{"gene":"PIK3IP1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2007,"finding":"PIK3IP1 directly binds to the p110 catalytic subunit of PI3K and reduces PI3K activity in vitro; PIK3IP1 shares homology with the p85 regulatory subunit of PI3K.","method":"In vitro binding assays, cell-based assays, PI3K activity assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of binding and enzymatic inhibition, replicated across multiple papers from independent labs","pmids":["17475214"],"is_preprint":false},{"year":2008,"finding":"PIK3IP1 overexpression in transgenic mouse hepatocytes blunts PI3K signaling, reduces DNA synthetic activity, motility, and survival, and dampens spontaneous liver tumorigenesis in vivo.","method":"Transgenic mouse model, PI3K activity assay, proliferation and motility assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic overexpression model with multiple orthogonal phenotypic readouts, replicated in vivo","pmids":["18632611"],"is_preprint":false},{"year":2008,"finding":"PIK3IP1 and its splice isoform PIK3IP1-v1 both localize to the cell membrane (containing signal peptide and transmembrane domain); both induce cell apoptosis when overexpressed; PIK3IP1-v1 lacks the extracellular Kringle domain.","method":"Fluorescence microscopy, flow cytometry, RT-PCR, bioinformatics structural analysis, luciferase reporter assay","journal":"Journal of Peking University. Health sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization by fluorescence microscopy with functional apoptosis readout, single lab, multiple methods","pmids":["19088825"],"is_preprint":false},{"year":2012,"finding":"PIK3IP1 is expressed in T cells; ectopic PIK3IP1 expression inhibits NFAT/AP-1 transcriptional activation; siRNA-mediated knockdown of PIK3IP1 augments Akt phosphorylation, T cell activation, and IL-2 production.","method":"Ectopic expression, siRNA knockdown, luciferase reporter assay, Western blot (pAkt), IL-2 ELISA","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss- and gain-of-function in T cell lines with multiple readouts, single lab","pmids":["22706993"],"is_preprint":false},{"year":2013,"finding":"PIK3IP1 is markedly reduced in mantle cell lymphoma (MCL) tumor cells; it is profoundly induced upon CDK4/CDK6 inhibition-mediated prolonged G1 arrest (pG1) and is required for pG1-dependent sensitization to PI3Kδ inhibition, placing PIK3IP1 downstream of cell cycle arrest in the PI3K pathway.","method":"Whole-transcriptome sequencing, gene expression analysis, functional knockdown assays in primary MCL cells","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional knockdown with specific phenotypic readout (apoptosis, PI3K inhibition sensitivity), single lab","pmids":["23676220"],"is_preprint":false},{"year":2015,"finding":"Pik3ip1 directly interacts with the p110α subunit of PI3K in cardiomyocytes (by co-immunoprecipitation); Pik3ip1 knockdown activates PI3K/AKT/mTOR signaling and induces cardiac hypertrophy, whereas adenovirus-mediated overexpression attenuates PI3K-mediated hypertrophy.","method":"Co-immunoprecipitation, siRNA knockdown, adenovirus-mediated overexpression, Western blot, cell size measurement in neonatal rat cardiomyocytes","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with p110α, bidirectional gain/loss-of-function with specific pathway and phenotypic readouts","pmids":["25826393"],"is_preprint":false},{"year":2015,"finding":"miR-let-7g targets Pik3ip1 mRNA in cardiac myocytes via the RISC/Argonaute complex; hypoxia-induced Lin28 represses miR-let-7, leading to Pik3ip1 upregulation, which suppresses PI3K/Akt signaling and promotes apoptosis.","method":"Crosslinking immunoprecipitation (RISC), lentiviral overexpression, caspase activation assay, Akt phosphorylation assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RISC crosslinking demonstrates miR-let-7g targets Pik3ip1, single lab with orthogonal methods","pmids":["26655604"],"is_preprint":false},{"year":2018,"finding":"PIK3IP1 (TrIP) is a transmembrane protein with an extracellular kringle domain and an intracellular p85-like domain; both domains are necessary for PI3K inhibition; the kringle domain mediates oligomerization of TrIP; TrIP is downmodulated from the T cell surface upon activation; TrIP-deficient T cells exhibit more robust activation and faster clearance of Listeria monocytogenes infection.","method":"Domain deletion/mutagenesis, inducible knockout mouse model, T cell activation assays, infection model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mutagenesis establishing structure-function, validated in inducible KO mouse model with in vivo infection readout","pmids":["30429249"],"is_preprint":false},{"year":2019,"finding":"Pik3ip1 inhibits TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region; Pik3ip1-deficient mice show enhanced antitumor immunity and are resistant to tumor growth.","method":"Immunoblotting, confocal microscopy, Pik3ip1-/- mouse model, tumor implantation models (MC38, B16-F10), Pik3ip1 fusion protein experiments","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with tumor model and biochemical mechanistic evidence (SLP76 degradation), single lab","pmids":["31350312"],"is_preprint":false},{"year":2020,"finding":"Activated Ras suppresses PIK3IP1 expression by recruiting LSD1 (lysine-specific demethylase 1) to the PIK3IP1 gene promoter and enhancer, causing erasure of active histone marks; doxycycline-inducible PIK3IP1 expression suppresses Ras-induced anchorage-independent growth.","method":"Doxycycline-inducible expression system, anchorage-independent growth assay, ChIP (LSD1 at PIK3IP1 promoter/enhancer)","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating LSD1 occupancy with functional rescue assay, single lab","pmids":["31900384"],"is_preprint":false},{"year":2020,"finding":"PIK3IP1 promotes extrafollicular class switching and early IgG production during T-dependent B cell responses by limiting PI3K signaling; PIK3IP1 is downregulated in B cells at late activation time points in a PI3K-dependent manner; B cell-specific PIK3IP1 deletion increases PI3K pathway activation