{"gene":"TPD52","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1998,"finding":"TPD52-like proteins interact in homo- and heteromeric fashions through their predicted coiled-coil domains, as demonstrated by yeast two-hybrid co-transfection and GST pull-down assays. Two-hybrid screening of a human breast carcinoma library identified hD53 and hD52 as interactors for both hD52 and hD53 baits.","method":"Yeast two-hybrid system and GST pull-down assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal yeast two-hybrid plus GST pull-down, two orthogonal methods in one study, replicated across multiple paired constructs","pmids":["9484778"],"is_preprint":false},{"year":2001,"finding":"The coiled-coil motif of TPD52 is necessary but not sufficient for interactions with other D52-like proteins; C-terminal regions facilitate and/or stabilize these interactions, as shown by analysis of C-terminally deleted D52 proteins in yeast two-hybrid and pull-down assays.","method":"Yeast two-hybrid system and GST pull-down assays with deletion mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (yeast two-hybrid + pull-down) with systematic deletion mapping, single lab","pmids":["11594751"],"is_preprint":false},{"year":2001,"finding":"TPD52 physically interacts with MAL2, a novel four-transmembrane proteolipid protein involved in apical vesicle transport, identifying MAL2 as the first heterologous binding partner of TPD52-like proteins. MAL2 bound all TPD52-like baits in yeast two-hybrid, and in vitro translated MAL2 specifically bound GST-Tpd52 in pull-down assays.","method":"Yeast two-hybrid screen and GST pull-down assay with in vitro translated MAL2","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid plus GST pull-down orthogonal confirmation, novel heterologous binding partner identified","pmids":["11549320"],"is_preprint":false},{"year":2004,"finding":"TPD52 binds annexin VI in a Ca2+-dependent manner in the Thiel myeloma cell line, suggesting these molecules may act together to regulate secretory processes in plasma cells, as demonstrated by co-immunoprecipitation.","method":"Co-immunoprecipitation in Thiel myeloma cells; 2D-PAGE/mass spectrometry protein identification","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP with Ca2+-dependence shown; protein identified by MS, but limited mechanistic follow-up","pmids":["15576473"],"is_preprint":false},{"year":2008,"finding":"Ca2+-dependent phosphorylation of TPD52 occurs at serine residue 136 (S136), mediated by CAMK2delta6. Mass spectrometry and site-directed mutagenesis identified S136 as the single major phospho-acceptor site, and a specific CAMK2 isoform (CAMK2delta6) co-migrated and co-localized with TPD52, with phosphorylation inhibited by KN93 and calmodulin antagonist W7.","method":"Mass spectrometry, site-directed mutagenesis, phospho-specific antibody, in-gel kinase assay, co-localization, pharmacological inhibitors","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (MS, mutagenesis, in-gel kinase assay, pharmacological inhibition) in one rigorous study identifying specific kinase and phosphorylation site","pmids":["18832449"],"is_preprint":false},{"year":2009,"finding":"Ca2+-dependent phosphorylation of TPD52 at S136 modulates trafficking of lysosomal membrane protein LAMP1 to the plasma membrane. Phosphomimetic mutants (S136E) constitutively induced LAMP1 plasma membrane accumulation independent of Ca2+, while the phospho-null mutant (S136A) abolished Ca2+-stimulated LAMP1 accumulation. TPD52 co-localized with AP-3, Rab27A, VAMP7, and LAMP1 in lysosome-like secretory organelles.","method":"Site-specific mutagenesis, immunofluorescence co-localization, cell surface antibody labeling, live-cell Ca2+ stimulation assays in CHO-K1, NRK, and HeLa cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphomutant reconstitution plus co-localization with multiple organelle markers, multiple cell types, mechanistic site validated","pmids":["20032513"],"is_preprint":false},{"year":2010,"finding":"TPD52 expression and phosphorylation at S136 play a role in cytokinesis via endomembrane trafficking. Ectopic expression of the phospho-null S136A mutant caused a 9-fold increase in multinucleated cells. TPD52 co-localized with VAMP8-positive vesicular structures at the cell midbody, and this co-localization increased with elevated Ca2+.","method":"Expression of phosphomutants (S136A, S136E), electron microscopy, immunofluorescence co-localization with VAMP8, multinucleation quantification","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — phosphomutant functional dissection with electron microscopy and co-localization, clear phenotypic readout","pmids":["20946871"],"is_preprint":false},{"year":2013,"finding":"TPD52 regulates apical endolysosomal secretion in pancreatic acinar cells. Adenoviral restoration of D52 levels in cultured acinar cells rescued levels of endolysosomal proteins (EEA1, Rab5, LAMP1) and strongly enhanced secretion of both LAMP1 (endolysosomal pathway) and amylase. Secretory effects were absent with alanine substitution at S136 (the major D52 phosphorylation site) and inhibited by brefeldin A.","method":"Adenoviral D52 delivery to isolated acinar cells, S136 site-directed mutagenesis, cell-surface antigen labeling of LAMP1, amylase secretion assays, brefeldin A inhibition","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — adenoviral gain-of-function, phosphosite mutagenesis, pharmacological inhibition, and multiple secretion readouts in one study","pmids":["23868405"],"is_preprint":false},{"year":2013,"finding":"TPD52 directly interacts with ATM kinase and acts as a negative regulator of ATM protein levels. Increased TPD52 expression downregulated steady-state ATM protein (but not mRNA), compromised ATM-mediated DNA damage responses following gamma irradiation, and increased radiation sensitivity. Interaction domains were mapped to TPD52 residues 111–131 and ATM residues 1–245 and 772–1102.","method":"GST pull-down and co-immunoprecipitation assays, domain mapping, clonogenic radiation assays, immunoblotting in breast cancer and 3T3 cells","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus GST pull-down with domain mapping, single lab, supported by functional radiation phenotype","pmids":["23974097"],"is_preprint":false},{"year":2015,"finding":"TPD52 expression increases neutral lipid storage in cultured cells by promoting fatty acid incorporation into triglyceride and increasing lipid droplet numbers. TPD52 co-localizes with Golgi (but not ER) markers and partially with ADRP-coated lipid droplets. Direct interaction between ADRP (PLIN2) and TPD52, but not TPD52L1, was demonstrated by yeast two-hybrid and confirmed by GST pull-down.","method":"Stable expression in 3T3 cells, lipid droplet quantification, fatty acid incorporation assays, subcellular fractionation, immunofluorescence co-localization, yeast two-hybrid, GST pull-down","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (stable cell lines, fractionation, yeast two-hybrid, GST pull-down, isotopic labeling), isoform specificity established","pmids":["26183179"],"is_preprint":false},{"year":2014,"finding":"TPD52 interacts with PLP2 and RAB5C as novel binding partners, identified by large yeast two-hybrid screen and confirmed by GST pull-down assays. Interaction domain mapping indicated that both proteins interact