{"gene":"TIPRL","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2001,"finding":"Yeast TIP41 (ortholog of TIPRL) interacts with TAP42 (ortholog of alpha4) and negatively regulates the TOR signaling pathway; deletion of TIP41 confers rapamycin resistance and prevents dissociation of SIT4 phosphatase from TAP42, blocking SIT4-dependent dephosphorylation of NPR1 and nuclear translocation of GLN3. TIP41 binding to TAP42 is stimulated by rapamycin treatment via SIT4-dependent dephosphorylation of TIP41, establishing a feedback loop that amplifies SIT4 phosphatase activity under TOR-inactivating conditions.","method":"Genetic epistasis (deletion/suppressor analysis), co-immunoprecipitation, phosphorylation assays, nuclear translocation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, Co-IP, biochemical assays), replicated across multiple readouts in a single focused study","pmids":["11741537"],"is_preprint":false},{"year":2007,"finding":"TIPRL interacts with the C-terminal region (residues 210–309) of the catalytic subunits of PP2A, PP4, and PP6 via a region distinct from the alpha4-binding site; TIPRL and alpha4 can simultaneously bind PP2Ac, forming a stable ternary complex (alpha4:PP2Ac:TIPRL). TIPRL inhibits PP2Ac activity in vitro. Single amino acid substitutions D71L, I136T, M196V, and D198N on TIPRL disrupt its interaction with PP2Ac. The complex is rapamycin-insensitive in human cells.","method":"Yeast two-hybrid screen, pull-down assays with recombinant proteins, reverse two-hybrid mutagenesis, in vitro phosphatase activity assay, co-immunoprecipitation from human cells","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphatase inhibition assay, mutagenesis mapping of interaction interface, reciprocal binding assays, multiple orthogonal methods in single study","pmids":["17944932"],"is_preprint":false},{"year":2013,"finding":"Mammalian TIPRL positively regulates mTORC1 signaling (in contrast to yeast TIP41 which is inhibitory); overexpression of TIPRL suppressed dephosphorylation of mTORC1 substrates under amino acid withdrawal, while knockdown of TIPRL attenuated phosphorylation of mTORC1 substrates after amino acid refeeding. This action requires TIPRL association with the catalytic subunit of PP2A (PP2Ac).","method":"Overexpression and siRNA knockdown with phosphorylation readouts (immunoblot), co-immunoprecipitation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function and gain-of-function with defined phosphorylation readouts plus Co-IP, single lab","pmids":["23892082"],"is_preprint":false},{"year":2015,"finding":"TIPRL negatively regulates protein phosphatase 4 (PP4) activity; knockdown of TIPRL increases PP4 phosphatase activity and promotes formation of the active PP4-C/PP4R2 complex that dephosphorylates γ-H2AX. Overexpression of TIPRL promotes H2AX phosphorylation and increases γ-H2AX foci in response to DNA damage, while TIPRL knockdown inhibits γ-H2AX phosphorylation and protects cells from genotoxic stress.","method":"siRNA knockdown, overexpression, phosphatase activity assay, co-immunoprecipitation (PP4-C/PP4R2 complex), immunofluorescence (γ-H2AX foci), cell viability assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphatase activity assay plus complex formation and cellular phenotype readouts, single lab with multiple orthogonal methods","pmids":["26717153"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of human TIPRL solved at 2.15 Å resolution reveals a novel fold organized around a central core of antiparallel beta-sheet with an N-terminal α/β region and a conserved cleft. Mutagenesis, pulldown, and hydrogen/deuterium exchange mass spectrometry demonstrate that this conserved cleft binds the conserved C-terminal tail of PP2Ac (mimicked by the peptide DYFL). TIPRL preferentially binds the unmodified PP2A C-terminal tail peptide over its tyrosine-phosphorylated version. Docking modeling suggests TIPRL blocks the phosphatase's active site.","method":"X-ray crystallography (2.15 Å), mutagenesis, pulldown assays, hydrogen/deuterium exchange mass spectrometry, docking modeling","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis, HDX-MS, and binding assays providing structural and biochemical validation of the PP2Ac binding mechanism","pmids":["27489114"],"is_preprint":false},{"year":2014,"finding":"TIPRL interacts with MKK7 (MAP kinase kinase 7) and this interaction contributes to resistance to TRAIL-induced apoptosis by inhibiting the MKK7-JNK pathway. Disruption of the MKK7-TIPRL interaction (by Tussilago farfara extract) restores MKK7/JNK phosphorylation and sensitizes cells to TRAIL-induced apoptosis.","method":"GST pull-down assay, ELISA-based interaction detection, co-treatment functional apoptosis assay (cell viability, caspase activation)","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GST pull-down identifies interaction and disruption of MKK7-TIPRL is functionally validated in apoptosis assays, single lab","pmids":["24969837"],"is_preprint":false},{"year":2017,"finding":"TIPRL directly interacts with MKK7, and inhibition of this