TIPRL

gene
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Also known as MGC3794dJ69E11.3TIP41TIPRL1

Summary

TIPRL (TOR signaling pathway regulator, HGNC:30231) is a protein-coding gene on chromosome 1q24.2, encoding TIP41-like protein (O75663). May be a allosteric regulator of serine/threonine-protein phosphatase 2A (PP2A). It is a selective cancer dependency (DepMap: 40.6% of cell lines).

TIPRL is an inhibitory regulator of protein phosphatase-2A (PP2A) (see PPP2CA; MIM 176915), PP4 (see PPP4C; MIM 602035), and PP6 (see PPP6C; MIM 612725) (McConnell et al., 2007 [PubMed 17384681]).

Source: NCBI Gene 261726 — RefSeq curated summary.

At a glance

  • GWAS associations: 2
  • Clinical variants (ClinVar): 35 total
  • Druggable target: yes
  • Cancer dependency (DepMap): dependent in 40.6% of screened cell lines
  • MANE Select transcript: NM_152902

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:30231
Approved symbolTIPRL
NameTOR signaling pathway regulator
Location1q24.2
Locus typegene with protein product
StatusApproved
AliasesMGC3794, dJ69E11.3, TIP41, TIPRL1
Ensembl geneENSG00000143155
Ensembl biotypeprotein_coding
OMIM611807
Entrez261726

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000367830, ENST00000367833, ENST00000940324, ENST00000940325, ENST00000940326

RefSeq mRNA: 2 — MANE Select: NM_152902 NM_001031800, NM_152902

CCDS: CCDS1270, CCDS30935

Canonical transcript exons

ENST00000367833 — 7 exons

ExonStartEnd
ENSE00000958402168183902168184081
ENSE00000958403168184779168184878
ENSE00000958404168191369168191500
ENSE00001193861168198919168198981
ENSE00001193868168196547168196642
ENSE00001445713168199903168202109
ENSE00001445714168178962168179181

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.9554 / max 487.5155, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter IDTPM avgSamples expressed
647323.09841813
647410.29621774
64752.95431478
2018050.6066339

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
cauda epididymisUBERON:000436097.20gold quality
caput epididymisUBERON:000435895.64gold quality
tongue squamous epitheliumUBERON:000691995.50gold quality
corpus epididymisUBERON:000435995.31gold quality
cortical plateUBERON:000534395.02gold quality
Brodmann (1909) area 23UBERON:001355494.50gold quality
nippleUBERON:000203094.43gold quality
mucosa of sigmoid colonUBERON:000499394.25gold quality
saphenous veinUBERON:000731893.90gold quality
mammary ductUBERON:000176593.73gold quality
entorhinal cortexUBERON:000272893.65gold quality
skeletal muscle tissue of biceps brachiiUBERON:000450293.60gold quality
hair follicleUBERON:000207393.39gold quality
colonic mucosaUBERON:000031793.35gold quality
epithelium of mammary glandUBERON:000324493.14gold quality
pylorusUBERON:000116692.94gold quality
vena cavaUBERON:000408792.92gold quality
adrenal tissueUBERON:001830392.87gold quality
ganglionic eminenceUBERON:000402392.83gold quality
ponsUBERON:000098892.19gold quality
CA1 field of hippocampusUBERON:000388192.17silver quality
parietal lobeUBERON:000187292.16gold quality
gingivaUBERON:000182892.15gold quality
gingival epitheliumUBERON:000194992.15gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099192.13gold quality
calcaneal tendonUBERON:000370192.13gold quality
cardia of stomachUBERON:000116292.12gold quality
seminal vesicleUBERON:000099892.07gold quality
superior surface of tongueUBERON:000737192.03gold quality
visceral pleuraUBERON:000240191.96gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-ANND-3yes5.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