in response to BCR+CD40 engagement.","method":"B cell-specific conditional knockout mouse, flow cytometry, Western blot (PI3K pathway activation), immunization experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined phenotype, single lab, multiple readouts","pmids":["32887751"],"is_preprint":false},{"year":2022,"finding":"PIK3IP1 inhibits H2O2-induced PI3K-mediated apoptosis in cardiomyocytes; by co-immunoprecipitation, PIK3IP1 binds both ETA (endothelin receptor type A) and PI3Kγ, placing it in an ETA-PI3Kγ-AKT anti-apoptotic axis.","method":"Co-immunoprecipitation, TUNEL assay, MTT assay, overexpression and knockdown in H9c2 cells, receptor-specific antagonists","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying binding partners with functional gain/loss-of-function, single lab","pmids":["35883611"],"is_preprint":false},{"year":2022,"finding":"Pik3ip1 loss in T cells causes a metabolic shift from oxidative phosphorylation to aerobic glycolysis via Hif1α, leading to T cell overactivation and exacerbated autoimmune disease; IL-21 signals through p38 MAPK and ADAM17 to downregulate Pik3ip1 on T cells.","method":"T cell-specific knockout mouse, EAE model, metabolic flux assays, pharmacological inhibition of glycolysis/Hif1α","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with in vivo disease readout, metabolic mechanistic analysis with multiple orthogonal interventions","pmids":["36179018"],"is_preprint":false},{"year":2024,"finding":"PIK3IP1 downregulation from the T cell surface is controlled by TCR signal strength and classical PKC isoforms; ADAM family proteases are required for both constitutive and stimulation-induced shedding of TrIP; the extracellular stalk domain of TrIP contains the proteolytic cleavage site.","method":"Monoclonal antibody staining, truncated TrIP domain expression, PKC inhibitors, ADAM protease inhibitors, flow cytometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain mapping with truncation mutants identifying cleavage site, pharmacological dissection of upstream kinases and proteases, published in peer-reviewed journal","pmids":["39454954"],"is_preprint":false},{"year":2024,"finding":"The novel protein PDE5A-500aa (encoded by circPDE5A) interacts with PIK3IP1 and promotes USP14-mediated de-ubiquitination of the K48-linked polyubiquitin chain at the K198 residue of PIK3IP1, thereby stabilizing PIK3IP1 and attenuating PI3K/AKT signaling in esophageal squamous cell carcinoma.","method":"LC-MS/MS, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K198), Western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K198 site-specific ubiquitination identified, USP14 as deubiquitinase mapped, single lab","pmids":["38658954"],"is_preprint":false},{"year":2025,"finding":"CD8 T cell-specific deletion of TrIP (PIK3IP1) reduces syngeneic tumor growth, increases tumor-infiltrating T cell numbers, delays acquisition of the exhausted phenotype, and expands T cell clonotype diversity responding to a tumor neoantigen.","method":"CD8-specific conditional knockout mouse, tumor implantation (B16, MC38), flow cytometry, transcriptomic analysis, TCR clonotype sequencing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with multiple in vivo readouts, preprint not yet peer-reviewed","pmids":["40791507"],"is_preprint":true}],"current_model":"PIK3IP1 (TrIP) is a transmembrane protein with an extracellular kringle domain and an intracellular p85-like domain that directly binds the p110 catalytic subunit of PI3K through its intracellular domain, inhibiting PI3K/AKT/mTOR signaling; in T cells, both domains are required for inhibition, the kringle domain mediates oligomerization, and surface expression is rapidly downregulated after TCR activation via PKC-dependent recruitment of ADAM family metalloproteases that cleave the extracellular stalk, a process reversed by ~24 h to reset signaling; in B cells it promotes extrafollicular class switching; in cardiomyocytes it interacts with PI3Kγ and ETA to limit apoptosis; PIK3IP1 levels are epigenetically suppressed by the Ras-LSD1 axis and post-translationally stabilized by USP14-mediated de-ubiquitination at K198, while miR-let-7 and other miRNAs target its 3′UTR to modulate its abundance in a tissue-specific manner."},"narrative":{"mechanistic_narrative":"PIK3IP1 (TrIP) is a transmembrane inhibitor of PI3K/AKT signaling that directly binds the p110 catalytic subunit of PI3K through a p85-homologous intracellular domain to suppress PI3K enzymatic activity [PMID:17475214, PMID:25826393]. Its extracellular kringle domain mediates oligomerization, and both the kringle and intracellular domains are required for full inhibition of PI3K [PMID:30429249]. By dampening PI3K signaling, PIK3IP1 restrains proliferation, motility, and survival, and its overexpression suppresses spontaneous liver tumorigenesis [PMID:18632611]. In T cells PIK3IP1 limits TCR-driven activation — inhibiting NFAT/AP-1 transcription, Akt phosphorylation, and IL-2 production [PMID:22706993] — in part by promoting degradation of the adaptor SLP76 [PMID:31350312], and its loss shifts T cell metabolism from oxidative phosphorylation toward Hif1α-driven aerobic glycolysis, causing overactivation and exacerbated autoimmunity [PMID:36179018]. Surface PIK3IP1 is rapidly shed after TCR engagement through TCR-signal-strength- and PKC-dependent recruitment of ADAM family metalloproteases that cleave the extracellular stalk [PMID:39454954], and IL-21 likewise drives downregulation via p38 MAPK and ADAM17 [PMID:36179018]. In B cells PIK3IP1 promotes extrafollicular class switching and early IgG production by limiting PI3K signaling during T-dependent responses [PMID:32887751], and in cardiomyocytes it binds p110α and the ETA receptor/PI3Kγ to restrain hypertrophy and apoptosis [PMID:25826393, PMID:35883611]. PIK3IP1 abundance is controlled at multiple levels: the Ras–LSD1 axis epigenetically silences its promoter/enhancer [PMID:31900384], miR-let-7g targets its mRNA through the RISC complex [PMID:26655604], and USP14-mediated de-ubiquitination at K198 stabilizes the protein [PMID:38658954].","teleology":[{"year":2007,"claim":"Established the core biochemical activity of PIK3IP1 — that it physically engages PI3K and acts as a direct enzymatic inhibitor, rather than merely correlating with reduced signaling.","evidence":"In vitro binding and PI3K activity assays, with sequence homology to the p85 regulatory subunit","pmids":["17475214"],"confidence":"High","gaps":["Did not define which protein domain mediates p110 binding","No cellular phenotype tested at this stage"]},{"year":2008,"claim":"Demonstrated that PIK3IP1's biochemical inhibition translates into tumor suppression in vivo, linking PI3K dampening to control of proliferation, motility, survival, and hepatic tumorigenesis.","evidence":"Transgenic mouse hepatocyte overexpression with PI3K activity and phenotypic readouts","pmids":["18632611"],"confidence":"High","gaps":["Overexpression rather than physiological-level study","Did not address loss-of-function consequences"]},{"year":2008,"claim":"Defined PIK3IP1 as a membrane protein with a signal peptide and transmembrane domain and identified a kringle-lacking splice isoform, both pro-apoptotic on overexpression.","evidence":"Fluorescence microscopy, flow cytometry, RT-PCR and structural bioinformatics","pmids":["19088825"],"confidence":"Medium","gaps":["Functional role of the splice isoform vs full-length not resolved","Apoptosis assayed only under overexpression"]},{"year":2012,"claim":"Extended PIK3IP1's inhibitory role to T cells, showing it negatively regulates TCR-driven Akt activation, transcription factor activity, and IL-2 output.","evidence":"Ectopic expression and siRNA knockdown with reporter, pAkt Western, and IL-2 ELISA in T cells","pmids":["22706993"],"confidence":"Medium","gaps":["Single lab, cell-line based","Did not address surface regulation or in vivo immunity"]},{"year":2013,"claim":"Placed PIK3IP1 downstream of cell cycle control, showing it is induced by CDK4/6 inhibition-driven G1 arrest and required for sensitization to PI3Kδ inhibition in lymphoma.","evidence":"Transcriptome sequencing and functional knockdown in primary mantle cell lymphoma cells","pmids":["23676220"],"confidence":"Medium","gaps":["Transcriptional inducer of PIK3IP1 upon arrest not identified","Mechanism linking arrest to PIK3IP1 induction unresolved"]},{"year":2015,"claim":"Confirmed direct p110α binding by reciprocal Co-IP and established PIK3IP1 as a brake on PI3K/AKT/mTOR-driven cardiac hypertrophy.","evidence":"Co-IP, bidirectional knockdown/overexpression and cell size measurement in cardiomyocytes","pmids":["25826393"],"confidence":"High","gaps":["Did not map binding interface","Tissue-specific in vivo cardiac knockout not done"]},{"year":2015,"claim":"Identified post-transcriptional control of PIK3IP1 by a Lin28/let-7 axis, connecting hypoxia signaling to PI3K pathway tuning and apoptosis.","evidence":"RISC crosslinking immunoprecipitation, lentiviral overexpression, caspase and Akt assays in cardiac myocytes","pmids":["26655604"],"confidence":"Medium","gaps":["Single lab","Relative contribution of let-7g vs other miRNAs unquantified"]},{"year":2018,"claim":"Resolved the structure-function logic of PIK3IP1: both kringle and intracellular p85-like domains are needed for inhibition, the kringle mediates oligomerization, and surface downmodulation occurs on T cell activation with loss enhancing immunity in vivo.","evidence":"Domain mutagenesis, inducible knockout mouse, T cell activation and Listeria infection models","pmids":["30429249"],"confidence":"High","gaps":["Mechanism of activation-induced downmodulation not yet defined here","Oligomer stoichiometry unresolved"]},{"year":2019,"claim":"Identified SLP76 degradation, driven by kringle-mediated oligomerization, as a downstream mechanism of TCR inhibition and showed loss confers antitumor immunity.","evidence":"Immunoblotting, confocal microscopy, Pik3ip1-/- mice, MC38/B16 tumor models, fusion protein experiments","pmids":["31350312"],"confidence":"Medium","gaps":["Mechanism linking PIK3IP1 oligomerization to SLP76 degradation not detailed","Single lab"]},{"year":2020,"claim":"Showed oncogenic Ras epigenetically silences PIK3IP1 via LSD1-mediated erasure of active histone marks, explaining its loss in transformed cells.","evidence":"ChIP for LSD1 at PIK3IP1 promoter/enhancer with doxycycline-inducible rescue of anchorage-independent growth","pmids":["31900384"],"confidence":"Medium","gaps":["Direct LSD1 recruitment factors not identified","Single lab"]},{"year":2020,"claim":"Defined a B cell role: PIK3IP1 limits PI3K signaling to promote extrafollicular class switching and early IgG production during T-dependent responses.","evidence":"B cell-specific conditional knockout, flow cytometry, PI3K-pathway Western, immunization","pmids":["32887751"],"confidence":"Medium","gaps":["Mechanism of PI3K-dependent downregulation in B cells unresolved","Single lab"]},{"year":2022,"claim":"Mapped a cardiomyocyte ETA–PI3Kγ–AKT anti-apoptotic axis, showing PIK3IP1 binds both ETA and PI3Kγ to restrain oxidative-stress-induced apoptosis.","evidence":"Co-IP, TUNEL/MTT, overexpression/knockdown and receptor antagonists in H9c2 cells","pmids":["35883611"],"confidence":"Medium","gaps":["Direct vs indirect ETA binding not resolved","In vivo relevance untested"]},{"year":2022,"claim":"Connected PIK3IP1 loss to a Hif1α-driven metabolic shift toward glycolysis causing T cell overactivation and autoimmunity, and identified IL-21/p38/ADAM17 as a downregulation pathway.","evidence":"T cell-specific knockout, EAE model, metabolic flux assays, pharmacological Hif1α/glycolysis inhibition","pmids":["36179018"],"confidence":"High","gaps":["Link between PI3K inhibition and Hif1α metabolic switch mechanistically incomplete"]},{"year":2024,"claim":"Dissected the surface-shedding mechanism: TCR signal strength and classical PKC isoforms drive ADAM-protease cleavage at the extracellular stalk, controlling constitutive and induced TrIP shedding.","evidence":"Monoclonal antibody staining, truncation mutants, PKC and ADAM inhibitors, flow cytometry","pmids":["39454954"],"confidence":"High","gaps":["Specific ADAM family