interaction by small molecule compounds leads to increased MKK7 and JNK phosphorylation and sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis in vitro and in vivo.","method":"ELISA-based high-throughput screening of MKK7-TIPRL interaction, cell viability assay, immunoblot for MKK7/JNK phosphorylation, xenograft in vivo tumor regression assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — interaction disruption validated by ELISA and functional phosphorylation assays, confirmed in vivo, single lab","pmids":["29348850"],"is_preprint":false},{"year":2019,"finding":"TIPRL interacts with eIF2α and promotes eIF2α phosphorylation, activating the eIF2α-ATF4 pathway to induce autophagy in non-small cell lung cancer cells. TIPRL depletion reduces autophagic clearance and increases apoptosis.","method":"Co-immunoprecipitation (TIPRL-eIF2α interaction), immunoblot for eIF2α phosphorylation and ATF4 levels, autophagy assays (LC3-II/p62), siRNA knockdown, xenograft assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifies TIPRL-eIF2α interaction, functional knockdown with phosphorylation readout and in vivo confirmation, single lab","pmids":["31862913"],"is_preprint":false},{"year":2024,"finding":"TIPRL binds directly to CaMKK2 (calcium/calmodulin-dependent protein kinase kinase 2) in lung cancer stem cells, causing sustained activation of the CaMKK2 signaling pathway, which phosphorylates CaMK4, leading to phosphorylation of CREB at Ser129 and Ser133. Activated CREB then drives expression of Bcl2 and HMG20A and transcriptionally activates TIPRL itself, forming a positive feedback loop. TIPRL depletion sensitizes lung cancer stem cells to afatinib and reduces distal metastasis in vivo.","method":"Co-immunoprecipitation (TIPRL-CaMKK2), immunoblot for CaMK4 and CREB phosphorylation, CREB transcriptional reporter, gene expression analysis, siRNA/CRISPR knockdown, xenograft metastasis assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifies novel interaction with CaMKK2, pathway placement by phosphorylation readouts with in vivo validation, single lab","pmids":["39076120"],"is_preprint":false},{"year":2023,"finding":"ATM kinase phosphorylates TIPRL1 at Ser265 upon irradiation. A non-phosphorylatable Ser265Ala mutant cannot rescue the increased radiosensitivity of TIPRL1-depleted HNSCC cells, demonstrating that ATM-dependent phosphorylation of TIPRL1 at Ser265 is required for its role in radiotherapy resistance. TIPRL1 was also found to interact with DNA-PKcs, RAD51, and nucleosomal histones (novel interactors beyond PP2A-family phosphatases); histone binding is stimulated by RT but adversely affected by Ser265 phosphorylation.","method":"Mass spectrometry (phosphorylation site mapping and interactomics), CRISPR/Cas9 deletion, rescue with Ser265Ala mutant, immunoblot (DDR signaling), microscopy (micronuclei), flow cytometry (cell cycle)","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site identified by MS, mechanistic rescue experiment with point mutant confirms functional requirement, single lab with multiple orthogonal methods","pmids":["37971644"],"is_preprint":false},{"year":2005,"finding":"Fission yeast (S. pombe) Tip41 ortholog regulates type 2A phosphatase activity: overexpression of tip41+ increases type 2A phosphatase activity, and in a ppa2 deletion strain with reduced PP2A activity, overexpression of tip41+ no longer blocks the cell cycle G1 shift upon nitrogen starvation, placing Tip41 upstream of PP2A in cellular responses to nitrogen nutrient conditions.","method":"Genetic epistasis (tip41 deletion and ppa2 deletion double mutant), overexpression, phosphatase activity assay, cell cycle analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with phosphatase activity measurement establishes pathway position, single lab ortholog study","pmids":["16297994"],"is_preprint":false}],"current_model":"TIPRL is a conserved regulatory protein that binds and inhibits the catalytic subunits of PP2A, PP4, and PP6 (type 2A serine/threonine phosphatases) through a conserved cleft revealed by its crystal structure, blocking their active sites; in mammalian cells it positively regulates mTORC1 signaling via PP2Ac inhibition, promotes H2AX phosphorylation in the DNA damage response by inhibiting PP4, interacts with MKK7 to suppress JNK-mediated apoptosis, activates the eIF2α-ATF4 autophagy axis, and binds CaMKK2 to sustain a CREB-driven stemness feedback loop, with ATM-dependent phosphorylation at Ser265 further modulating its role in DNA damage response and radioresistance."