with a novel binding region of TPD52 distinct from the coiled-coil domain.","method":"Yeast two-hybrid screen, GST pull-down assays, interaction domain mapping","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus GST pull-down with domain mapping, single lab","pmids":["24604726"],"is_preprint":false},{"year":2017,"finding":"TPD52 post-transcriptional regulation is mediated by RNA-binding proteins TIA-1 and TIAR, which bind to the 78–280 region of the TPD52 mRNA 3'-UTR to stabilize the transcript. Knockdown of TIA-1/TIAR decreased TPD52 mRNA stability and expression. TGF-β and EGF stimulation decreased TIA-1/TIAR binding to TPD52 mRNA, resulting in decreased mRNA stability.","method":"RNA immunoprecipitation (RIP), biotin pull-down, mRNA degradation assays, 3'-UTR deletion reporter constructs, siRNA knockdown of TIA-1/TIAR","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RIP, biotin pull-down, reporter assays, mRNA stability assays, KD) in a single systematic study","pmids":["28298474"],"is_preprint":false},{"year":2008,"finding":"TPD52 knockdown in LNCaP prostate cancer cells induces apoptosis involving caspase-3 and caspase-9 activation and loss of mitochondrial membrane potential, placing TPD52 function upstream of the mitochondrial apoptotic pathway. Overexpression of TPD52 increased proliferation and promoted cell migration via αvβ3 integrin through activation of the PKB/Akt signaling pathway.","method":"shRNA knockdown and EGFP-TPD52 overexpression in LNCaP cells, caspase activity assays, mitochondrial membrane potential measurement, migration assays, integrin blocking","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined molecular readouts (caspase activation, Akt), single lab","pmids":["18959755"],"is_preprint":false},{"year":2007,"finding":"Expression of murine TPD52 (mD52) in BALB/c 3T3 fibroblasts induced cellular transformation, anchorage-independent growth, tumorigenesis in immunocompetent mice, and spontaneous lung metastasis. TGF-βR1 expression decreased and TGF-β1 secretion increased in mD52-expressing cells, suggesting TGF-β pathway involvement in mD52-induced metastasis.","method":"Stable transfection of 3T3 cells with mD52 cDNA, in vitro growth assays, syngeneic subcutaneous tumor challenge, lung nodule quantification, cDNA microarray, TGF-β pathway analysis","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo tumorigenesis and metastasis demonstrated in immunocompetent syngeneic model with molecular pathway support","pmids":["17314271"],"is_preprint":false},{"year":2008,"finding":"D52 overexpression in BALB/c 3T3 cells (but not D53 overexpression) confers increased proliferation and anchorage-independent growth capacity, while D52 knockdown (but not D53) in SK-BR-3 cells significantly increases apoptosis, demonstrating non-redundant and isoform-specific functions for D52 versus its paralogs.","method":"Stable expression in BALB/c 3T3 fibroblasts, transient siRNA knockdown in breast carcinoma cell lines, proliferation and soft agar assays, apoptosis assays","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with paralog comparisons, single lab, defined cellular phenotypes","pmids":["18698023"],"is_preprint":false},{"year":2017,"finding":"TPD52 (isoform 3) directly interacts with NF-κB p65 (RelA) and promotes accumulation of phosphorylated NF-κB (p65)S536, transactivating NF-κB target genes. TPD52 also activates STAT3 through an NF-κB–STAT3 cross-talk. TPD52 promotes invasion via increased MMP-9 expression and promotes EMT by inducing loss of E-cadherin and expression of vimentin and VCAM, as well as activation of focal adhesion kinase.","method":"Co-immunoprecipitation (TPD52–NF-κB p65), overexpression and shRNA knockdown of TPD52 in LNCaP cells, NF-κB inhibition, cytokine secretion assays, MMP activity assays, Western blotting","journal":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus multiple downstream functional readouts, single lab","pmids":["28466782"],"is_preprint":false},{"year":2019,"finding":"TPD52 (isoform 3) interacts with Peroxiredoxin 1 (PRDX1) at the C-terminal PEST domain (residues 152–179) of TPD52, and this interaction increases PRDX1 peroxidase activity and promotes PRDX1 dimerization. H2O2 exposure evoked increased TPD52–PRDX1 interaction. Depletion of both proteins led to H2O2 accumulation, linking TPD52 to oxidative stress management in prostate cancer cells.","method":"GST pull-down, tandem affinity purification, co-immunoprecipitation, interaction domain mapping, peroxidase activity assays, dimerization assays, H2O2 measurement","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (TAP, GST pull-down, co-IP, domain mapping, enzymatic assay) in single study","pmids":["30981892"],"is_preprint":false},{"year":2021,"finding":"TPD52 enhances chaperone-mediated autophagy (CMA) activation by directly interacting with HSPA8/HSC70 and enhancing substrate degradation in prostate cancer cells. TPD52 is acetylated by KAT2B at K163; this acetylation is reversed by HDAC2. Acetylation of TPD52 at K163 compromises the TPD52–HSPA8 interaction, leading to impaired CMA function and reduced tumor growth in vivo.","method":"Co-immunoprecipitation (TPD52–HSPA8), CMA activity assays, in vitro acetylation assay (KAT2B), HDAC2 inhibition, K163 mutagenesis, xenograft tumor models","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP, enzymatic acetylation assay, site mutagenesis, in vivo validation, multiple orthogonal methods","pmids":["34034634"],"is_preprint":false},{"year":2022,"finding":"TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. TPD52 transgenic mice showed AMPK inhibition and multiple metabolic defects, identifying TPD52 as a novel negative regulator of energy stress-induced AMPK activation.","method":"Tandem affinity purification/mass spectrometry to identify AMPKα as TPD52-interacting protein, co-immunoprecipitation, in vitro kinase assay, TPD52 transgenic mice with metabolic phenotyping","journal":"Cancer medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — TAP-MS plus co-IP plus in vitro kinase assay plus in vivo transgenic model, multiple orthogonal methods","pmids":["35666017"],"is_preprint":false},{"year":2023,"finding":"TPD52 (isoform 3) interacts with LKB1 (serine/threonine kinase 11), and this interaction suppresses LKB1 auto-phosphorylation and consequently inhibits AMPK activation (reducing pLKB1-Ser428 and pAMPK-Thr172). AMPK activation by AICAR downregulated TPD52 via GSK3β, inhibiting PCa cell proliferation and migration.","method":"Co-immunoprecipitation, molecular modeling and MD simulations (interaction domain), AICAR treatment, GSK3β inhibition (LiCl), Western blotting for pLKB1 and pAMPK","journal":"Journal of cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP confirmed with computational modelling and pharmacological epistasis, single lab; in vitro kinase assay for LKB1 not directly demonstrated","pmids":["37040029"],"is_preprint":false},{"year":2024,"finding":"TPD52 functions as a tumor suppressor in bladder cancer by promoting S2P-mediated cleavage of ATF6 to integrate ER stress and UPR signaling with the chaperone machinery. The APC/C-Cdc20 E3 ligase mediates polyubiquitination and proteolysis of TPD52, and Cdc20 inactivation sensitized cancer cells to ER stress inducers in a TPD52-dependent manner.","method":"Co-immunoprecipitation (TPD52–ATF6, TPD52–Cdc20), ubiquitination