103 targeting TIPRL, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-8485100.0077.574731
HSA-MIR-6867-5P100.0082.213464
HSA-MIR-3163100.0077.238605
HSA-MIR-3689D100.0066.141181
HSA-MIR-6851-5P100.0065.631294
HSA-MIR-3613-3P100.0076.367965
HSA-MIR-5193100.0067.261744
HSA-MIR-428299.9975.366408
HSA-MIR-371B-5P99.9975.344759
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-373-5P99.9875.364753
HSA-MIR-616-5P99.9875.584775
HSA-MIR-524-5P99.9873.434882
HSA-MIR-520D-5P99.9873.344883
HSA-MIR-569699.9872.364487
HSA-MIR-548AN99.9770.912817
HSA-MIR-551B-5P99.9671.283493
HSA-MIR-570-3P99.9672.414910
HSA-MIR-335-3P99.9373.364958
HSA-MIR-6835-3P99.9370.492904
HSA-MIR-515-5P99.9269.822343
HSA-MIR-519E-5P99.9269.622358
HSA-MIR-498-3P99.9171.271114
HSA-MIR-990299.8969.152250
HSA-MIR-380-3P99.8970.181978
HSA-MIR-153-5P99.8973.866317
HSA-MIR-579-3P99.8671.663628
HSA-MIR-664B-3P99.8471.653590
HSA-MIR-576-5P99.8470.462582
HSA-MIR-202-5P99.7867.65991

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

  • Data indicate that PP2A holoenzyme biogenesis and activity are controlled by five PP2A modulators, consisting of alpha4, PTPA, LCMT1, PME-1 and TIPRL1, which serve to prevent promiscuous phosphatase activity until the holoenzyme is completely assembled. (PMID:22443683)
  • TIPRL is highly up-regulated in human HCC samples and cell lines, compared with noncancerous liver tissues. (PMID:22841785)
  • Unlike yeast TIP41, TIPRL has a positive effect on mTORC1 signaling through the association with PP2Ac. (PMID:23892082)
  • overexpression of TIPRL promotes phosphorylation of H2AX, and increases gamma-H2AX positive foci in response to DNA damage, whereas knockdown of TIPRL inhibits gamma-H2AX phosphorylation (PMID:26717153)
  • MPC2 rs10489202 was genome-wide significantly associated with schizophrenia. The expression quantitative trait loci analysis in lymphoblastoid cell lines from East Asian donors revealed that MPC2 rs10489202 was specifically and significantly associated with the expression of TIPRL gene. (PMID:30087317)
  • The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer. (PMID:31727942)
  • TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2alpha-ATF4 pathway. (PMID:31862913)
  • TIPRL, a Potential Double-edge Molecule to be Targeted and Re-targeted Toward Cancer. (PMID:38888871)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_reriotiprlENSDARG00000032353
mus_musculusTiprlENSMUSG00000040843
rattus_norvegicusTiprlENSRNOG00000003048
drosophila_melanogasterCG9578FBGN0031094
caenorhabditis_elegansWBGENE00022803

Protein

Protein identifiers

TIP41-like proteinO75663 (reviewed: O75663)

Alternative names: Putative MAPK-activating protein PM10, Type 2A-interacting protein

All UniProt accessions (1): O75663

UniProt curated annotations — full annotation on UniProt →

Function. May be a allosteric regulator of serine/threonine-protein phosphatase 2A (PP2A). Isoform 1 inhibits catalytic activity of the PP2A(D) core complex in vitro. The PP2A(C):TIPRL complex does not show phosphatase activity. Acts as a negative regulator of serine/threonine-protein phosphatase 4 probably by inhibiting the formation of the active PPP4C:PPP4R2 complex; the function is proposed to implicate it in DNA damage response by promoting H2AX phosphorylated on Ser-140 (gamma-H2AX). May play a role in the regulation of ATM/ATR signaling pathway controlling DNA replication and repair.

Subunit / interactions. Isoform 1 interacts with PPP2CA. Isoform 2 does not interact with PPP2CA. Interacts with PPP2CB, PPP4C and PPP6C. Interacts with IGBP1; the interaction is dependent on PPP2CA. Associates with a protein phosphatase 2A PP2A(C):IGBP1 complex. Interacts with PPP4C and PPP4R2.