},"narrative":{"mechanistic_narrative":"TIPRL is a conserved regulator of the type 2A serine/threonine phosphatases (PP2A, PP4, and PP6), binding their catalytic subunits and inhibiting their activity [PMID:17944932, PMID:27489114]. Its crystal structure reveals a novel fold with a conserved cleft that engages the conserved C-terminal tail of PP2Ac (DYFL motif), preferentially recognizing the unmodified over the tyrosine-phosphorylated tail and blocking access to the phosphatase active site [PMID:27489114]. TIPRL binds the catalytic subunits through a region distinct from the alpha4-binding site, allowing formation of a stable alpha4:PP2Ac:TIPRL ternary complex [PMID:17944932]. The yeast ortholog TIP41 acts within a TOR-coupled feedback loop with TAP42 to amplify SIT4 phosphatase activity under TOR-inactivating conditions [PMID:11741537], whereas mammalian TIPRL positively regulates mTORC1 signaling by associating with PP2Ac and protecting mTORC1 substrate phosphorylation during nutrient stress [PMID:23892082]. Through phosphatase inhibition TIPRL controls multiple stress and survival pathways: it suppresses PP4-mediated dephosphorylation of γ-H2AX to promote the DNA damage response [PMID:26717153], and ATM phosphorylates TIPRL at Ser265 upon irradiation, a modification required for its role in radioresistance alongside newly identified interactions with DNA-PKcs, RAD51, and nucleosomal histones [PMID:37971644]. In cancer cells TIPRL additionally promotes survival by binding MKK7 to suppress JNK-mediated TRAIL-induced apoptosis [PMID:24969837, PMID:29348850], by interacting with eIF2α to activate the eIF2α-ATF4 autophagy axis [PMID:31862913], and by binding CaMKK2 to sustain a CaMK4-CREB stemness feedback loop that transcriptionally reinforces TIPRL expression [PMID:39076120].","teleology":[{"year":2001,"claim":"Established the ancestral function of the TIPRL family by showing the yeast ortholog couples TOR signaling to type 2A phosphatase regulation through a TAP42 feedback loop.","evidence":"Genetic epistasis, Co-IP, and phosphorylation/nuclear translocation assays in budding yeast","pmids":["11741537"],"confidence":"High","gaps":["Did not address whether the mammalian ortholog conserves the inhibitory directionality on TOR","Direct phosphatase inhibition not biochemically demonstrated"]},{"year":2005,"claim":"Placed the Tip41 ortholog upstream of PP2A in nutrient-responsive cell cycle control, confirming phosphatase regulation as a conserved function.","evidence":"Genetic epistasis with ppa2 deletion, overexpression, and phosphatase activity assays in fission yeast","pmids":["16297994"],"confidence":"Medium","gaps":["Direction of effect on phosphatase appeared activating, contrasting later mammalian inhibition data","No physical interaction mapping"]},{"year":2007,"claim":"Defined TIPRL as a direct inhibitor of multiple type 2A phosphatase catalytic subunits and mapped its binding to a site distinct from alpha4, enabling a ternary complex.","evidence":"Yeast two-hybrid, recombinant pull-downs, reverse two-hybrid mutagenesis, and in vitro phosphatase assays","pmids":["17944932"],"confidence":"High","gaps":["Structural basis of inhibition unresolved","Functional consequence of the ternary complex in cells unknown"]},{"year":2013,"claim":"Showed that mammalian TIPRL positively regulates mTORC1 via PP2Ac, reversing the inhibitory directionality of the yeast ortholog.","evidence":"Overexpression/siRNA with mTORC1 substrate phosphorylation readouts and Co-IP","pmids":["23892082"],"confidence":"Medium","gaps":["Mechanism of directionality switch from yeast not explained","Single-lab phosphorylation readouts"]},{"year":2014,"claim":"Extended TIPRL function to apoptosis control by identifying its interaction with MKK7 and showing it restrains the JNK death pathway.","evidence":"GST pull-down, ELISA interaction detection, and functional apoptosis assays with an interaction-disrupting extract","pmids":["24969837"],"confidence":"Medium","gaps":["Whether MKK7 regulation depends on phosphatase activity unknown","Interaction interface not mapped"]},{"year":2015,"claim":"Connected TIPRL to the DNA damage response by showing it inhibits PP4 and thereby sustains γ-H2AX phosphorylation.","evidence":"siRNA/overexpression, phosphatase activity assays, PP4-C/PP4R2 Co-IP, and γ-H2AX foci imaging","pmids":["26717153"],"confidence":"Medium","gaps":["Whether TIPRL competes with PP4R2 directly not resolved","Single-lab evidence"]},{"year":2016,"claim":"Provided the structural mechanism of phosphatase inhibition: a conserved cleft binds the PP2Ac C-terminal tail and occludes the active site.","evidence":"X-ray crystallography at 2.15 Å with mutagenesis, HDX-MS, peptide binding, and docking","pmids":["27489114"],"confidence":"High","gaps":["No co-crystal structure with full-length phosphatase","Selectivity among PP2A/PP4/PP6 not structurally explained"]},{"year":2017,"claim":"Validated the MKK7-TIPRL interaction as a druggable node by sensitizing hepatocellular carcinoma to TRAIL-induced apoptosis upon disruption.","evidence":"ELISA-based screening, phosphorylation immunoblots, and xenograft tumor regression","pmids":["29348850"],"confidence":"Medium","gaps":["Selectivity of small-molecule disruptors not established","Relationship to phosphatase function unclear"]},{"year":2019,"claim":"Identified TIPRL as a promoter of autophagy through interaction with eIF2α and activation of the eIF2α-ATF4 axis.","evidence":"Co-IP, eIF2α phosphorylation/ATF4 immunoblots, LC3-II/p62 autophagy assays, and xenografts in NSCLC","pmids":["31862913"],"confidence":"Medium","gaps":["How