assays, ER stress/UPR signaling assays, loss-of-function and rescue experiments, in vivo tumor models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination, and functional rescue assays, single lab","pmids":["39401430"],"is_preprint":false},{"year":2019,"finding":"Delayed recruitment of TPD52 to lipid droplets (LDs) occurs via the Golgi/trans-Golgi network (TGN) and is microtubule-dependent. After Brefeldin A treatment, TPD52 first co-localizes with TGN marker syntaxin 6 (1–3 hours) before moving to LDs (5 hours), and this shift is disrupted by nocodazole (microtubule depolymerizer). An N-terminally deleted TPD52 mutant (residues 40–184) constitutively targeted to LDs regardless of treatment.","method":"Immunofluorescence co-localization (BFA treatment time course), nocodazole treatment, N-terminal deletion mutant expression, LD quantification in 3T3 and breast cancer cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutant analysis and pharmacological perturbation with co-localization, single lab","pmids":["31278300"],"is_preprint":false},{"year":2016,"finding":"TPD52 isoform 1 (PC-1) promotes neuroendocrine (NE) transdifferentiation of LNCaP prostate cancer cells. Overexpression of PC-1 alone initiates NE characteristics; IL-6 treatment markedly enhanced this effect and significantly upregulated PC-1 (but not other TPD52 isoforms). Immunofluorescence showed PC-1 accumulation at the ends of neuron-like cell processes in NE-differentiated cells.","method":"Inducible overexpression system (LNCaP), IL-6 treatment, NE marker immunostaining (chromogranin A, synaptophysin, β-3 tubulin), immunofluorescence localization, AR status analysis","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain-of-function with isoform specificity established and defined NE phenotype, single lab","pmids":["26846108"],"is_preprint":false},{"year":2021,"finding":"Under hypoxic conditions in oral squamous cell carcinoma cells, TPD52 mRNA is stabilized by binding of T-cell intercellular antigen 1 (TIA-1) and TIA-related protein (TIAR) to TPD52 mRNA, upregulating TPD52 expression in a HIF-independent manner. In vivo, TPD52 acted as an autophagy inhibitor by reducing p62 levels.","method":"qRT-PCR, Western blotting under hypoxia, HIF inhibition, mRNA stability assays, RBP–mRNA binding (TIA-1/TIAR), RNAi knockdown, xenograft experiments","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RBP binding assays plus mRNA stability and HIF epistasis, single lab; consistent with prior TIA-1/TIAR mechanism report (PMID 28298474)","pmids":["34217360"],"is_preprint":false},{"year":1998,"finding":"Alternative splicing within the D52 gene family alters the protein-protein interaction capabilities of encoded isoforms. A truncated hD53 isoform displayed altered interaction capabilities in the yeast two-hybrid system compared to full-length hD53, demonstrating functional consequences of alternative splicing.","method":"Yeast two-hybrid interaction analysis of alternatively spliced isoforms","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (yeast two-hybrid), single isoform tested, no biochemical confirmation","pmids":["9838088"],"is_preprint":false}],"current_model":"TPD52 is a coiled-coil-bearing protein that homo- and heterodimerizes with other TPD52-family members and interacts with diverse partners (MAL2, annexin VI, ADRP/PLIN2, PLP2, RAB5C, ATM, HSPA8, PRDX1, AMPKα, LKB1, NF-κB p65, ATF6) to regulate vesicle/lysosomal trafficking, Ca2+-dependent secretion, lipid droplet formation, chaperone-mediated autophagy, and cell metabolism; its activity is governed by Ca2+-dependent phosphorylation at S136 (mediated by CAMK2delta6) and by acetylation at K163 (written by KAT2B, erased by HDAC2), while its protein levels are controlled by APC/C-Cdc20-mediated ubiquitination and its mRNA stability is regulated by TIA-1/TIAR binding to the 3'-UTR; overexpression drives cellular transformation, proliferation, migration, and resistance to apoptosis partly through PI3K/Akt, NF-κB–STAT3, and AMPK pathway modulation."},"narrative":{"mechanistic_narrative":"TPD52 is a coiled-coil adaptor protein that couples Ca2+-regulated membrane trafficking to secretory, autophagic, and metabolic programs, and whose overexpression drives oncogenic transformation [PMID:17314271, PMID:20032513]. Through its coiled-coil motif—necessary but not sufficient, with C-terminal regions stabilizing binding—it homo- and heterodimerizes with other TPD52-family members and engages heterologous partners including the apical-transport proteolipid MAL2 [PMID:9484778, PMID:11594751, PMID:11549320]. Its trafficking activity is gated by Ca2+-dependent phosphorylation at S136, catalyzed by CAMK2delta6; phosphomimetic S136E constitutively drives LAMP1 to the plasma membrane while S136A abolishes Ca2+-stimulated LAMP1 accumulation, and TPD52 co-localizes with AP-3, Rab27A, VAMP7 and LAMP1 in lysosome-like secretory organelles [PMID:18832449, PMID:20032513]. This same S136-dependent endomembrane trafficking is required for midbody vesicle delivery during cytokinesis and for apical endolysosomal secretion of LAMP1 and amylase in pancreatic acinar cells [PMID:20946871, PMID:23868405]. TPD52 also localizes to the Golgi/TGN and is delivered to lipid droplets in a microtubule-dependent manner, where it promotes triglyceride synthesis and droplet formation through direct interaction with ADRP/PLIN2 [PMID:26183179, PMID:31278300]. Beyond trafficking, TPD52 acts as a regulatory hub: it directly binds HSPA8/HSC70 to enhance chaperone-mediated autophagy—an interaction disrupted by KAT2B-mediated K163 acetylation that HDAC2 reverses [PMID:34034634]—binds PRDX1 to boost peroxidase activity and oxidative-stress handling [PMID:30981892], and negatively regulates ATM protein levels and AMPK/LKB1 signaling [PMID:23974097, PMID:35666017, PMID:37040029]. In cancer cells TPD52 promotes proliferation, migration via αvβ3 integrin/Akt, NF-κB–STAT3-driven invasion and EMT, and resistance to mitochondrial apoptosis [PMID:18959755, PMID:28466782], while its abundance is controlled by APC/C-Cdc20-mediated ubiquitination and its mRNA stabilized by TIA-1/TIAR binding to the 3'-UTR [PMID:39401430, PMID:28298474].","teleology":[{"year":1998,"claim":"Established the structural basis of TPD52 oligomerization, showing the family self-associates through predicted coiled-coil domains—the founding mechanistic feature of these proteins.","evidence":"Reciprocal yeast two-hybrid and GST pull-down across paired family constructs from a breast carcinoma library","pmids":["9484778"],"confidence":"High","gaps":["No heterologous partners identified","No functional consequence of dimerization established","No structure of the coiled-coil interface"]},{"year":2001,"claim":"Refined the interaction determinants and identified the first non-family partner, showing the coiled-coil is necessary but not sufficient and that TPD52 binds the apical-transport proteolipid MAL2, linking it to membrane trafficking.","evidence":"Yeast two-hybrid plus GST pull-down with C-terminal deletion mapping; MAL2 screen confirmed with in vitro translated protein","pmids":["11594751","11549320"],"confidence":"High","gaps":["Functional role of MAL2 binding not demonstrated","Cellular trafficking step not defined"]},{"year":2004,"claim":"Connected TPD52 to regulated secretion, showing Ca2+-dependent