Subcellular location. Cytoplasm.

Similarity. Belongs to the TIP41 family.

Isoforms (2)

UniProt IDNamesCanonical?
O75663-11yes
O75663-22, TIP_i2

RefSeq proteins (2): NP_001026970, NP_690866* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR007303TIP41-likeFamily
IPR051330Phosphatase_reg/MetRdxFamily

Pfam: PF04176

UniProt features (33 total): strand 12, helix 8, mutagenesis site 5, modified residue 2, turn 2, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
5D9GX-RAY DIFFRACTION2.15

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-O75663-F185.040.71

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 (2): 106, 265

Mutagenesis-validated functional residues (5):

PositionPhenotype
198abolishes interaction with ppp2ca, ppp2cb and ppp4c.
71abolishes interaction with ppp2ca, ppp2cb and ppp4c.
79diminishes interaction with ppp2ca.
136abolishes interaction with ppp2ca, ppp2cb and ppp4c.
196abolishes interaction with ppp2ca, ppp2cb and ppp4c.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 151 (showing top): ATF_B, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CELL_CYCLE_PHASE_TRANSITION, CREBP1_Q2, SP1_Q2_01, CREB_Q4, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_DNA_DAMAGE_RESPONSE, ATF3_Q6, CREB_Q2_01, ATF4_Q2, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_TOR_SIGNALING

GO Biological Process (2): DNA damage checkpoint signaling (GO:0000077), TOR signaling (GO:0031929)

GO Molecular Function (3): protein phosphatase inhibitor activity (GO:0004864), protein phosphatase activator activity (GO:0072542), protein binding (GO:0005515)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
phosphoprotein phosphatase activity2
protein phosphatase regulator activity2
cellular anatomical structure2
DNA integrity checkpoint signaling1
signal transduction in response to DNA damage1
intracellular signal transduction1
phosphatase inhibitor activity1
phosphatase activator activity1
binding1
cytoplasm1
intracellular anatomical structure1

Protein interactions and networks

STRING

2216 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
TIPRLPPP4CP33172957
TIPRLPPP2CAP05323952
TIPRLPPP6CO00743879
TIPRLMAP2K7O14733821
TIPRLLCMT1Q9UIC8710
TIPRLIGBP1P78318670
TIPRLPPP2R1AP30153595
TIPRLTBCELQ5QJ74570
TIPRLTUBP50607547
TIPRLPLCH1Q4KWH8517
TIPRLPTPAQ15257516
TIPRLATMQ13315495
TIPRLPPME1Q9Y570470
TIPRLEEF1A2P54266467
TIPRLEEF1A1P04719434

IntAct

70 interactions, top by confidence:

ABTypeScore
PPP2R1ASTRNpsi-mi:“MI:0914”(association)0.880
PPP2R1ASTRNpsi-mi:“MI:2364”(proximity)0.880
PPP6CANKRD28psi-mi:“MI:0914”(association)0.870
TIPRLPPP4Cpsi-mi:“MI:0914”(association)0.850
PPP4CTIPRLpsi-mi:“MI:0407”(direct interaction)0.850
PPP4CTIPRLpsi-mi:“MI:0915”(physical association)0.850
PPP4R2TIPRLpsi-mi:“MI:0914”(association)0.800
CFTRESYT2psi-mi:“MI:2364”(proximity)0.710
PPP6CTIPRLpsi-mi:“MI:0407”(direct interaction)0.700
TIPRLPPP6Cpsi-mi:“MI:0915”(physical association)0.700
DYNLT1DYNC1LI2psi-mi:“MI:0914”(association)0.640
PPP4CSUPT5Hpsi-mi:“MI:0914”(association)0.640
PPP2CBTIPRLpsi-mi:“MI:0407”(direct interaction)0.590
TIPRLPPP2CApsi-mi:“MI:0915”(physical association)0.590
PPP4R2SF3B1psi-mi:“MI:0914”(association)0.570
PPP4R2SF3B1psi-mi:“MI:2364”(proximity)0.570
L3MBTL1DNAJB6psi-mi:“MI:0914”(association)0.530
PPP2R1AENSApsi-mi:“MI:0914”(association)0.530
DYNLT2BTIPRLpsi-mi:“MI:0914”(association)0.510
PPP2CATIPRLpsi-mi:“MI:0914”(association)0.500
PPP2CATIPRLpsi-mi:“MI:0915”(physical association)0.500