TIPRL promotes eIF2α phosphorylation mechanistically unknown","Link to phosphatase inhibition not established"]},{"year":2023,"claim":"Revealed ATM-dependent phosphorylation of TIPRL at Ser265 as required for radioresistance and identified DDR-related interactors beyond phosphatases.","evidence":"MS phosphosite mapping and interactomics, CRISPR deletion, and Ser265Ala rescue in HNSCC","pmids":["37971644"],"confidence":"Medium","gaps":["Functional roles of DNA-PKcs/RAD51/histone interactions not dissected","Whether Ser265 phosphorylation alters phosphatase inhibition unknown"]},{"year":2024,"claim":"Linked TIPRL to cancer stemness through a CaMKK2-CaMK4-CREB feedback loop that transcriptionally reinforces TIPRL expression.","evidence":"Co-IP, phosphorylation immunoblots, CREB reporter, knockdown, and xenograft metastasis assays in lung cancer stem cells","pmids":["39076120"],"confidence":"Medium","gaps":["Direct vs indirect activation of CaMKK2 not resolved","Relationship of this loop to phosphatase inhibition unclear"]},{"year":null,"claim":"It remains unresolved how a single phosphatase-inhibitory scaffold mechanistically toggles between its PP2A/PP4/PP6 binding mode and its diverse kinase-pathway interactions (MKK7, eIF2α, CaMKK2) and DDR partners.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TIPRL bound to non-phosphatase partners","Unknown whether phosphatase inhibition is required for the JNK, autophagy, and stemness phenotypes","Substrate selectivity among the three type 2A phosphatases not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,6]}],"complexes":["alpha4:PP2Ac:TIPRL ternary complex"],"partners":["PP2A (PPP2CA)","PP4","PP6","MKK7","EIF2A","CAMKK2","DNA-PKCS","RAD51"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75663","full_name":"TIP41-like protein","aliases":["Putative MAPK-activating protein PM10","Type 2A-interacting protein","TIP"],"length_aa":272,"mass_kda":31.4,"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","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O75663/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TIPRL","classification":"Not Classified","n_dependent_lines":549,"n_total_lines":1208,"dependency_fraction":0.4544701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TIPRL","total_profiled":1310},"omim":[{"mim_id":"611807","title":"TIP41-LIKE PROTEIN; TIPRL","url":"https://www.omim.org/entry/611807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TIPRL"},"hgnc":{"alias_symbol":["MGC3794","dJ69E11.3","TIP41","TIPRL1"],"prev_symbol":[]},"alphafold":{"accession":"O75663","domains":[{"cath_id":"-","chopping":"8-79_106-252","consensus_level":"medium","plddt":93.7986,"start":8,"end":252}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75663","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75663-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75663-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TIPRL","jax_strain_url":"https://www.jax.org/strain/search?query=TIPRL"},"sequence":{"accession":"O75663","fasta_url":"https://rest.uniprot.org/uniprotkb/O75663.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75663/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75663"}},"corpus_meta":[{"pmid":"11741537","id":"PMC_11741537","title":"TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway.","date":"2001","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11741537","citation_count":194,"is_preprint":false},{"pmid":"10750022","id":"PMC_10750022","title":"Expression of the prolactin receptor (tiPRL-R) gene in tilapia Oreochromis niloticus: tissue distribution and cellular localization in osmoregulatory organs.","date":"2000","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10750022","citation_count":48,"is_preprint":false},{"pmid":"23892082","id":"PMC_23892082","title":"A positive role of mammalian Tip41-like protein, TIPRL, in the amino-acid dependent mTORC1-signaling pathway through interaction with PP2A.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23892082","citation_count":36,"is_preprint":false},{"pmid":"17944932","id":"PMC_17944932","title":"Interaction analysis of the heterotrimer formed by the phosphatase 2A catalytic subunit, alpha4 and the mammalian ortholog of yeast Tip41 (TIPRL).","date":"2007","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/17944932","citation_count":31,"is_preprint":false},{"pmid":"33494763","id":"PMC_33494763","title":"Hsa_circ_0010235 functions as an oncogenic drive in non-small cell lung cancer by modulating miR-433-3p/TIPRL axis.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33494763","citation_count":31,"is_preprint":false},{"pmid":"31862913","id":"PMC_31862913","title":"TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31862913","citation_count":29,"is_preprint":false},{"pmid":"24969837","id":"PMC_24969837","title":"Tussilago farfara L. augments TRAIL-induced apoptosis through MKK7/JNK activation by inhibition of MKK7‑TIPRL in human hepatocellular carcinoma cells.