member(s) not pinned down","Fate of cleaved intracellular fragment unknown"]},{"year":2024,"claim":"Established post-translational stabilization of PIK3IP1, showing PDE5A-500aa recruits USP14 to remove K48-linked polyubiquitin at K198, raising PIK3IP1 levels to attenuate PI3K/AKT in cancer.","evidence":"LC-MS/MS, Co-IP, ubiquitination assays, K198 site-directed mutagenesis in esophageal squamous cell carcinoma","pmids":["38658954"],"confidence":"Medium","gaps":["E3 ligase opposing USP14 at K198 not identified","Single lab"]},{"year":2025,"claim":"Tested PIK3IP1 as a CD8 T cell checkpoint, showing deletion enhances tumor control, increases infiltration, delays exhaustion, and broadens TCR clonotype diversity.","evidence":"CD8-specific conditional knockout, B16/MC38 tumor models, flow cytometry, transcriptomics, TCR sequencing (preprint)","pmids":["40791507"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Therapeutic targeting strategy not established"]},{"year":null,"claim":"How PIK3IP1 oligomerization mechanistically couples to both PI3K inhibition and SLP76 degradation, and whether its multiple tissue roles share a unified molecular logic, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the PIK3IP1-p110 complex","Mechanism connecting oligomerization to downstream degradation unknown","Opposing E3 ligase and specific ADAM protease unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,11,6]}],"complexes":[],"partners":["PIK3CA","PIK3CG","EDNRA","SLP76","USP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96FE7","full_name":"Phosphoinositide-3-kinase-interacting protein 1","aliases":["Kringle domain-containing protein HGFL"],"length_aa":263,"mass_kda":28.2,"function":"Negative regulator of hepatic phosphatidylinositol 3-kinase (PI3K) activity","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96FE7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIK3IP1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PIK3IP1","total_profiled":1310},"omim":[{"mim_id":"619158","title":"PHOSPHATIDYLINOSITOL 3-KINASE-INTERACTING PROTEIN 1; PIK3IP1","url":"https://www.omim.org/entry/619158"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIK3IP1"},"hgnc":{"alias_symbol":["HGFL","MGC17330","TrIP"],"prev_symbol":[]},"alphafold":{"accession":"Q96FE7","domains":[{"cath_id":"2.40.20.10","chopping":"23-99","consensus_level":"medium","plddt":79.4031,"start":23,"end":99},{"cath_id":"1.20.5","chopping":"173-214","consensus_level":"medium","plddt":92.0024,"start":173,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FE7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FE7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FE7-F1-predicted_aligned_error_v6.png","plddt_mean":67.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIK3IP1","jax_strain_url":"https://www.jax.org/strain/search?query=PIK3IP1"},"sequence":{"accession":"Q96FE7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FE7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FE7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FE7"}},"corpus_meta":[{"pmid":"18632611","id":"PMC_18632611","title":"PIK3IP1, a negative regulator of PI3K, suppresses the development of hepatocellular carcinoma.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18632611","citation_count":89,"is_preprint":false},{"pmid":"17475214","id":"PMC_17475214","title":"PI3K is negatively regulated by PIK3IP1, a novel p110 interacting protein.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17475214","citation_count":72,"is_preprint":false},{"pmid":"23676220","id":"PMC_23676220","title":"Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1.","date":"2013","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23676220","citation_count":64,"is_preprint":false},{"pmid":"30429249","id":"PMC_30429249","title":"PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30429249","citation_count":41,"is_preprint":false},{"pmid":"26655604","id":"PMC_26655604","title":"A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26655604","citation_count":40,"is_preprint":false},{"pmid":"31350312","id":"PMC_31350312","title":"Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/31350312","citation_count":39,"is_preprint":false},{"pmid":"28549102","id":"PMC_28549102","title":"Long non-coding RNA CCAT1/miR-148a axis promotes osteosarcoma proliferation and migration through regulating PIK3IP1.","date":"2017","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/28549102","citation_count":38,"is_preprint":false},{"pmid":"22706993","id":"PMC_22706993","title":"Inhibition of T-cell activation by PIK3IP1.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22706993","citation_count":37,"is_preprint":false},{"pmid":"25826393","id":"PMC_25826393","title":"Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25826393","citation_count":33,"is_preprint":false},{"pmid":"38658954","id":"PMC_38658954","title":"CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38658954","citation_count":25,"is_preprint":false},{"pmid":"33082912","id":"PMC_33082912","title":"RiPerC Attenuates Cerebral Ischemia Injury through Regulation of miR-98/PIK3IP1/PI3K/AKT Signaling Pathway.","date":"2020","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33082912","citation_count":18,"is_preprint":false},{"pmid":"32201518","id":"PMC_32201518","title":"MicroRNA-19a-3p regulates cell growth through modulation of the PIK3IP1-AKT pathway in hepatocellular carcinoma.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32201518","citation_count":17,"is_preprint":false},{"pmid":"36179018","id":"PMC_36179018","title":"Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36179018","citation_count":15,"is_preprint":false},{"pmid":"35000528","id":"PMC_35000528","title":"Knockdown of forkhead box protein P1 alleviates hypoxia reoxygenation injury in H9c2 cells through regulating Pik3ip1/Akt/eNOS and ROS/mPTP pathway.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35000528","citation_count":12,"is_preprint":false},{"pmid":"31900384","id":"PMC_31900384","title":"A Ras-LSD1 axis activates PI3K signaling through PIK3IP1 suppression.","date":"2020","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31900384","citation_count":11,"is_preprint":false},{"pmid":"29289536","id":"PMC_29289536","title":"Expression of PIK3IP1 in the murine uterus during early pregnancy.