BioGRID (157): TIPRL (Affinity Capture-MS), TIPRL (Affinity Capture-Western), TIPRL (Affinity Capture-Western), IGBP1 (Affinity Capture-Western), Ppp2ca (Affinity Capture-Western), ARHGAP44 (Co-fractionation), MCMBP (Co-fractionation), NPEPL1 (Co-fractionation), SH3BP1 (Co-fractionation), TIPRL (Co-fractionation), TIPRL (Co-fractionation), TIPRL (Co-fractionation), TIPRL (Co-fractionation), TIPRL (Co-fractionation), TIPRL (Co-fractionation)

ESM2 similar proteins: A1BDQ9, A1DPK7, A8G2V3, B3EFT2, B3EM52, B4S4Y9, B4SCX8, B6YS15, C0SPB1, C4QGM3, C7ZPG2, O15145, O32042, O41126, O48397, O75663, O92551, P04028, P05673, P06942, P06944, P09877, P0C141, P0C571, P0CA30, P0CA85, P0CA86, P13137, P13844, P18611, P20402, P24730, P35976, P41358, Q01639, Q1ECJ7, Q1WTX9, Q32RZ2, Q3T035, Q54EY1

Diamond homologs: A2VCX1, O75663, P34274, Q12199, Q54MI6, Q5FW12, Q6IRA8, Q8BH58, Q8VXY4, Q9USK5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance20
Likely benign0
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1208 predictions. Top by Δscore:

VariantEffectΔscore
1:168179161:G:GTdonor_gain1.0000
1:168179171:G:GTdonor_gain1.0000
1:168179175:TGGAG:Tdonor_gain1.0000
1:168179179:G:GTdonor_gain1.0000
1:168179179:GAA:Gdonor_gain1.0000
1:168179182:G:GGdonor_gain1.0000
1:168183935:T:TAacceptor_gain1.0000
1:168183940:T:TAacceptor_gain1.0000
1:168184768:T:TAacceptor_gain1.0000
1:168191367:A:AGacceptor_gain1.0000
1:168191367:AG:Aacceptor_gain1.0000
1:168191367:AGGTT:Aacceptor_gain1.0000
1:168191368:G:GTacceptor_gain1.0000
1:168191368:GG:Gacceptor_gain1.0000
1:168191368:GGT:Gacceptor_gain1.0000
1:168191368:GGTT:Gacceptor_gain1.0000
1:168191368:GGTTG:Gacceptor_gain1.0000
1:168191496:AGATT:Adonor_gain1.0000
1:168191497:GATT:Gdonor_gain1.0000
1:168191497:GATTG:Gdonor_gain1.0000
1:168191498:ATTG:Adonor_loss1.0000
1:168191499:TT:Tdonor_gain1.0000
1:168191500:TGTG:Tdonor_loss1.0000
1:168191501:G:GGdonor_gain1.0000
1:168191501:G:Tdonor_loss1.0000
1:168191504:A:AGdonor_gain1.0000
1:168191505:G:GGdonor_gain1.0000
1:168196542:TCCA:Tacceptor_loss1.0000
1:168196544:CAGAG:Cacceptor_gain1.0000
1:168196545:A:AGacceptor_gain1.0000