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24969837","citation_count":22,"is_preprint":false},{"pmid":"26717153","id":"PMC_26717153","title":"TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26717153","citation_count":21,"is_preprint":false},{"pmid":"32719745","id":"PMC_32719745","title":"TIPRL, a Novel Tumor Suppressor, Suppresses Cell Migration, and Invasion Through Regulating AMPK/mTOR Signaling Pathway in Gastric Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32719745","citation_count":17,"is_preprint":false},{"pmid":"31727942","id":"PMC_31727942","title":"The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31727942","citation_count":16,"is_preprint":false},{"pmid":"27489114","id":"PMC_27489114","title":"Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27489114","citation_count":15,"is_preprint":false},{"pmid":"36298819","id":"PMC_36298819","title":"TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects.","date":"2022","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/36298819","citation_count":13,"is_preprint":false},{"pmid":"39076120","id":"PMC_39076120","title":"TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39076120","citation_count":12,"is_preprint":false},{"pmid":"29348850","id":"PMC_29348850","title":"Novel indazole-based small compounds enhance TRAIL-induced apoptosis by inhibiting the MKK7-TIPRL interaction in hepatocellular carcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29348850","citation_count":12,"is_preprint":false},{"pmid":"37971644","id":"PMC_37971644","title":"TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer.","date":"2023","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/37971644","citation_count":8,"is_preprint":false},{"pmid":"16297994","id":"PMC_16297994","title":"Fission yeast homologue of Tip41-like proteins regulates type 2A phosphatases and responses to nitrogen sources.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16297994","citation_count":8,"is_preprint":false},{"pmid":"38888871","id":"PMC_38888871","title":"TIPRL, a Potential Double-edge Molecule to be Targeted and Re-targeted Toward Cancer.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/38888871","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.07.616947","title":"Towards a greener AlphaFold2 protocol for antibody-antigen modeling: Insights from CAPRI Round 55","date":"2024-10-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.07.616947","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10475,"output_tokens":3353,"usd":0.04086,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10983,"output_tokens":3703,"usd":0.073745,"stage2_stop_reason":"end_turn"},"total_usd":0.114605,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Yeast TIP41 (ortholog of TIPRL) interacts with TAP42 (ortholog of alpha4) and negatively regulates the TOR signaling pathway; deletion of TIP41 confers rapamycin resistance and prevents dissociation of SIT4 phosphatase from TAP42, blocking SIT4-dependent dephosphorylation of NPR1 and nuclear translocation of GLN3. TIP41 binding to TAP42 is stimulated by rapamycin treatment via SIT4-dependent dephosphorylation of TIP41, establishing a feedback loop that amplifies SIT4 phosphatase activity under TOR-inactivating conditions.\",\n      \"method\": \"Genetic epistasis (deletion/suppressor analysis), co-immunoprecipitation, phosphorylation assays, nuclear translocation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, Co-IP, biochemical assays), replicated across multiple readouts in a single focused study\",\n      \"pmids\": [\"11741537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIPRL interacts with the C-terminal region (residues 210–309) of the catalytic subunits of PP2A, PP4, and PP6 via a region distinct from the alpha4-binding site; TIPRL and alpha4 can simultaneously bind PP2Ac, forming a stable ternary complex (alpha4:PP2Ac:TIPRL). TIPRL inhibits PP2Ac activity in vitro. Single amino acid substitutions D71L, I136T, M196V, and D198N on TIPRL disrupt its interaction with PP2Ac. The complex is rapamycin-insensitive in human cells.\",\n      \"method\": \"Yeast two-hybrid screen, pull-down assays with recombinant proteins, reverse two-hybrid mutagenesis, in vitro phosphatase activity assay, co-immunoprecipitation from human cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphatase inhibition assay, mutagenesis mapping of interaction interface, reciprocal binding assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17944932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mammalian TIPRL positively regulates mTORC1 signaling (in contrast to yeast TIP41 which is inhibitory); overexpression of TIPRL suppressed dephosphorylation of mTORC1 substrates under amino acid withdrawal, while knockdown of TIPRL attenuated phosphorylation of mTORC1 substrates after amino acid refeeding. This action requires TIPRL association with the catalytic subunit of PP2A (PP2Ac).