binding to annexin VI in plasma cells.","evidence":"Co-immunoprecipitation in Thiel myeloma cells with MS identification","pmids":["15576473"],"confidence":"Medium","gaps":["Single co-IP without reciprocal validation","Secretory function inferred, not directly tested"]},{"year":2008,"claim":"Defined the regulatory switch on TPD52, pinpointing S136 as the single major Ca2+-dependent phospho-acceptor and CAMK2delta6 as the responsible kinase.","evidence":"Mass spectrometry, site-directed mutagenesis, phospho-specific antibody, in-gel kinase assay, and pharmacological inhibition (KN93, W7)","pmids":["18832449"],"confidence":"High","gaps":["Downstream effect of phosphorylation not yet shown","Direct kinase-substrate reconstitution not performed"]},{"year":2009,"claim":"Assigned a function to S136 phosphorylation, showing it controls Ca2+-stimulated trafficking of LAMP1 to the plasma membrane via lysosome-like secretory organelles.","evidence":"Phosphomutant reconstitution (S136E/S136A), cell-surface labeling, and co-localization with AP-3/Rab27A/VAMP7/LAMP1 across CHO-K1, NRK, HeLa","pmids":["20032513"],"confidence":"High","gaps":["Molecular machinery linking TPD52 to the docking/fusion step unresolved","Direct cargo-selection mechanism unknown"]},{"year":2010,"claim":"Extended the trafficking role to cell division, showing S136-dependent endomembrane delivery to the midbody is required for cytokinesis.","evidence":"Phosphomutant expression with electron microscopy, VAMP8 co-localization, and multinucleation quantification","pmids":["20946871"],"confidence":"High","gaps":["Precise abscission step affected not defined","Relationship to other midbody trafficking factors unknown"]},{"year":2013,"claim":"Demonstrated a physiological secretory role and a separate DNA-damage-related function: TPD52 drives apical endolysosomal secretion in acinar cells and acts as a negative regulator of ATM protein levels.","evidence":"Adenoviral gain-of-function with S136 mutagenesis and amylase/LAMP1 secretion assays; GST pull-down, reciprocal co-IP, domain mapping, and clonogenic radiation assays","pmids":["23868405","23974097"],"confidence":"Medium","gaps":["Mechanism of ATM downregulation (degradation route) not defined","ATM finding from a single lab"]},{"year":2015,"claim":"Identified a lipid-metabolic function, showing TPD52 promotes triglyceride synthesis and lipid droplet formation through direct, isoform-specific binding to ADRP/PLIN2 at the Golgi.","evidence":"Stable expression, fatty acid incorporation, subcellular fractionation, yeast two-hybrid, and GST pull-down in 3T3 cells","pmids":["26183179"],"confidence":"High","gaps":["Enzymatic step in triglyceride synthesis affected unknown","Physiological relevance in vivo not tested here"]},{"year":2014,"claim":"Expanded the interactome with PLP2 and RAB5C binding to a region distinct from the coiled-coil, reinforcing an endosomal-trafficking role.","evidence":"Yeast two-hybrid screen, GST pull-down, and interaction domain mapping","pmids":["24604726"],"confidence":"Medium","gaps":["Functional consequence of PLP2/RAB5C binding not shown","Single lab"]},{"year":2016,"claim":"Linked a specific TPD52 isoform to prostate cancer phenotype, showing isoform 1 (PC-1) drives IL-6-enhanced neuroendocrine transdifferentiation.","evidence":"Inducible overexpression with NE marker immunostaining and IL-6 treatment in LNCaP","pmids":["26846108"],"confidence":"Medium","gaps":["Mechanism connecting PC-1 to NE program unknown","Isoform-specific partners not identified"]},{"year":2017,"claim":"Established post-transcriptional control and an oncogenic signaling axis: TIA-1/TIAR stabilize TPD52 mRNA via the 3'-UTR, while TPD52 binds NF-κB p65 to drive STAT3 cross-talk, invasion, and EMT.","evidence":"RIP, biotin pull-down, 3'-UTR reporter and mRNA-stability assays; co-IP with NF-κB p65 plus MMP-9/EMT readouts in LNCaP","pmids":["28298474","28466782"],"confidence":"Medium","gaps":["Direct vs indirect NF-κB binding not fully resolved","Growth-factor regulation of TIA-1/TIAR binding mechanism partial"]},{"year":2019,"claim":"Defined oxidative-stress and trafficking-route mechanisms: TPD52 binds PRDX1 at its C-terminal PEST domain to enhance peroxidase activity, and reaches lipid droplets via a microtubule-dependent TGN route.","evidence":"TAP, GST pull-down, co-IP, domain mapping and peroxidase/dimerization assays; BFA time-course, nocodazole, and N-terminal deletion mutant localization","pmids":["30981892","31278300"],"confidence":"High","gaps":["How TPD52 enhances PRDX1 catalysis structurally unknown","TGN-to-LD transfer machinery not identified"]},{"year":2021,"claim":"Connected TPD52 to autophagy regulation by two routes: direct HSPA8 binding enhances chaperone-mediated autophagy under acetylation control (KAT2B/HDAC2 at K163), and hypoxia-stabilized TPD52 inhibits autophagy by lowering p62.","evidence":"Co-IP, in vitro acetylation, K163 mutagenesis and xenografts; hypoxia mRNA-stability and HIF-epistasis assays with TIA-1/TIAR binding","pmids":["34034634","34217360"],"confidence":"High","gaps":["Apparent dual autophagy roles (CMA-enhancing vs autophagy-inhibiting) not reconciled","Substrate selectivity of TPD52-HSPA8 CMA not defined"]},{"year":2022,"claim":"Identified TPD52 as a direct negative regulator of energy-stress AMPK signaling, with metabolic consequences in vivo.","evidence":"TAP-MS, co-IP, in vitro kinase assay, and TPD52 transgenic mice with metabolic phenotyping","pmids":["35666017"],"confidence":"High","gaps":["Mechanism by which binding inhibits AMPKα catalysis unclear","Relationship to LKB1 axis not integrated here"]},{"year":2023,"claim":"Refined the AMPK axis upstream, showing TPD52 binds LKB1 to suppress LKB1 autophosphorylation and AMPK activation, with AMPK reciprocally downregulating TPD52 via GSK3β.","evidence":"Co-IP, MD simulation, AICAR and LiCl pharmacology, and pLKB1/pAMPK immunoblotting in prostate cancer cells","pmids":["37040029"],"confidence":"Medium","gaps":["Direct LKB1 kinase inhibition not demonstrated in vitro","Single lab; computational interaction model unconfirmed structurally"]},{"year":2024,"claim":"Revealed a context-dependent tumor-suppressor role and degradation pathway: TPD52 promotes S2P-mediated ATF6 cleavage to couple ER stress/UPR to chaperone machinery, and is targeted for proteolysis by APC/C-Cdc20.","evidence":"Co-IP (ATF6, Cdc20), ubiquitination assays, UPR signaling, rescue experiments, and in vivo tumor models in bladder cancer","pmids":["39401430"],"confidence":"Medium","gaps":["Tumor-suppressor vs oncogenic role reconciliation across tissues unresolved","Cdc20 degron on TPD52 not mapped"]},{"year":null,"claim":"How TPD52's many partner interactions and post-translational controls are integrated into a single coherent regulatory logic—and what determines its opposing oncogenic versus tumor-suppressive outputs across tissues—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of any TPD52 complex","Determinants of tissue-specific tumor-suppressor vs oncogene behavior unknown","Interplay among S136 phosphorylation, K163 acetylation, and Cdc20 ubiquitination