AlphaMissense

1816 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
1:168183945:T:CF50L1.000
1:168183947:T:AF50L1.000
1:168183947:T:GF50L1.000
1:168184068:T:AW91R1.000
1:168184068:T:CW91R1.000
1:168184070:G:CW91C1.000
1:168184070:G:TW91C1.000
1:168184822:T:AW110R1.000
1:168184822:T:CW110R1.000
1:168184824:G:CW110C1.000
1:168184824:G:TW110C1.000
1:168184846:G:AG118R1.000
1:168184846:G:CG118R1.000
1:168191463:T:CL160P1.000
1:168191469:A:CD162A1.000
1:168191469:A:TD162V1.000
1:168191475:G:AG164E1.000
1:168179129:T:AW18R0.999
1:168179129:T:CW18R0.999
1:168183934:C:AP46H0.999
1:168183940:T:CM48T0.999
1:168183940:T:GM48R0.999
1:168183945:T:AF50I0.999
1:168183956:C:AN53K0.999
1:168183956:C:GN53K0.999
1:168183997:T:CF67S0.999
1:168184012:C:AA72E0.999
1:168184847:G:AG118E0.999
1:168191406:T:CL141S0.999
1:168191456:G:CD158H0.999

dbSNP variants (sampled 300 via entrez): RS1000113715 (1:168182243 G>A,C), RS1000187322 (1:168194958 A>G), RS1000301209 (1:168189102 C>G), RS1000306552 (1:168178292 ATT>A,AT,ATTT), RS1000467935 (1:168182010 G>A,T), RS1000635112 (1:168187829 G>A), RS1000831370 (1:168194599 A>G), RS1000924313 (1:168193445 T>C), RS1000963310 (1:168182884 C>A,T), RS1001075815 (1:168196442 T>C), RS1001269762 (1:168182601 G>A), RS1001431072 (1:168196348 T>A,C), RS1001442334 (1:168197108 G>A), RS1001524197 (1:168177901 A>T), RS1001661404 (1:168178194 C>A,T)

Disease associations

OMIM: gene MIM:611807 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

StudyTraitp-value
GCST011741_65LDL cholesterol levels in HIV infection8.000000e-06
GCST90002404_436Red cell distribution width6.000000e-21

EFO canonical traits (2, from GWAS)

EFO IDTrait name
EFO:0004611low density lipoprotein cholesterol measurement
EFO:0009188Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067004 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChemblTypeValueUnitMolecule
5.16Kd7005nMCHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149592: Binding affinity to human TIPRL incubated for 45 mins by Kinobead based pull down assaykd7.0055uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
bisphenol Aaffects cotreatment, increases methylation, decreases expression, increases expression5
sodium arseniteaffects binding, increases reaction, affects cotreatment, increases abundance, increases expression2
dicrotophosdecreases expression1
2,4,6-tribromophenoldecreases expression1
testosterone enanthateaffects expression1
sodium arsenateincreases expression1
decabromobiphenyl etherdecreases expression1
arseniteaffects binding, increases reaction1
tetrabromobisphenol Adecreases expression1
manganese chlorideincreases abundance, increases expression, affects cotreatment1
beta-methylcholineaffects expression1
di-n-butylphosphoric acidaffects expression1
CGP 52608affects binding, increases reaction1
2-palmitoylglycerolincreases expression1
K 7174increases expression1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, increases expression1
abrineincreases expression1
2,2’,4,4’-tetrabromodiphenyl etherdecreases expression1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amideincreases expression1
pentabrominated diphenyl ether 100decreases expression1
hexabrominated diphenyl ether 153decreases expression1
LDN 193189increases expression, affects cotreatment1
(+)-JQ1 compounddecreases expression1
MT19c compoundincreases expression1
bisphenol AFincreases expression1
Fulvestrantaffects cotreatment, increases methylation1
Air Pollutantsaffects expression, increases abundance1
Air Pollutants, Occupationalaffects expression1
Arsenicaffects cotreatment, increases abundance, increases expression1
Cisplatindecreases response to substance, increases expression1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5652634BindingBinding affinity to human TIPRL incubated for 45 mins by Kinobead based pull down assayNVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

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

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

CellosaurusNameCategorySex
CVCL_B3JAAbcam HEK293T TIPRL KOTransformed cell lineFemale
CVCL_TS42HAP1 TIPRL (-)Cancer cell lineMale

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.