\",\n      \"method\": \"Overexpression and siRNA knockdown with phosphorylation readouts (immunoblot), co-immunoprecipitation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function and gain-of-function with defined phosphorylation readouts plus Co-IP, single lab\",\n      \"pmids\": [\"23892082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIPRL negatively regulates protein phosphatase 4 (PP4) activity; knockdown of TIPRL increases PP4 phosphatase activity and promotes formation of the active PP4-C/PP4R2 complex that dephosphorylates γ-H2AX. Overexpression of TIPRL promotes H2AX phosphorylation and increases γ-H2AX foci in response to DNA damage, while TIPRL knockdown inhibits γ-H2AX phosphorylation and protects cells from genotoxic stress.\",\n      \"method\": \"siRNA knockdown, overexpression, phosphatase activity assay, co-immunoprecipitation (PP4-C/PP4R2 complex), immunofluorescence (γ-H2AX foci), cell viability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphatase activity assay plus complex formation and cellular phenotype readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26717153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of human TIPRL solved at 2.15 Å resolution reveals a novel fold organized around a central core of antiparallel beta-sheet with an N-terminal α/β region and a conserved cleft. Mutagenesis, pulldown, and hydrogen/deuterium exchange mass spectrometry demonstrate that this conserved cleft binds the conserved C-terminal tail of PP2Ac (mimicked by the peptide DYFL). TIPRL preferentially binds the unmodified PP2A C-terminal tail peptide over its tyrosine-phosphorylated version. Docking modeling suggests TIPRL blocks the phosphatase's active site.\",\n      \"method\": \"X-ray crystallography (2.15 Å), mutagenesis, pulldown assays, hydrogen/deuterium exchange mass spectrometry, docking modeling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis, HDX-MS, and binding assays providing structural and biochemical validation of the PP2Ac binding mechanism\",\n      \"pmids\": [\"27489114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIPRL interacts with MKK7 (MAP kinase kinase 7) and this interaction contributes to resistance to TRAIL-induced apoptosis by inhibiting the MKK7-JNK pathway. Disruption of the MKK7-TIPRL interaction (by Tussilago farfara extract) restores MKK7/JNK phosphorylation and sensitizes cells to TRAIL-induced apoptosis.\",\n      \"method\": \"GST pull-down assay, ELISA-based interaction detection, co-treatment functional apoptosis assay (cell viability, caspase activation)\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GST pull-down identifies interaction and disruption of MKK7-TIPRL is functionally validated in apoptosis assays, single lab\",\n      \"pmids\": [\"24969837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIPRL directly interacts with MKK7, and inhibition of this interaction by small molecule compounds leads to increased MKK7 and JNK phosphorylation and sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis in vitro and in vivo.\",\n      \"method\": \"ELISA-based high-throughput screening of MKK7-TIPRL interaction, cell viability assay, immunoblot for MKK7/JNK phosphorylation, xenograft in vivo tumor regression assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — interaction disruption validated by ELISA and functional phosphorylation assays, confirmed in vivo, single lab\",\n      \"pmids\": [\"29348850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIPRL interacts with eIF2α and promotes eIF2α phosphorylation, activating the eIF2α-ATF4 pathway to induce autophagy in non-small cell lung cancer cells. TIPRL depletion reduces autophagic clearance and increases apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (TIPRL-eIF2α interaction), immunoblot for eIF2α phosphorylation and ATF4 levels, autophagy assays (LC3-II/p62), siRNA knockdown, xenograft assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifies TIPRL-eIF2α interaction, functional knockdown with phosphorylation readout and in vivo confirmation, single lab\",\n      \"pmids\": [\"31862913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TIPRL binds directly to CaMKK2 (calcium/calmodulin-dependent protein kinase kinase 2) in lung cancer stem cells, causing sustained activation of the CaMKK2 signaling pathway, which phosphorylates CaMK4, leading to phosphorylation of CREB at Ser129 and Ser133. Activated CREB then drives expression of Bcl2 and HMG20A and transcriptionally activates TIPRL itself, forming a positive feedback loop. TIPRL depletion sensitizes lung cancer stem cells to afatinib and reduces distal metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (TIPRL-CaMKK2), immunoblot for CaMK4 and CREB phosphorylation, CREB transcriptional reporter, gene expression analysis, siRNA/CRISPR knockdown, xenograft metastasis assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifies novel interaction with CaMKK2, pathway placement by phosphorylation readouts with in vivo validation, single lab\",\n      \"pmids\": [\"39076120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATM kinase phosphorylates TIPRL1 at Ser265 upon irradiation. A non-phosphorylatable Ser265Ala mutant cannot rescue the increased radiosensitivity of TIPRL1-depleted HNSCC cells, demonstrating that ATM-dependent phosphorylation of TIPRL1 at Ser265 is required for its role in radiotherapy resistance. TIPRL1 was also found to interact with DNA-PKcs, RAD51, and nucleosomal histones (novel interactors beyond PP2A-family phosphatases); histone binding is stimulated by RT but adversely affected by Ser265 phosphorylation.