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29289536","citation_count":7,"is_preprint":false},{"pmid":"32887751","id":"PMC_32887751","title":"PIK3IP1 Promotes Extrafollicular Class Switching in T-Dependent Immune Responses.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32887751","citation_count":7,"is_preprint":false},{"pmid":"36521557","id":"PMC_36521557","title":"Upregulation of PIK3IP1 monitors the anti-cancer activity of PI3Kα inhibitors in gastric cancer cells.","date":"2022","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36521557","citation_count":6,"is_preprint":false},{"pmid":"37550343","id":"PMC_37550343","title":"Downregulation of PIK3IP1 in retinal microglia promotes retinal pathological neovascularization via PI3K-AKT pathway activation.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37550343","citation_count":6,"is_preprint":false},{"pmid":"35883611","id":"PMC_35883611","title":"Anti-Ischemic Effects of PIK3IP1 Are Mediated through Its Interactions with the ETA-PI3Kγ-AKT Axis.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35883611","citation_count":6,"is_preprint":false},{"pmid":"38897445","id":"PMC_38897445","title":"PIK3IP1: structure, aberration, function, and regulation in diseases.","date":"2024","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38897445","citation_count":5,"is_preprint":false},{"pmid":"19088825","id":"PMC_19088825","title":"[Both PIK3IP1 and its novel found splicing isoform, PIK3IP1-v1, are located on cell membrane and induce cell apoptosis].","date":"2008","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19088825","citation_count":4,"is_preprint":false},{"pmid":"39454954","id":"PMC_39454954","title":"Downregulation of PIK3IP1/TrIP on T cells is controlled by TCR signal strength, PKC, and metalloprotease-mediated cleavage.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39454954","citation_count":1,"is_preprint":false},{"pmid":"41315520","id":"PMC_41315520","title":"Ifebemtinib and paclitaxel synergistically inhibit the proliferation and metastasis of TNBC by blocking PI3K/Akt pathway through LSD1/PIK3IP1 axis.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41315520","citation_count":0,"is_preprint":false},{"pmid":"40791507","id":"PMC_40791507","title":"Pik3ip1/TrIP Regulation of PI3K Restricts CD8 T Cell Anti-Tumor Immunity.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40791507","citation_count":0,"is_preprint":false},{"pmid":"38746242","id":"PMC_38746242","title":"Downregulation of PIK3IP1/TrIP on T cells is controlled by TCR signal strength, PKC and metalloprotease-mediated cleavage.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38746242","citation_count":0,"is_preprint":false},{"pmid":"41571844","id":"PMC_41571844","title":"GANT61 suppresses proliferation and induces apoptosis in ALK-Positive anaplastic large cell lymphoma via modulating the Hh-PIK3IP1-Akt signaling axis.","date":"2026","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41571844","citation_count":0,"is_preprint":false},{"pmid":"20423653","id":"PMC_20423653","title":"[Generation and characterization of monoclonal antibody against human PIK3IP1].","date":"2010","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20423653","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16214,"output_tokens":3867,"usd":0.053324,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11637,"output_tokens":4658,"usd":0.087318,"stage2_stop_reason":"end_turn"},"total_usd":0.140642,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"PIK3IP1 directly binds to the p110 catalytic subunit of PI3K and reduces PI3K activity in vitro; PIK3IP1 shares homology with the p85 regulatory subunit of PI3K.\",\n      \"method\": \"In vitro binding assays, cell-based assays, PI3K activity assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of binding and enzymatic inhibition, replicated across multiple papers from independent labs\",\n      \"pmids\": [\"17475214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PIK3IP1 overexpression in transgenic mouse hepatocytes blunts PI3K signaling, reduces DNA synthetic activity, motility, and survival, and dampens spontaneous liver tumorigenesis in vivo.\",\n      \"method\": \"Transgenic mouse model, PI3K activity assay, proliferation and motility assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic overexpression model with multiple orthogonal phenotypic readouts, replicated in vivo\",\n      \"pmids\": [\"18632611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PIK3IP1 and its splice isoform PIK3IP1-v1 both localize to the cell membrane (containing signal peptide and transmembrane domain); both induce cell apoptosis when overexpressed; PIK3IP1-v1 lacks the extracellular Kringle domain.\",\n      \"method\": \"Fluorescence microscopy, flow cytometry, RT-PCR, bioinformatics structural analysis, luciferase reporter assay\",\n      \"journal\": \"Journal of Peking University. Health sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization by fluorescence microscopy with functional apoptosis readout, single lab, multiple methods\",\n      \"pmids\": [\"19088825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PIK3IP1 is expressed in T cells; ectopic PIK3IP1 expression inhibits NFAT/AP-1 transcriptional activation; siRNA-mediated knockdown of PIK3IP1 augments Akt phosphorylation, T cell activation, and IL-2 production.\",\n      \"method\": \"Ectopic expression, siRNA knockdown, luciferase reporter assay, Western blot (pAkt), IL-2 ELISA\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss- and gain-of-function in T cell lines with multiple readouts, single lab\",\n      \"pmids\": [\"22706993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PIK3IP1 is markedly reduced in mantle cell lymphoma (MCL) tumor cells; it is profoundly induced upon CDK4/CDK6 inhibition-mediated prolonged G1 arrest (pG1) and is required for pG1-dependent sensitization to PI3Kδ inhibition, placing PIK3IP1 downstream of cell cycle arrest in the PI3K pathway.