TPTE2

Summary

TPTE2 (transmembrane phosphoinositide 3-phosphatase and tensin homolog 2, HGNC:17299) is a protein-coding gene on chromosome 13q12.11, encoding Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase TPTE2 (Q6XPS3). Acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate.

TPIP is a member of a large class of membrane-associated phosphatases with substrate specificity for the 3-position phosphate of inositol phospholipids.

Source: NCBI Gene 93492 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 104 total
• MANE Select transcript: NM_001395978

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17299
Approved symbol	TPTE2
Name	transmembrane phosphoinositide 3-phosphatase and tensin homolog 2
Location	13q12.11
Locus type	gene with protein product
Status	Approved
Aliases	TPIP
Ensembl gene	ENSG00000132958
Ensembl biotype	protein_coding
OMIM	606791
Entrez	93492

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 nonsense_mediated_decay

ENST00000382978, ENST00000390680, ENST00000400103, ENST00000462409, ENST00000696857, ENST00000696858, ENST00000696859, ENST00000696860, ENST00000696861, ENST00000696988, ENST00000697147

RefSeq mRNA: 4 — MANE Select: NM_001395978 NM_001141968, NM_001395978, NM_130785, NM_199254

CCDS: CCDS45013, CCDS45014, CCDS9285

Canonical transcript exons

ENST00000697147 — 23 exons

Exon	Start	End
ENSE00001494134	19422877	19423164
ENSE00001679534	19426425	19426517
ENSE00001689428	19475573	19475623
ENSE00001710546	19450263	19450344
ENSE00001789231	19450076	19450164
ENSE00003968651	19493448	19493501
ENSE00003968653	19482488	19482547
ENSE00003968655	19552571	19552673
ENSE00003968656	19503224	19503277
ENSE00003968661	19559028	19559129
ENSE00003968662	19430468	19430547
ENSE00003968663	19473914	19474075
ENSE00003968664	19467225	19467344
ENSE00003968668	19424947	19425017
ENSE00003968670	19492850	19492903
ENSE00003968672	19432473	19432578
ENSE00003968674	19436226	19436306
ENSE00003968675	19465255	19465318
ENSE00003968676	19451165	19451225
ENSE00003968677	19464456	19464520
ENSE00003968678	19561434	19561532
ENSE00003968679	19438092	19438153
ENSE00003968680	19465465	19465564

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 83.17.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.17	gold quality
right testis	UBERON:0004534	79.62	gold quality
left testis	UBERON:0004533	79.05	gold quality
testis	UBERON:0000473	78.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.80	gold quality
sural nerve	UBERON:0015488	62.98	silver quality
prefrontal cortex	UBERON:0000451	59.91	gold quality
bone marrow cell	CL:0002092	59.70	silver quality
frontal cortex	UBERON:0001870	57.80	gold quality
Brodmann (1909) area 9	UBERON:0013540	57.67	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	57.42	gold quality
cerebellar hemisphere	UBERON:0002245	57.23	gold quality
cerebellar cortex	UBERON:0002129	57.21	gold quality
cerebellum	UBERON:0002037	56.96	gold quality
superior frontal gyrus	UBERON:0002661	56.63	gold quality
mucosa of stomach	UBERON:0001199	56.34	gold quality
putamen	UBERON:0001874	56.18	gold quality
ventricular zone	UBERON:0003053	56.17	gold quality
cerebral cortex	UBERON:0000956	56.14	gold quality
anterior cingulate cortex	UBERON:0009835	55.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	55.75	gold quality
right frontal lobe	UBERON:0002810	55.27	gold quality
duodenum	UBERON:0002114	54.79	gold quality
lymph node	UBERON:0000029	53.94	gold quality
brain	UBERON:0000955	53.52	gold quality
primary visual cortex	UBERON:0002436	53.38	gold quality
mucosa of transverse colon	UBERON:0004991	52.85	gold quality
hypothalamus	UBERON:0001898	52.78	gold quality
caudate nucleus	UBERON:0001873	52.74	gold quality
right adrenal gland cortex	UBERON:0035827	52.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting TPTE2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-127-3P	93.92	66.42	36

Literature-anchored findings (GeneRIF, showing 4)

• the TPIP splice-variant (TPIP-C2) mRNA is expressed in human and mouse tissues and strongly inhibits cell growth in HeLa cells (PMID:22164291)
• findings suggest that C2-domain of TPIP-C2 may act as a dominant negative effector, which may bind to and arrest the cell proliferation signalling complex (PMID:22311048)
• TPTE2 was originally reported to be a phosphoinositide 3’-phosphatase, like the tumor suppressor PTEN. Later on, other homologous phosphatases, such as Ci-VSP and Dr-VSP, have been described. These proteins are 5’-phosphatases. More recently, using a chimeric construct, we have shown that the catalytic domain of TPTE2 behaves as a 5’-phosphatase as well. (PMID:22896666)
• The role of TPTE2 in gallbladder cancer cells (PMID:25676706)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpte	ENSDARG00000056985
mus_musculus	Tpte	ENSMUSG00000031481
rattus_norvegicus	Tpte2	ENSRNOG00000024837

Paralogs (6): TNS1 (ENSG00000079308), HVCN1 (ENSG00000122986), TNS3 (ENSG00000136205), TMEM266 (ENSG00000169758), PTEN (ENSG00000171862), TPTE (ENSG00000274391)

Protein

Protein identifiers

Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase TPTE2 — Q6XPS3 (reviewed: Q6XPS3)

Alternative names: Lipid phosphatase TPIP, TPTE and PTEN homologous inositol lipid phosphatase

All UniProt accessions (6): A0A8Q3SIW4, Q6XPS3, A0A8Q3SJ09, A0A8Q3SJ26, A0A8Q3SJ67, G3V171

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate. Shows no phosphoinositide phosphatase activity.