\",\n      \"method\": \"Mass spectrometry (phosphorylation site mapping and interactomics), CRISPR/Cas9 deletion, rescue with Ser265Ala mutant, immunoblot (DDR signaling), microscopy (micronuclei), flow cytometry (cell cycle)\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site identified by MS, mechanistic rescue experiment with point mutant confirms functional requirement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37971644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fission yeast (S. pombe) Tip41 ortholog regulates type 2A phosphatase activity: overexpression of tip41+ increases type 2A phosphatase activity, and in a ppa2 deletion strain with reduced PP2A activity, overexpression of tip41+ no longer blocks the cell cycle G1 shift upon nitrogen starvation, placing Tip41 upstream of PP2A in cellular responses to nitrogen nutrient conditions.\",\n      \"method\": \"Genetic epistasis (tip41 deletion and ppa2 deletion double mutant), overexpression, phosphatase activity assay, cell cycle analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with phosphatase activity measurement establishes pathway position, single lab ortholog study\",\n      \"pmids\": [\"16297994\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIPRL is a conserved regulatory protein that binds and inhibits the catalytic subunits of PP2A, PP4, and PP6 (type 2A serine/threonine phosphatases) through a conserved cleft revealed by its crystal structure, blocking their active sites; in mammalian cells it positively regulates mTORC1 signaling via PP2Ac inhibition, promotes H2AX phosphorylation in the DNA damage response by inhibiting PP4, interacts with MKK7 to suppress JNK-mediated apoptosis, activates the eIF2α-ATF4 autophagy axis, and binds CaMKK2 to sustain a CREB-driven stemness feedback loop, with ATM-dependent phosphorylation at Ser265 further modulating its role in DNA damage response and radioresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TIPRL is a conserved regulator of the type 2A serine/threonine phosphatases (PP2A, PP4, and PP6), binding their catalytic subunits and inhibiting their activity [#1, #4]. Its crystal structure reveals a novel fold with a conserved cleft that engages the conserved C-terminal tail of PP2Ac (DYFL motif), preferentially recognizing the unmodified over the tyrosine-phosphorylated tail and blocking access to the phosphatase active site [#4]. TIPRL binds the catalytic subunits through a region distinct from the alpha4-binding site, allowing formation of a stable alpha4:PP2Ac:TIPRL ternary complex [#1]. The yeast ortholog TIP41 acts within a TOR-coupled feedback loop with TAP42 to amplify SIT4 phosphatase activity under TOR-inactivating conditions [#0], whereas mammalian TIPRL positively regulates mTORC1 signaling by associating with PP2Ac and protecting mTORC1 substrate phosphorylation during nutrient stress [#2]. Through phosphatase inhibition TIPRL controls multiple stress and survival pathways: it suppresses PP4-mediated dephosphorylation of \\u03b3-H2AX to promote the DNA damage response [#3], and ATM phosphorylates TIPRL at Ser265 upon irradiation, a modification required for its role in radioresistance alongside newly identified interactions with DNA-PKcs, RAD51, and nucleosomal histones [#9]. In cancer cells TIPRL additionally promotes survival by binding MKK7 to suppress JNK-mediated TRAIL-induced apoptosis [#5, #6], by interacting with eIF2\\u03b1 to activate the eIF2\\u03b1-ATF4 autophagy axis [#7], and by binding CaMKK2 to sustain a CaMK4-CREB stemness feedback loop that transcriptionally reinforces TIPRL expression [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the ancestral function of the TIPRL family by showing the yeast ortholog couples TOR signaling to type 2A phosphatase regulation through a TAP42 feedback loop.\",\n      \"evidence\": \"Genetic epistasis, Co-IP, and phosphorylation/nuclear translocation assays in budding yeast\",\n      \"pmids\": [\"11741537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether the mammalian ortholog conserves the inhibitory directionality on TOR\", \"Direct phosphatase inhibition not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed the Tip41 ortholog upstream of PP2A in nutrient-responsive cell cycle control, confirming phosphatase regulation as a conserved function.\",\n      \"evidence\": \"Genetic epistasis with ppa2 deletion, overexpression, and phosphatase activity assays in fission yeast\",\n      \"pmids\": [\"16297994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of effect on phosphatase appeared activating, contrasting later mammalian inhibition data\", \"No physical interaction mapping\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined TIPRL as a direct inhibitor of multiple type 2A phosphatase catalytic subunits and mapped its binding to a site distinct from alpha4, enabling a ternary complex.