\",\n      \"method\": \"Whole-transcriptome sequencing, gene expression analysis, functional knockdown assays in primary MCL cells\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional knockdown with specific phenotypic readout (apoptosis, PI3K inhibition sensitivity), single lab\",\n      \"pmids\": [\"23676220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pik3ip1 directly interacts with the p110α subunit of PI3K in cardiomyocytes (by co-immunoprecipitation); Pik3ip1 knockdown activates PI3K/AKT/mTOR signaling and induces cardiac hypertrophy, whereas adenovirus-mediated overexpression attenuates PI3K-mediated hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, adenovirus-mediated overexpression, Western blot, cell size measurement in neonatal rat cardiomyocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with p110α, bidirectional gain/loss-of-function with specific pathway and phenotypic readouts\",\n      \"pmids\": [\"25826393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-let-7g targets Pik3ip1 mRNA in cardiac myocytes via the RISC/Argonaute complex; hypoxia-induced Lin28 represses miR-let-7, leading to Pik3ip1 upregulation, which suppresses PI3K/Akt signaling and promotes apoptosis.\",\n      \"method\": \"Crosslinking immunoprecipitation (RISC), lentiviral overexpression, caspase activation assay, Akt phosphorylation assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RISC crosslinking demonstrates miR-let-7g targets Pik3ip1, single lab with orthogonal methods\",\n      \"pmids\": [\"26655604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIK3IP1 (TrIP) is a transmembrane protein with an extracellular kringle domain and an intracellular p85-like domain; both domains are necessary for PI3K inhibition; the kringle domain mediates oligomerization of TrIP; TrIP is downmodulated from the T cell surface upon activation; TrIP-deficient T cells exhibit more robust activation and faster clearance of Listeria monocytogenes infection.\",\n      \"method\": \"Domain deletion/mutagenesis, inducible knockout mouse model, T cell activation assays, infection model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mutagenesis establishing structure-function, validated in inducible KO mouse model with in vivo infection readout\",\n      \"pmids\": [\"30429249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pik3ip1 inhibits TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region; Pik3ip1-deficient mice show enhanced antitumor immunity and are resistant to tumor growth.\",\n      \"method\": \"Immunoblotting, confocal microscopy, Pik3ip1-/- mouse model, tumor implantation models (MC38, B16-F10), Pik3ip1 fusion protein experiments\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with tumor model and biochemical mechanistic evidence (SLP76 degradation), single lab\",\n      \"pmids\": [\"31350312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Activated Ras suppresses PIK3IP1 expression by recruiting LSD1 (lysine-specific demethylase 1) to the PIK3IP1 gene promoter and enhancer, causing erasure of active histone marks; doxycycline-inducible PIK3IP1 expression suppresses Ras-induced anchorage-independent growth.\",\n      \"method\": \"Doxycycline-inducible expression system, anchorage-independent growth assay, ChIP (LSD1 at PIK3IP1 promoter/enhancer)\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating LSD1 occupancy with functional rescue assay, single lab\",\n      \"pmids\": [\"31900384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIK3IP1 promotes extrafollicular class switching and early IgG production during T-dependent B cell responses by limiting PI3K signaling; PIK3IP1 is downregulated in B cells at late activation time points in a PI3K-dependent manner; B cell-specific PIK3IP1 deletion increases PI3K pathway activation in response to BCR+CD40 engagement.\",\n      \"method\": \"B cell-specific conditional knockout mouse, flow cytometry, Western blot (PI3K pathway activation), immunization experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"32887751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PIK3IP1 inhibits H2O2-induced PI3K-mediated apoptosis in cardiomyocytes; by co-immunoprecipitation, PIK3IP1 binds both ETA (endothelin receptor type A) and PI3Kγ, placing it in an ETA-PI3Kγ-AKT anti-apoptotic axis.\",\n      \"method\": \"Co-immunoprecipitation, TUNEL assay, MTT assay, overexpression and knockdown in H9c2 cells, receptor-specific antagonists\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying binding partners with functional gain/loss-of-function, single lab\",\n      \"pmids\": [\"35883611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pik3ip1 loss in T cells causes a metabolic shift from oxidative phosphorylation to aerobic glycolysis via Hif1α, leading to T cell overactivation and exacerbated autoimmune disease; IL-21 signals through p38 MAPK and ADAM17 to downregulate Pik3ip1 on T cells.\",\n      \"method\": \"T cell-specific knockout mouse, EAE model, metabolic flux assays, pharmacological inhibition of glycolysis/Hif1α\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with in vivo disease readout, metabolic mechanistic analysis with multiple orthogonal interventions\",\n      \"pmids\": [\"36179018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIK3IP1 downregulation from the T cell surface is controlled by TCR signal strength and classical PKC isoforms; ADAM family proteases are required for both constitutive and stimulation-induced shedding of TrIP; the extracellular stalk domain of TrIP contains the proteolytic cleavage site.\",\n      \"method\": \"Monoclonal antibody staining, truncated TrIP domain expression, PKC inhibitors, ADAM protease inhibitors, flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain mapping with truncation mutants identifying cleavage site, pharmacological dissection of upstream kinases and proteases, published in peer-reviewed journal\",\n      \"pmids\": [\"39454954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The novel protein PDE5A-500aa (encoded by circPDE5A) interacts with PIK3IP1 and promotes USP14-mediated de-ubiquitination of the K48-linked polyubiquitin chain at the K198 residue of PIK3IP1, thereby stabilizing PIK3IP1 and attenuating PI3K/AKT signaling in esophageal squamous cell carcinoma.