not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,9,16,17,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,16,18,19]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,21]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[9,21]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[9,21]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,16]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,18,19]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,23]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to 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protein.","date":"2016","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/27617178","citation_count":8,"is_preprint":false},{"pmid":"31649118","id":"PMC_31649118","title":"Star-PAP regulates tumor protein D52 through modulating miR-449a/34a in breast cancer.","date":"2019","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/31649118","citation_count":7,"is_preprint":false},{"pmid":"25746840","id":"PMC_25746840","title":"Tumor protein D52-like 2 accelerates gastric cancer cell proliferation in vitro.","date":"2015","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/25746840","citation_count":6,"is_preprint":false},{"pmid":"37833790","id":"PMC_37833790","title":"Cross talk of tumor protein D52 (TPD52) with KLF9, PKCε, and MicroRNA 223 in ovarian cancer.","date":"2023","source":"Journal of ovarian 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journal","url":"https://pubmed.ncbi.nlm.nih.gov/28298474","citation_count":5,"is_preprint":false},{"pmid":"31769704","id":"PMC_31769704","title":"Analysis of the CD8+ IL-10+ T cell response elicited by vaccination with the oncogenic tumor-self protein D52.","date":"2019","source":"Human vaccines & immunotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31769704","citation_count":5,"is_preprint":false},{"pmid":"25262828","id":"PMC_25262828","title":"Knockdown of tumor protein D52-like 2 induces cell growth inhibition and apoptosis in oral squamous cell carcinoma.","date":"2014","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/25262828","citation_count":5,"is_preprint":false},{"pmid":"34099820","id":"PMC_34099820","title":"Tissue microarray profiling and integrative proteomics indicate the modulatory potential of Maytenus royleanus in inhibition of overexpressed TPD52 in prostate cancers.","date":"2021","source":"Scientific 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N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/35716110","citation_count":4,"is_preprint":false},{"pmid":"26909548","id":"PMC_26909548","title":"Retracted: Knockdown of tumor protein D52-like 2 induces cell growth inhibition and apoptosis in oral squamous cell carcinoma.","date":"2016","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/26909548","citation_count":4,"is_preprint":false},{"pmid":"39359616","id":"PMC_39359616","title":"Circular RNA circEZH2 Promotes Lung Adenocarcinoma Progression by Regulating microRNA-495-3p/Tumor Protein D52 Axis and Activating Nuclear Factor-Kappa B Pathway.","date":"2024","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39359616","citation_count":3,"is_preprint":false},{"pmid":"37935328","id":"PMC_37935328","title":"Tumor protein D52 (isoform 3) induces NF-κB - STAT3 mediated EMT driving neuroendocrine differentiation of prostate cancer cells.","date":"2023","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37935328","citation_count":2,"is_preprint":false},{"pmid":"41140081","id":"PMC_41140081","title":"Role of TPD52 in Endometrial Cancer: Impact on EMT and the PI3K/AKT and ERK/MAPK Signaling.","date":"2025","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/41140081","citation_count":2,"is_preprint":false},{"pmid":"39690542","id":"PMC_39690542","title":"[Non-small cell lung cancer-derived exosomal circular RNA circEZH2 activates fibroblasts by regulating the miR-495-3p / TPD52 axis and NF-κB pathway].","date":"2024","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/39690542","citation_count":2,"is_preprint":false},{"pmid":"39757112","id":"PMC_39757112","title":"TPD52 as a Therapeutic Target Identified by Machine Learning Shapes the Immune Microenvironment in Breast Cancer.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39757112","citation_count":2,"is_preprint":false},{"pmid":"39983549","id":"PMC_39983549","title":"TPD52 (isoform 3) promotes resistance to mTOR-targeted inhibitors by regulating c-Myc, PTEN, and direct activation of 4E-BP1 in LNCaP androgen-dependent cells.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/39983549","citation_count":2,"is_preprint":false},{"pmid":"37904517","id":"PMC_37904517","title":"Preclinical support for tumor protein D52 as a cancer vaccine antigen.","date":"2023","source":"Human vaccines & immunotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37904517","citation_count":1,"is_preprint":false},{"pmid":"39349129","id":"PMC_39349129","title":"Heightened TPD52 linked to metabolic dysfunction and associated abnormalities in zebrafish.","date":"2024","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39349129","citation_count":1,"is_preprint":false},{"pmid":"40973691","id":"PMC_40973691","title":"Dual oncogenic roles of TPD52 and TPD52L2 in gastric cancer progression via PI3K/AKT activation and immunosuppressive microenvironment remodeling.","date":"2025","source":"Briefings in functional genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40973691","citation_count":1,"is_preprint":false},{"pmid":"40341647","id":"PMC_40341647","title":"Comprehensive analysis of the LINC01122/TPD52 axis as a predictive biomarker in prostate adenocarcinoma.","date":"2025","source":"Scientific 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Two-hybrid screening of a human breast carcinoma library identified hD53 and hD52 as interactors for both hD52 and hD53 baits.\",\n      \"method\": \"Yeast two-hybrid system and GST pull-down assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal yeast two-hybrid plus GST pull-down, two orthogonal methods in one study, replicated across multiple paired constructs\",\n      \"pmids\": [\"9484778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The coiled-coil motif of TPD52 is necessary but not sufficient for interactions with other D52-like proteins; C-terminal regions facilitate and/or stabilize these interactions, as shown by analysis of C-terminally deleted D52 proteins in yeast two-hybrid and pull-down assays.\",\n      \"method\": \"Yeast two-hybrid system and GST pull-down assays with deletion mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (yeast two-hybrid + pull-down) with systematic deletion mapping, single lab\",\n      \"pmids\": [\"11594751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TPD52 physically interacts with MAL2, a novel four-transmembrane proteolipid protein involved in apical vesicle transport, identifying MAL2 as the first heterologous binding partner of TPD52-like proteins. MAL2 bound all TPD52-like baits in yeast two-hybrid, and in vitro translated MAL2 specifically bound GST-Tpd52 in pull-down assays.