\",\n      \"evidence\": \"Yeast two-hybrid, recombinant pull-downs, reverse two-hybrid mutagenesis, and in vitro phosphatase assays\",\n      \"pmids\": [\"17944932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of inhibition unresolved\", \"Functional consequence of the ternary complex in cells unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that mammalian TIPRL positively regulates mTORC1 via PP2Ac, reversing the inhibitory directionality of the yeast ortholog.\",\n      \"evidence\": \"Overexpression/siRNA with mTORC1 substrate phosphorylation readouts and Co-IP\",\n      \"pmids\": [\"23892082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of directionality switch from yeast not explained\", \"Single-lab phosphorylation readouts\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended TIPRL function to apoptosis control by identifying its interaction with MKK7 and showing it restrains the JNK death pathway.\",\n      \"evidence\": \"GST pull-down, ELISA interaction detection, and functional apoptosis assays with an interaction-disrupting extract\",\n      \"pmids\": [\"24969837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MKK7 regulation depends on phosphatase activity unknown\", \"Interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected TIPRL to the DNA damage response by showing it inhibits PP4 and thereby sustains \\u03b3-H2AX phosphorylation.\",\n      \"evidence\": \"siRNA/overexpression, phosphatase activity assays, PP4-C/PP4R2 Co-IP, and \\u03b3-H2AX foci imaging\",\n      \"pmids\": [\"26717153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TIPRL competes with PP4R2 directly not resolved\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural mechanism of phosphatase inhibition: a conserved cleft binds the PP2Ac C-terminal tail and occludes the active site.\",\n      \"evidence\": \"X-ray crystallography at 2.15 \\u00c5 with mutagenesis, HDX-MS, peptide binding, and docking\",\n      \"pmids\": [\"27489114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure with full-length phosphatase\", \"Selectivity among PP2A/PP4/PP6 not structurally explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Validated the MKK7-TIPRL interaction as a druggable node by sensitizing hepatocellular carcinoma to TRAIL-induced apoptosis upon disruption.\",\n      \"evidence\": \"ELISA-based screening, phosphorylation immunoblots, and xenograft tumor regression\",\n      \"pmids\": [\"29348850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of small-molecule disruptors not established\", \"Relationship to phosphatase function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified TIPRL as a promoter of autophagy through interaction with eIF2\\u03b1 and activation of the eIF2\\u03b1-ATF4 axis.\",\n      \"evidence\": \"Co-IP, eIF2\\u03b1 phosphorylation/ATF4 immunoblots, LC3-II/p62 autophagy assays, and xenografts in NSCLC\",\n      \"pmids\": [\"31862913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TIPRL promotes eIF2\\u03b1 phosphorylation mechanistically unknown\", \"Link to phosphatase inhibition not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed ATM-dependent phosphorylation of TIPRL at Ser265 as required for radioresistance and identified DDR-related interactors beyond phosphatases.\",\n      \"evidence\": \"MS phosphosite mapping and interactomics, CRISPR deletion, and Ser265Ala rescue in HNSCC\",\n      \"pmids\": [\"37971644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of DNA-PKcs/RAD51/histone interactions not dissected\", \"Whether Ser265 phosphorylation alters phosphatase inhibition unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked TIPRL to cancer stemness through a CaMKK2-CaMK4-CREB feedback loop that transcriptionally reinforces TIPRL expression.\",\n      \"evidence\": \"Co-IP, phosphorylation immunoblots, CREB reporter, knockdown, and xenograft metastasis assays in lung cancer stem cells\",\n      \"pmids\": [\"39076120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect activation of CaMKK2 not resolved\", \"Relationship of this loop to phosphatase inhibition unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single phosphatase-inhibitory scaffold mechanistically toggles between its PP2A/PP4/PP6 binding mode and its diverse kinase-pathway interactions (MKK7, eIF2\\u03b1, CaMKK2) and DDR partners.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TIPRL bound to non-phosphatase partners\", \"Unknown whether phosphatase inhibition is required for the JNK, autophagy, and stemness phenotypes\", \"Substrate selectivity among the three type 2A phosphatases not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"alpha4:PP2Ac:TIPRL ternary complex\"],\n    \"partners\": [\"PP2A (PPP2CA)\", \"PP4\", \"PP6\", \"MKK7\", \"EIF2A\", \"CAMKK2\", \"DNA-PKcs\", \"RAD51\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}