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K198), Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K198 site-specific ubiquitination identified, USP14 as deubiquitinase mapped, single lab\",\n      \"pmids\": [\"38658954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD8 T cell-specific deletion of TrIP (PIK3IP1) reduces syngeneic tumor growth, increases tumor-infiltrating T cell numbers, delays acquisition of the exhausted phenotype, and expands T cell clonotype diversity responding to a tumor neoantigen.\",\n      \"method\": \"CD8-specific conditional knockout mouse, tumor implantation (B16, MC38), flow cytometry, transcriptomic analysis, TCR clonotype sequencing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with multiple in vivo readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"40791507\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PIK3IP1 (TrIP) is a transmembrane protein with an extracellular kringle domain and an intracellular p85-like domain that directly binds the p110 catalytic subunit of PI3K through its intracellular domain, inhibiting PI3K/AKT/mTOR signaling; in T cells, both domains are required for inhibition, the kringle domain mediates oligomerization, and surface expression is rapidly downregulated after TCR activation via PKC-dependent recruitment of ADAM family metalloproteases that cleave the extracellular stalk, a process reversed by ~24 h to reset signaling; in B cells it promotes extrafollicular class switching; in cardiomyocytes it interacts with PI3Kγ and ETA to limit apoptosis; PIK3IP1 levels are epigenetically suppressed by the Ras-LSD1 axis and post-translationally stabilized by USP14-mediated de-ubiquitination at K198, while miR-let-7 and other miRNAs target its 3′UTR to modulate its abundance in a tissue-specific manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIK3IP1 (TrIP) is a transmembrane inhibitor of PI3K/AKT signaling that directly binds the p110 catalytic subunit of PI3K through a p85-homologous intracellular domain to suppress PI3K enzymatic activity [#0, #5]. Its extracellular kringle domain mediates oligomerization, and both the kringle and intracellular domains are required for full inhibition of PI3K [#7]. By dampening PI3K signaling, PIK3IP1 restrains proliferation, motility, and survival, and its overexpression suppresses spontaneous liver tumorigenesis [#1]. In T cells PIK3IP1 limits TCR-driven activation — inhibiting NFAT/AP-1 transcription, Akt phosphorylation, and IL-2 production [#3] — in part by promoting degradation of the adaptor SLP76 [#8], and its loss shifts T cell metabolism from oxidative phosphorylation toward Hif1α-driven aerobic glycolysis, causing overactivation and exacerbated autoimmunity [#12]. Surface PIK3IP1 is rapidly shed after TCR engagement through TCR-signal-strength- and PKC-dependent recruitment of ADAM family metalloproteases that cleave the extracellular stalk [#13], and IL-21 likewise drives downregulation via p38 MAPK and ADAM17 [#12]. In B cells PIK3IP1 promotes extrafollicular class switching and early IgG production by limiting PI3K signaling during T-dependent responses [#10], and in cardiomyocytes it binds p110α and the ETA receptor/PI3Kγ to restrain hypertrophy and apoptosis [#5, #11]. PIK3IP1 abundance is controlled at multiple levels: the Ras–LSD1 axis epigenetically silences its promoter/enhancer [#9], miR-let-7g targets its mRNA through the RISC complex [#6], and USP14-mediated de-ubiquitination at K198 stabilizes the protein [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the core biochemical activity of PIK3IP1 — that it physically engages PI3K and acts as a direct enzymatic inhibitor, rather than merely correlating with reduced signaling.\",\n      \"evidence\": \"In vitro binding and PI3K activity assays, with sequence homology to the p85 regulatory subunit\",\n      \"pmids\": [\"17475214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which protein domain mediates p110 binding\", \"No cellular phenotype tested at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that PIK3IP1's biochemical inhibition translates into tumor suppression in vivo, linking PI3K dampening to control of proliferation, motility, survival, and hepatic tumorigenesis.\",\n      \"evidence\": \"Transgenic mouse hepatocyte overexpression with PI3K activity and phenotypic readouts\",\n      \"pmids\": [\"18632611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression rather than physiological-level study\", \"Did not address loss-of-function consequences\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined PIK3IP1 as a membrane protein with a signal peptide and transmembrane domain and identified a kringle-lacking splice isoform, both pro-apoptotic on overexpression.\",\n      \"evidence\": \"Fluorescence microscopy, flow cytometry, RT-PCR and structural bioinformatics\",\n      \"pmids\": [\"19088825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the splice isoform vs full-length not resolved\", \"Apoptosis assayed only under overexpression\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended PIK3IP1's inhibitory role to T cells, showing it negatively regulates TCR-driven Akt activation, transcription factor activity, and IL-2 output.\",\n      \"evidence\": \"Ectopic expression and siRNA knockdown with reporter, pAkt Western, and IL-2 ELISA in T cells\",\n      \"pmids\": [\"22706993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, cell-line based\", \"Did not address surface regulation or in vivo immunity\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed PIK3IP1 downstream of cell cycle control, showing it is induced by CDK4/6 inhibition-driven G1 arrest and required for sensitization to PI3Kδ inhibition in lymphoma.