\",\n      \"method\": \"Yeast two-hybrid screen and GST pull-down assay with in vitro translated MAL2\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid plus GST pull-down orthogonal confirmation, novel heterologous binding partner identified\",\n      \"pmids\": [\"11549320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TPD52 binds annexin VI in a Ca2+-dependent manner in the Thiel myeloma cell line, suggesting these molecules may act together to regulate secretory processes in plasma cells, as demonstrated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation in Thiel myeloma cells; 2D-PAGE/mass spectrometry protein identification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP with Ca2+-dependence shown; protein identified by MS, but limited mechanistic follow-up\",\n      \"pmids\": [\"15576473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ca2+-dependent phosphorylation of TPD52 occurs at serine residue 136 (S136), mediated by CAMK2delta6. Mass spectrometry and site-directed mutagenesis identified S136 as the single major phospho-acceptor site, and a specific CAMK2 isoform (CAMK2delta6) co-migrated and co-localized with TPD52, with phosphorylation inhibited by KN93 and calmodulin antagonist W7.\",\n      \"method\": \"Mass spectrometry, site-directed mutagenesis, phospho-specific antibody, in-gel kinase assay, co-localization, pharmacological inhibitors\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (MS, mutagenesis, in-gel kinase assay, pharmacological inhibition) in one rigorous study identifying specific kinase and phosphorylation site\",\n      \"pmids\": [\"18832449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ca2+-dependent phosphorylation of TPD52 at S136 modulates trafficking of lysosomal membrane protein LAMP1 to the plasma membrane. Phosphomimetic mutants (S136E) constitutively induced LAMP1 plasma membrane accumulation independent of Ca2+, while the phospho-null mutant (S136A) abolished Ca2+-stimulated LAMP1 accumulation. TPD52 co-localized with AP-3, Rab27A, VAMP7, and LAMP1 in lysosome-like secretory organelles.\",\n      \"method\": \"Site-specific mutagenesis, immunofluorescence co-localization, cell surface antibody labeling, live-cell Ca2+ stimulation assays in CHO-K1, NRK, and HeLa cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphomutant reconstitution plus co-localization with multiple organelle markers, multiple cell types, mechanistic site validated\",\n      \"pmids\": [\"20032513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TPD52 expression and phosphorylation at S136 play a role in cytokinesis via endomembrane trafficking. Ectopic expression of the phospho-null S136A mutant caused a 9-fold increase in multinucleated cells. TPD52 co-localized with VAMP8-positive vesicular structures at the cell midbody, and this co-localization increased with elevated Ca2+.\",\n      \"method\": \"Expression of phosphomutants (S136A, S136E), electron microscopy, immunofluorescence co-localization with VAMP8, multinucleation quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — phosphomutant functional dissection with electron microscopy and co-localization, clear phenotypic readout\",\n      \"pmids\": [\"20946871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TPD52 regulates apical endolysosomal secretion in pancreatic acinar cells. Adenoviral restoration of D52 levels in cultured acinar cells rescued levels of endolysosomal proteins (EEA1, Rab5, LAMP1) and strongly enhanced secretion of both LAMP1 (endolysosomal pathway) and amylase. Secretory effects were absent with alanine substitution at S136 (the major D52 phosphorylation site) and inhibited by brefeldin A.\",\n      \"method\": \"Adenoviral D52 delivery to isolated acinar cells, S136 site-directed mutagenesis, cell-surface antigen labeling of LAMP1, amylase secretion assays, brefeldin A inhibition\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — adenoviral gain-of-function, phosphosite mutagenesis, pharmacological inhibition, and multiple secretion readouts in one study\",\n      \"pmids\": [\"23868405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TPD52 directly interacts with ATM kinase and acts as a negative regulator of ATM protein levels. Increased TPD52 expression downregulated steady-state ATM protein (but not mRNA), compromised ATM-mediated DNA damage responses following gamma irradiation, and increased radiation sensitivity. Interaction domains were mapped to TPD52 residues 111–131 and ATM residues 1–245 and 772–1102.\",\n      \"method\": \"GST pull-down and co-immunoprecipitation assays, domain mapping, clonogenic radiation assays, immunoblotting in breast cancer and 3T3 cells\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus GST pull-down with domain mapping, single lab, supported by functional radiation phenotype\",\n      \"pmids\": [\"23974097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TPD52 expression increases neutral lipid storage in cultured cells by promoting fatty acid incorporation into triglyceride and increasing lipid droplet numbers. TPD52 co-localizes with Golgi (but not ER) markers and partially with ADRP-coated lipid droplets. Direct interaction between ADRP (PLIN2) and TPD52, but not TPD52L1, was demonstrated by yeast two-hybrid and confirmed by GST pull-down.\",\n      \"method\": \"Stable expression in 3T3 cells, lipid droplet quantification, fatty acid incorporation assays, subcellular fractionation, immunofluorescence co-localization, yeast two-hybrid, GST pull-down\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (stable cell lines, fractionation, yeast two-hybrid, GST pull-down, isotopic labeling), isoform specificity established\",\n      \"pmids\": [\"26183179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TPD52 interacts with PLP2 and RAB5C as novel binding partners, identified by large yeast two-hybrid screen and confirmed by GST pull-down assays. Interaction domain mapping indicated that both proteins interact with a novel binding region of TPD52 distinct from the coiled-coil domain.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down assays, interaction domain mapping\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus GST pull-down with domain mapping, single lab\",\n      \"pmids\": [\"24604726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TPD52 post-transcriptional regulation is mediated by RNA-binding proteins TIA-1 and TIAR, which bind to the 78–280 region of the TPD52 mRNA 3'-UTR to stabilize the transcript. Knockdown of TIA-1/TIAR decreased TPD52 mRNA stability and expression. TGF-β and EGF stimulation decreased TIA-1/TIAR binding to TPD52 mRNA, resulting in decreased mRNA stability.\",\n      \"method\": \"RNA immunoprecipitation (RIP), biotin pull-down, mRNA degradation assays, 3'-UTR deletion reporter constructs, siRNA knockdown of TIA-1/TIAR\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RIP, biotin pull-down, reporter assays, mRNA stability assays, KD) in a single systematic study\",\n      \"pmids\": [\"28298474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TPD52 knockdown in LNCaP prostate cancer cells induces apoptosis involving caspase-3 and caspase-9 activation and loss of mitochondrial membrane potential, placing TPD52 function upstream of the mitochondrial apoptotic pathway. Overexpression of TPD52 increased proliferation and promoted cell migration via αvβ3 integrin through activation of the PKB/Akt signaling pathway.\",\n      \"method\": \"shRNA knockdown and EGFP-TPD52 overexpression in LNCaP cells, caspase activity assays, mitochondrial membrane potential measurement, migration assays, integrin blocking\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined molecular readouts (caspase activation, Akt), single lab\",\n      \"pmids\": [\"18959755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Expression of murine TPD52 (mD52) in BALB/c 3T3 fibroblasts induced cellular transformation, anchorage-independent growth, tumorigenesis in immunocompetent mice, and spontaneous lung metastasis. TGF-βR1 expression decreased and TGF-β1 secretion increased in mD52-expressing cells, suggesting TGF-β pathway involvement in mD52-induced metastasis.