMAD2	Q15796	487
MTMR4	YWHAE	P29360	468
MTMR4	PICALM	Q13492	458
MTMR4	DLGAP2	Q9P1A6	457
MTMR4	POLE	Q07864	453
MTMR4	MAPK1	P28482	441
MTMR4	PTPN4	P29074	440
MTMR4	MAMLD1	Q13495	423
MTMR4	SBF1	O95248	416
MTMR4	CDC25C	P30307	414
MTMR4	MTMR3	Q13615	413

IntAct

127 interactions, top by confidence:

A	B	Type	Score
BCL2	BCL2L11	psi-mi:“MI:0914”(association)	0.930
MED18	MED19	psi-mi:“MI:0914”(association)	0.840
PPIE	AQR	psi-mi:“MI:0914”(association)	0.810
INO80C	YY1	psi-mi:“MI:0914”(association)	0.740
HOOK3	FHIP1A	psi-mi:“MI:0914”(association)	0.710
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
DIDO1	OGT	psi-mi:“MI:0914”(association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
NEMP1	RANGAP1	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
CSNK1E	POTEF	psi-mi:“MI:0914”(association)	0.530
ZNF669	LRP4	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
CDO1	DBT	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
AURKA	WDR62	psi-mi:“MI:0914”(association)	0.530
ZNF408	LRP4	psi-mi:“MI:0914”(association)	0.530
ZSCAN31	DHX57	psi-mi:“MI:0914”(association)	0.530
ASB6	POLR2D	psi-mi:“MI:0914”(association)	0.530
FOXJ1	PEX14	psi-mi:“MI:0914”(association)	0.530
SALL4	MBD3	psi-mi:“MI:0914”(association)	0.530

BioGRID (222): MTMR4 (Affinity Capture-MS), MTMR4 (Affinity Capture-MS), MTMR4 (Affinity Capture-MS), CEP55 (Affinity Capture-MS), MTMR3 (Affinity Capture-MS), RB1CC1 (Affinity Capture-MS), MTMR4 (Proximity Label-MS), MTMR3 (Proximity Label-MS), TMEM160 (Proximity Label-MS), PRKCI (Proximity Label-MS), SMG7 (Proximity Label-MS), GOLGA5 (Proximity Label-MS), MTMR4 (Affinity Capture-Western), MTMR4 (Affinity Capture-Western), MTMR4 (Affinity Capture-Western)

ESM2 similar proteins: A0JMF6, A2BGG1, A4FU01, B1WC10, E7FAW3, E9PUQ8, E9PXF8, F4JWB3, O00750, O15327, O70167, O70173, O95248, O95876, P0CE43, P97874, Q2I0E5, Q2I6J0, Q32NR9, Q3V1L6, Q4R4D7, Q5PQT2, Q5R991, Q5RA60, Q5U581, Q5ZLG9, Q60760, Q60949, Q68DX3, Q6NTN5, Q6NU08, Q6P1Y8, Q6PJI9, Q6ZPE2, Q6ZS30, Q7TPM9, Q7ZXF1, Q80U56, Q86WG5, Q8C0M0

Diamond homologs: A0A0G2JXT6, A0JMK5, A2BGG1, A4FU01, A6QLT2, A6QLT4, A7MB43, E9PXF8, F4J3T8, F4JWB3, G5ED68, O13819, P47147, Q13496, Q13613, Q13614, Q13615, Q22712, Q2KJ24, Q3V1L6, Q52KU6, Q54GQ1, Q55E58, Q5EB32, Q5F452, Q5PQT2, Q5R6F6, Q5R9S3, Q5REB9, Q5U581, Q5ZIV1, Q6AXQ4, Q6NTN5, Q6NU08, Q6TEL0, Q7TPM9, Q7ZXF1, Q80TA6, Q8K296, Q8VE11

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MTMR4	down-regulates	SMAD2	dephosphorylation
MTMR4	down-regulates	SMAD3	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 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
Activation of BAD and translocation to mitochondria	8	58.6×	9e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	51.7×	2e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	51.7×	2e-10
Activation of BH3-only proteins	9	43.0×	9e-11
FOXO-mediated transcription	9	29.1×	2e-09
Intrinsic Pathway for Apoptosis	9	25.3×	6e-09
RHO GTPases activate PKNs	8	24.4×	8e-08
Signaling by RAS mutants	5	20.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	15.7×	1e-03
intracellular protein localization	10	7.5×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	125
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3047 predictions. Top by Δscore:

Variant	Effect	Δscore
17:58491838:TTT:T	acceptor_gain	1.0000
17:58491839:TT:T	acceptor_gain	1.0000
17:58491841:C:CC	acceptor_gain	1.0000
17:58492505:TCTTA:T	donor_loss	1.0000
17:58492506:CTTAC:C	donor_loss	1.0000
17:58492507:TTACC:T	donor_loss	1.0000
17:58492508:TACCT:T	donor_loss	1.0000
17:58492510:C:CA	donor_loss	1.0000
17:58492837:CATA:C	donor_loss	1.0000
17:58492838:ATAC:A	donor_loss	1.0000
17:58492839:TACCT:T	donor_loss	1.0000
17:58492841:C:A	donor_loss	1.0000
17:58492841:CCT:C	donor_gain	1.0000
17:58492948:CATGT:C	acceptor_gain	1.0000
17:58492949:ATGT:A	acceptor_gain	1.0000
17:58492950:TGT:T	acceptor_gain	1.0000
17:58492951:GT:G	acceptor_gain	1.0000
17:58492953:C:CA	acceptor_loss	1.0000
17:58492953:C:CC	acceptor_gain	1.0000
17:58492954:T:C	acceptor_loss	1.0000
17:58492956:A:AC	acceptor_gain	1.0000
17:58492956:A:C	acceptor_gain	1.0000
17:58494930:A:AC	donor_gain	1.0000
17:58494931:C:CC	donor_gain	1.0000
17:58504045:CTCA:C	donor_loss	1.0000
17:58504046:TCA:T	donor_loss	1.0000
17:58504047:CA:C	donor_loss	1.0000
17:58504048:A:AC	donor_gain	1.0000
17:58504048:ACCAT:A	donor_loss	1.0000
17:58504049:C:CC	donor_gain	1.0000

AlphaMissense

7993 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:58491744:A:C	C1169W	1.000
17:58491745:C:T	C1169Y	1.000
17:58491746:A:G	C1169R	1.000
17:58491753:A:C	C1166W	1.000
17:58491754:C:G	C1166S	1.000
17:58491754:C:T	C1166Y	1.000
17:58491755:A:G	C1166R	1.000
17:58491755:A:T	C1166S	1.000
17:58491812:A:G	C1147R	1.000
17:58491819:A:C	C1144W	1.000
17:58491820:C:T	C1144Y	1.000
17:58491821:A:G	C1144R	1.000
17:58491822:A:C	F1143L	1.000
17:58491822:A:T	F1143L	1.000
17:58491824:A:G	F1143L	1.000
17:58491832:C:A	G1140V	1.000
17:58491832:C:T	G1140E	1.000
17:58491833:C:A	G1140W	1.000
17:58491834:A:C	C1139W	1.000
17:58491835:C:G	C1139S	1.000
17:58491835:C:T	C1139Y	1.000
17:58491836:A:G	C1139R	1.000
17:58491836:A:T	C1139S	1.000
17:58492513:G:C	C1136W	1.000
17:58492514:C:G	C1136S	1.000
17:58492514:C:T	C1136Y	1.000
17:58492515:A:G	C1136R	1.000
17:58492515:A:T	C1136S	1.000
17:58492518:G:C	H1135D	1.000
17:58492540:G:C	F1127L	1.000

dbSNP variants (sampled 300 via entrez): RS1000021174 (17:58496471 C>A), RS1000049219 (17:58513003 T>G), RS1000139594 (17:58520344 C>A), RS1000445365 (17:58497659 C>A,T), RS1000472762 (17:58519519 C>G,T), RS1000517834 (17:58507714 GACA>G), RS1000587561 (17:58514855 C>T), RS1000657806 (17:58490337 C>A,T), RS1000744276 (17:58500488 G>A), RS1000973873 (17:58510796 T>C,G), RS1001010288 (17:58489809 C>T), RS1001035142 (17:58500525 T>A,G), RS1001077343 (17:58518327 G>A,T), RS1001147572 (17:58503953 T>C), RS1001196185 (17:58500242 TC>T)

Disease associations

OMIM: gene MIM:603559 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002602_6	Vitamin D levels	1.000000e-06
GCST002774_29	Cognitive function	3.000000e-07
GCST010002_126	Refractive error	7.000000e-42

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation, affects cotreatment	4
sodium arsenite	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	increases expression	1
glycidyl methacrylate	decreases expression	1
cobaltous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
ciglitazone	affects binding, increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
Leflunomide	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	increases oxidation, affects cotreatment, increases abundance	1
Copper	affects binding, decreases expression	1
Coumestrol	affects cotreatment, increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Methyl Methanesulfonate	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3BG	Abcam HEK293T MTMR4 KO	Transformed cell line	Female
CVCL_SZ30	HAP1 MTMR4 (-) 1	Cancer cell line	Male
CVCL_SZ31	HAP1 MTMR4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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