\",\n      \"evidence\": \"Transcriptome sequencing and functional knockdown in primary mantle cell lymphoma cells\",\n      \"pmids\": [\"23676220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional inducer of PIK3IP1 upon arrest not identified\", \"Mechanism linking arrest to PIK3IP1 induction unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed direct p110α binding by reciprocal Co-IP and established PIK3IP1 as a brake on PI3K/AKT/mTOR-driven cardiac hypertrophy.\",\n      \"evidence\": \"Co-IP, bidirectional knockdown/overexpression and cell size measurement in cardiomyocytes\",\n      \"pmids\": [\"25826393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map binding interface\", \"Tissue-specific in vivo cardiac knockout not done\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified post-transcriptional control of PIK3IP1 by a Lin28/let-7 axis, connecting hypoxia signaling to PI3K pathway tuning and apoptosis.\",\n      \"evidence\": \"RISC crosslinking immunoprecipitation, lentiviral overexpression, caspase and Akt assays in cardiac myocytes\",\n      \"pmids\": [\"26655604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution of let-7g vs other miRNAs unquantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structure-function logic of PIK3IP1: both kringle and intracellular p85-like domains are needed for inhibition, the kringle mediates oligomerization, and surface downmodulation occurs on T cell activation with loss enhancing immunity in vivo.\",\n      \"evidence\": \"Domain mutagenesis, inducible knockout mouse, T cell activation and Listeria infection models\",\n      \"pmids\": [\"30429249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of activation-induced downmodulation not yet defined here\", \"Oligomer stoichiometry unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SLP76 degradation, driven by kringle-mediated oligomerization, as a downstream mechanism of TCR inhibition and showed loss confers antitumor immunity.\",\n      \"evidence\": \"Immunoblotting, confocal microscopy, Pik3ip1-/- mice, MC38/B16 tumor models, fusion protein experiments\",\n      \"pmids\": [\"31350312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PIK3IP1 oligomerization to SLP76 degradation not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed oncogenic Ras epigenetically silences PIK3IP1 via LSD1-mediated erasure of active histone marks, explaining its loss in transformed cells.\",\n      \"evidence\": \"ChIP for LSD1 at PIK3IP1 promoter/enhancer with doxycycline-inducible rescue of anchorage-independent growth\",\n      \"pmids\": [\"31900384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LSD1 recruitment factors not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a B cell role: PIK3IP1 limits PI3K signaling to promote extrafollicular class switching and early IgG production during T-dependent responses.\",\n      \"evidence\": \"B cell-specific conditional knockout, flow cytometry, PI3K-pathway Western, immunization\",\n      \"pmids\": [\"32887751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PI3K-dependent downregulation in B cells unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped a cardiomyocyte ETA–PI3Kγ–AKT anti-apoptotic axis, showing PIK3IP1 binds both ETA and PI3Kγ to restrain oxidative-stress-induced apoptosis.\",\n      \"evidence\": \"Co-IP, TUNEL/MTT, overexpression/knockdown and receptor antagonists in H9c2 cells\",\n      \"pmids\": [\"35883611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect ETA binding not resolved\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PIK3IP1 loss to a Hif1α-driven metabolic shift toward glycolysis causing T cell overactivation and autoimmunity, and identified IL-21/p38/ADAM17 as a downregulation pathway.\",\n      \"evidence\": \"T cell-specific knockout, EAE model, metabolic flux assays, pharmacological Hif1α/glycolysis inhibition\",\n      \"pmids\": [\"36179018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between PI3K inhibition and Hif1α metabolic switch mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected the surface-shedding mechanism: TCR signal strength and classical PKC isoforms drive ADAM-protease cleavage at the extracellular stalk, controlling constitutive and induced TrIP shedding.\",\n      \"evidence\": \"Monoclonal antibody staining, truncation mutants, PKC and ADAM inhibitors, flow cytometry\",\n      \"pmids\": [\"39454954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ADAM family member(s) not pinned down\", \"Fate of cleaved intracellular fragment unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established post-translational stabilization of PIK3IP1, showing PDE5A-500aa recruits USP14 to remove K48-linked polyubiquitin at K198, raising PIK3IP1 levels to attenuate PI3K/AKT in cancer.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, ubiquitination assays, K198 site-directed mutagenesis in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"38658954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP14 at K198 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tested PIK3IP1 as a CD8 T cell checkpoint, showing deletion enhances tumor control, increases infiltration, delays exhaustion, and broadens TCR clonotype diversity.\",\n      \"evidence\": \"CD8-specific conditional knockout, B16/MC38 tumor models, flow cytometry, transcriptomics, TCR sequencing (preprint)\",\n      \"pmids\": [\"40791507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Therapeutic targeting strategy not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIK3IP1 oligomerization mechanistically couples to both PI3K inhibition and SLP76 degradation, and whether its multiple tissue roles share a unified molecular logic, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the PIK3IP1-p110 complex\", \"Mechanism connecting oligomerization to downstream degradation unknown\", \"Opposing E3 ligase and specific ADAM protease unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 11, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PIK3CA\", \"PIK3CG\", \"EDNRA\", \"SLP76\", \"USP14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}