\",\n      \"method\": \"Stable transfection of 3T3 cells with mD52 cDNA, in vitro growth assays, syngeneic subcutaneous tumor challenge, lung nodule quantification, cDNA microarray, TGF-β pathway analysis\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo tumorigenesis and metastasis demonstrated in immunocompetent syngeneic model with molecular pathway support\",\n      \"pmids\": [\"17314271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"D52 overexpression in BALB/c 3T3 cells (but not D53 overexpression) confers increased proliferation and anchorage-independent growth capacity, while D52 knockdown (but not D53) in SK-BR-3 cells significantly increases apoptosis, demonstrating non-redundant and isoform-specific functions for D52 versus its paralogs.\",\n      \"method\": \"Stable expression in BALB/c 3T3 fibroblasts, transient siRNA knockdown in breast carcinoma cell lines, proliferation and soft agar assays, apoptosis assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with paralog comparisons, single lab, defined cellular phenotypes\",\n      \"pmids\": [\"18698023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TPD52 (isoform 3) directly interacts with NF-κB p65 (RelA) and promotes accumulation of phosphorylated NF-κB (p65)S536, transactivating NF-κB target genes. TPD52 also activates STAT3 through an NF-κB–STAT3 cross-talk. TPD52 promotes invasion via increased MMP-9 expression and promotes EMT by inducing loss of E-cadherin and expression of vimentin and VCAM, as well as activation of focal adhesion kinase.\",\n      \"method\": \"Co-immunoprecipitation (TPD52–NF-κB p65), overexpression and shRNA knockdown of TPD52 in LNCaP cells, NF-κB inhibition, cytokine secretion assays, MMP activity assays, Western blotting\",\n      \"journal\": \"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus multiple downstream functional readouts, single lab\",\n      \"pmids\": [\"28466782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TPD52 (isoform 3) interacts with Peroxiredoxin 1 (PRDX1) at the C-terminal PEST domain (residues 152–179) of TPD52, and this interaction increases PRDX1 peroxidase activity and promotes PRDX1 dimerization. H2O2 exposure evoked increased TPD52–PRDX1 interaction. Depletion of both proteins led to H2O2 accumulation, linking TPD52 to oxidative stress management in prostate cancer cells.\",\n      \"method\": \"GST pull-down, tandem affinity purification, co-immunoprecipitation, interaction domain mapping, peroxidase activity assays, dimerization assays, H2O2 measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (TAP, GST pull-down, co-IP, domain mapping, enzymatic assay) in single study\",\n      \"pmids\": [\"30981892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TPD52 enhances chaperone-mediated autophagy (CMA) activation by directly interacting with HSPA8/HSC70 and enhancing substrate degradation in prostate cancer cells. TPD52 is acetylated by KAT2B at K163; this acetylation is reversed by HDAC2. Acetylation of TPD52 at K163 compromises the TPD52–HSPA8 interaction, leading to impaired CMA function and reduced tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (TPD52–HSPA8), CMA activity assays, in vitro acetylation assay (KAT2B), HDAC2 inhibition, K163 mutagenesis, xenograft tumor models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP, enzymatic acetylation assay, site mutagenesis, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"34034634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. TPD52 transgenic mice showed AMPK inhibition and multiple metabolic defects, identifying TPD52 as a novel negative regulator of energy stress-induced AMPK activation.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry to identify AMPKα as TPD52-interacting protein, co-immunoprecipitation, in vitro kinase assay, TPD52 transgenic mice with metabolic phenotyping\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — TAP-MS plus co-IP plus in vitro kinase assay plus in vivo transgenic model, multiple orthogonal methods\",\n      \"pmids\": [\"35666017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TPD52 (isoform 3) interacts with LKB1 (serine/threonine kinase 11), and this interaction suppresses LKB1 auto-phosphorylation and consequently inhibits AMPK activation (reducing pLKB1-Ser428 and pAMPK-Thr172). AMPK activation by AICAR downregulated TPD52 via GSK3β, inhibiting PCa cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, molecular modeling and MD simulations (interaction domain), AICAR treatment, GSK3β inhibition (LiCl), Western blotting for pLKB1 and pAMPK\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP confirmed with computational modelling and pharmacological epistasis, single lab; in vitro kinase assay for LKB1 not directly demonstrated\",\n      \"pmids\": [\"37040029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TPD52 functions as a tumor suppressor in bladder cancer by promoting S2P-mediated cleavage of ATF6 to integrate ER stress and UPR signaling with the chaperone machinery. The APC/C-Cdc20 E3 ligase mediates polyubiquitination and proteolysis of TPD52, and Cdc20 inactivation sensitized cancer cells to ER stress inducers in a TPD52-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation (TPD52–ATF6, TPD52–Cdc20), ubiquitination assays, ER stress/UPR signaling assays, loss-of-function and rescue experiments, in vivo tumor models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination, and functional rescue assays, single lab\",\n      \"pmids\": [\"39401430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Delayed recruitment of TPD52 to lipid droplets (LDs) occurs via the Golgi/trans-Golgi network (TGN) and is microtubule-dependent. After Brefeldin A treatment, TPD52 first co-localizes with TGN marker syntaxin 6 (1–3 hours) before moving to LDs (5 hours), and this shift is disrupted by nocodazole (microtubule depolymerizer). An N-terminally deleted TPD52 mutant (residues 40–184) constitutively targeted to LDs regardless of treatment.\",\n      \"method\": \"Immunofluorescence co-localization (BFA treatment time course), nocodazole treatment, N-terminal deletion mutant expression, LD quantification in 3T3 and breast cancer cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutant analysis and pharmacological perturbation with co-localization, single lab\",\n      \"pmids\": [\"31278300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TPD52 isoform 1 (PC-1) promotes neuroendocrine (NE) transdifferentiation of LNCaP prostate cancer cells. Overexpression of PC-1 alone initiates NE characteristics; IL-6 treatment markedly enhanced this effect and significantly upregulated PC-1 (but not other TPD52 isoforms). Immunofluorescence showed PC-1 accumulation at the ends of neuron-like cell processes in NE-differentiated cells.