Subcellular location. Endoplasmic reticulum membrane Endoplasmic reticulum membrane. Golgi apparatus membrane Cytoplasm.

Tissue specificity. Isoform 3 is expressed in testis, brain and stomach while isoform 4 seems to be testis-specific.

Miscellaneous. Expressed in testis, strongly inhibits cell growth in HeLa cells.

Isoforms (7)

UniProt ID	Names	Canonical?
Q6XPS3-1	1, TPIP gamma	yes
Q6XPS3-2	2
Q6XPS3-3	3, TPIP alpha
Q6XPS3-4	4, TPIP beta
Q6XPS3-5	5
Q6XPS3-6	6, TPIP-C2
Q6XPS3-7	7

RefSeq proteins (4): NP_001135440, NP_001382907, NP_570141, NP_954863 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000387	Tyr_Pase_dom	Domain
IPR005821	Ion_trans_dom	Domain
IPR014020	Tensin_C2-dom	Domain
IPR016130	Tyr_Pase_AS	Active_site
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR029023	Tensin_phosphatase	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR045102	PTP_VSP_TPTE	Domain
IPR051281	Dual-spec_lipid-protein_phosph	Family
IPR057023	PTP-SAK	Domain

Pfam: PF00520, PF10409, PF22784

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + phosphate (RHEA:25017)

UniProt features (21 total): splice variant 7, transmembrane region 3, sequence variant 2, domain 2, compositionally biased region 2, chain 1, mutagenesis site 1, sequence conflict 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6XPS3-F1	85.00	0.58

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): 320 (phosphocysteine intermediate)

Mutagenesis-validated functional residues (1):

Position	Phenotype
320	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1660514	Synthesis of PIPs at the Golgi membrane

MSigDB gene sets: 48 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, MODULE_493, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, MODULE_285, MODULE_171, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_TRANSMEMBRANE_TRANSPORT, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_DN

GO Biological Process (8): phosphatidylinositol biosynthetic process (GO:0006661), lipid metabolic process (GO:0006629), phosphate-containing compound metabolic process (GO:0006796), monoatomic ion transport (GO:0006811), dephosphorylation (GO:0016311), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (6): monoatomic ion channel activity (GO:0005216), phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity (GO:0016314), phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity (GO:0051800), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), voltage-gated proton channel activity (GO:0030171)

GO Cellular Component (9): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
PI Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
transport	2
endomembrane system	2
intracellular membrane-bounded organelle	2
biosynthetic process	1
phosphatidylinositol metabolic process	1
primary metabolic process	1
metabolic process	1
phosphate-containing compound metabolic process	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
monoatomic cation transmembrane transport	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
phosphatidylinositol trisphosphate phosphatase activity	1
phosphatidylinositol-3,4-bisphosphate phosphatase activity	1
catalytic activity	1
phosphoric ester hydrolase activity	1
proton channel activity	1
voltage-gated monoatomic cation channel activity	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
transmembrane transporter complex	1

Protein interactions and networks

STRING

1635 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPTE2	MTMR2	Q13614	861
TPTE2	TMEM266	Q2M3C6	489
TPTE2	HAUS6	Q7Z4H7	470
TPTE2	GUCY1A2	P33402	469
TPTE2	PTEN	P60484	441
TPTE2	NUDT21	O43809	433
TPTE2	NDUFS6	O75380	432
TPTE2	PGAM2	P15259	417
TPTE2	MTMR7	Q9Y216	410
TPTE2	MTMR6	Q9Y217	404
TPTE2	SDHA	P31040	389
TPTE2	OR10S1	Q8NGN2	368
TPTE2	MTMR14	Q8NCE2	348
TPTE2	ZNF530	Q6P9A1	348
TPTE2	INPP5B	P32019	342

IntAct

10 interactions, top by confidence:

A	B	Type	Score
TPTE2	TLN1	psi-mi:“MI:0407”(direct interaction)	0.440
TPTE2	CALD1	psi-mi:“MI:0915”(physical association)	0.400
TPTE2	LMTK2	psi-mi:“MI:0915”(physical association)	0.370
TPTE2	AATK	psi-mi:“MI:0915”(physical association)	0.370
TPTE2	PTK7	psi-mi:“MI:0915”(physical association)	0.370
TPTE2	EPHA2	psi-mi:“MI:0915”(physical association)	0.370
P		psi-mi:“MI:0914”(association)	0.350
TPTE2	DNAJB5	psi-mi:“MI:0914”(association)	0.350
TPTE2	ARRB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): HAUS1 (Affinity Capture-MS), OTUD4 (Affinity Capture-MS), PEX19 (Affinity Capture-MS), PPP2R3A (Proximity Label-MS), CCDC14 (Proximity Label-MS), CEP290 (Proximity Label-MS), NCKAP5L (Proximity Label-MS), AKAP9 (Proximity Label-MS), KIAA0753 (Proximity Label-MS), PIBF1 (Proximity Label-MS), CCDC77 (Proximity Label-MS), CCDC18 (Proximity Label-MS), CCDC61 (Proximity Label-MS), SSFA2 (Proximity Label-MS), CEP72 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JXT6, A0JMF6, A0JMK5, A2ALK8, A2BGG1, A6QLT4, A7MB43, G5ED68, O13819, O14830, P26045, P33402, P51432, Q09M05, Q13496, Q13613, Q15111, Q3USB7, Q4KWH5, Q4R6N0, Q4U2V3, Q52KU6, Q5EB32, Q5F452, Q5R6F6, Q5R9S3, Q5U581, Q62688, Q6AXQ4, Q6NU08, Q6TEL0, Q6XPS3, Q7TPM9, Q7ZXF1, Q8K394, Q8NCE2, Q8VE11, Q8VEL2, Q96EF0, Q96MI9

Diamond homologs: E9Q0S6, G5EE01, O08586, O54857, O94526, P56180, P60483, P60484, Q04205, Q4R6N0, Q54JL7, Q5B323, Q5SSZ5, Q68CZ2, Q6XPS3, Q86IL4, Q8H106, Q8T9S7, Q99KY4, Q9FLZ5, Q9GLM4, Q9HBL0, Q9LT75, Q9P7H1, Q9PUT6, A0AUV4, A8WYE4, B0WAU8, D2I3C6, D3ZBE5, F1LP90, F1MH24, F1SPM8, G5ECQ3, O13773, O14976, O34507, O43066, O75061, O75716

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2875 predictions. Top by Δscore:

Variant	Effect	Δscore
13:19425018:C:CC	acceptor_gain	1.0000
13:19450165:C:CC	acceptor_gain	1.0000
13:19451163:A:AC	donor_gain	1.0000
13:19451164:C:CT	donor_gain	1.0000
13:19451164:CTG:C	donor_gain	1.0000
13:19465317:AC:A	acceptor_gain	1.0000
13:19465318:CC:C	acceptor_gain	1.0000
13:19482558:C:CT	acceptor_gain	1.0000
13:19425016:TT:T	acceptor_gain	0.9900
13:19438150:CTTC:C	acceptor_gain	0.9900
13:19438154:C:CC	acceptor_gain	0.9900
13:19438154:CTA:C	acceptor_loss	0.9900
13:19438155:T:C	acceptor_loss	0.9900
13:19450161:CTCA:C	acceptor_gain	0.9900
13:19450163:CA:C	acceptor_gain	0.9900
13:19451160:CATA:C	donor_gain	0.9900
13:19451222:CTTC:C	acceptor_gain	0.9900
13:19464517:CGTT:C	acceptor_gain	0.9900
13:19465250:CAAA:C	donor_loss	0.9900
13:19465251:AAACC:A	donor_loss	0.9900
13:19465252:AAC:A	donor_loss	0.9900
13:19465253:A:G	donor_loss	0.9900
13:19465254:C:CG	donor_loss	0.9900
13:19465319:C:T	acceptor_gain	0.9900
13:19473912:AC:A	donor_gain	0.9900
13:19473913:CC:C	donor_gain	0.9900
13:19473913:CCCTT:C	donor_gain	0.9900
13:19482559:A:T	acceptor_gain	0.9900
13:19492904:C:CC	acceptor_gain	0.9900
13:19493443:CTTA:C	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008667 (13:19468361 G>C), RS1000017231 (13:19558265 C>A,T), RS1000081267 (13:19424464 T>A,C), RS1000115151 (13:19538013 A>T), RS1000124539 (13:19519811 A>G), RS1000125070 (13:19504916 T>C), RS1000155530 (13:19519492 G>T), RS1000209057 (13:19523803 G>A), RS1000232115 (13:19524216 A>G), RS1000234488 (13:19467904 T>C,G), RS1000269193 (13:19511397 A>G), RS1000353241 (13:19497734 G>C,T), RS1000371772 (13:19430104 G>A), RS1000388654 (13:19526676 T>C), RS1000458000 (13:19517579 A>C)

Disease associations

OMIM: gene MIM:606791 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010678_5	Liver fibrosis (total hepatic collagen content)	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010576	liver fibrosis measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation	1
nickel sulfate	increases expression	1
tanespimycin	increases expression	1
scriptaid	affects expression	1
Hydralazine	affects cotreatment, increases expression	1
Methotrexate	increases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Aflatoxin B1	decreases expression	1
Permethrin	decreases expression	1
Nanotubes, Carbon	increases expression	1

Clinical trials (associated diseases)

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