\",\n      \"method\": \"Inducible overexpression system (LNCaP), IL-6 treatment, NE marker immunostaining (chromogranin A, synaptophysin, β-3 tubulin), immunofluorescence localization, AR status analysis\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain-of-function with isoform specificity established and defined NE phenotype, single lab\",\n      \"pmids\": [\"26846108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Under hypoxic conditions in oral squamous cell carcinoma cells, TPD52 mRNA is stabilized by binding of T-cell intercellular antigen 1 (TIA-1) and TIA-related protein (TIAR) to TPD52 mRNA, upregulating TPD52 expression in a HIF-independent manner. In vivo, TPD52 acted as an autophagy inhibitor by reducing p62 levels.\",\n      \"method\": \"qRT-PCR, Western blotting under hypoxia, HIF inhibition, mRNA stability assays, RBP–mRNA binding (TIA-1/TIAR), RNAi knockdown, xenograft experiments\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RBP binding assays plus mRNA stability and HIF epistasis, single lab; consistent with prior TIA-1/TIAR mechanism report (PMID 28298474)\",\n      \"pmids\": [\"34217360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Alternative splicing within the D52 gene family alters the protein-protein interaction capabilities of encoded isoforms. A truncated hD53 isoform displayed altered interaction capabilities in the yeast two-hybrid system compared to full-length hD53, demonstrating functional consequences of alternative splicing.\",\n      \"method\": \"Yeast two-hybrid interaction analysis of alternatively spliced isoforms\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (yeast two-hybrid), single isoform tested, no biochemical confirmation\",\n      \"pmids\": [\"9838088\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TPD52 is a coiled-coil-bearing protein that homo- and heterodimerizes with other TPD52-family members and interacts with diverse partners (MAL2, annexin VI, ADRP/PLIN2, PLP2, RAB5C, ATM, HSPA8, PRDX1, AMPKα, LKB1, NF-κB p65, ATF6) to regulate vesicle/lysosomal trafficking, Ca2+-dependent secretion, lipid droplet formation, chaperone-mediated autophagy, and cell metabolism; its activity is governed by Ca2+-dependent phosphorylation at S136 (mediated by CAMK2delta6) and by acetylation at K163 (written by KAT2B, erased by HDAC2), while its protein levels are controlled by APC/C-Cdc20-mediated ubiquitination and its mRNA stability is regulated by TIA-1/TIAR binding to the 3'-UTR; overexpression drives cellular transformation, proliferation, migration, and resistance to apoptosis partly through PI3K/Akt, NF-κB–STAT3, and AMPK pathway modulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TPD52 is a coiled-coil adaptor protein that couples Ca2+-regulated membrane trafficking to secretory, autophagic, and metabolic programs, and whose overexpression drives oncogenic transformation [#13, #5]. Through its coiled-coil motif—necessary but not sufficient, with C-terminal regions stabilizing binding—it homo- and heterodimerizes with other TPD52-family members and engages heterologous partners including the apical-transport proteolipid MAL2 [#0, #1, #2]. Its trafficking activity is gated by Ca2+-dependent phosphorylation at S136, catalyzed by CAMK2delta6; phosphomimetic S136E constitutively drives LAMP1 to the plasma membrane while S136A abolishes Ca2+-stimulated LAMP1 accumulation, and TPD52 co-localizes with AP-3, Rab27A, VAMP7 and LAMP1 in lysosome-like secretory organelles [#4, #5]. This same S136-dependent endomembrane trafficking is required for midbody vesicle delivery during cytokinesis and for apical endolysosomal secretion of LAMP1 and amylase in pancreatic acinar cells [#6, #7]. TPD52 also localizes to the Golgi/TGN and is delivered to lipid droplets in a microtubule-dependent manner, where it promotes triglyceride synthesis and droplet formation through direct interaction with ADRP/PLIN2 [#9, #21]. Beyond trafficking, TPD52 acts as a regulatory hub: it directly binds HSPA8/HSC70 to enhance chaperone-mediated autophagy—an interaction disrupted by KAT2B-mediated K163 acetylation that HDAC2 reverses [#17]—binds PRDX1 to boost peroxidase activity and oxidative-stress handling [#16], and negatively regulates ATM protein levels and AMPK/LKB1 signaling [#8, #18, #19]. In cancer cells TPD52 promotes proliferation, migration via αvβ3 integrin/Akt, NF-κB–STAT3-driven invasion and EMT, and resistance to mitochondrial apoptosis [#12, #15], while its abundance is controlled by APC/C-Cdc20-mediated ubiquitination and its mRNA stabilized by TIA-1/TIAR binding to the 3'-UTR [#20, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the structural basis of TPD52 oligomerization, showing the family self-associates through predicted coiled-coil domains—the founding mechanistic feature of these proteins.\",\n      \"evidence\": \"Reciprocal yeast two-hybrid and GST pull-down across paired family constructs from a breast carcinoma library\",\n      \"pmids\": [\"9484778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No heterologous partners identified\", \"No functional consequence of dimerization established\", \"No structure of the coiled-coil interface\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Refined the interaction determinants and identified the first non-family partner, showing the coiled-coil is necessary but not sufficient and that TPD52 binds the apical-transport proteolipid MAL2, linking it to membrane trafficking.\",\n      \"evidence\": \"Yeast two-hybrid plus GST pull-down with C-terminal deletion mapping; MAL2 screen confirmed with in vitro translated protein\",\n      \"pmids\": [\"11594751\", \"11549320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of MAL2 binding not demonstrated\", \"Cellular trafficking step not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected TPD52 to regulated secretion, showing Ca2+-dependent binding to annexin VI in plasma cells.\",\n      \"evidence\": \"Co-immunoprecipitation in Thiel myeloma cells with MS identification\",\n      \"pmids\": [\"15576473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single co-IP without reciprocal validation\", \"Secretory function inferred, not directly tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the regulatory switch on TPD52, pinpointing S136 as the single major Ca2+-dependent phospho-acceptor and CAMK2delta6 as the responsible kinase.\",\n      \"evidence\": \"Mass spectrometry, site-directed mutagenesis, phospho-specific antibody, in-gel kinase assay, and pharmacological inhibition (KN93, W7)\",\n      \"pmids\": [\"18832449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effect of phosphorylation not yet shown\", \"Direct kinase-substrate reconstitution not performed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Assigned a function to S136 phosphorylation, showing it controls Ca2+-stimulated trafficking of LAMP1 to the plasma membrane via lysosome-like secretory organelles.\",\n      \"evidence\": \"Phosphomutant reconstitution (S136E/S136A), cell-surface labeling, and co-localization with AP-3/Rab27A/VAMP7/LAMP1 across CHO-K1, NRK, HeLa\",\n      \"pmids\": [\"20032513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery linking TPD52 to the docking/fusion step unresolved\", \"Direct cargo-selection mechanism unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the trafficking role to cell division, showing S136-dependent endomembrane delivery to the midbody is required for cytokinesis.\",\n      \"evidence\": \"Phosphomutant expression with electron microscopy, VAMP8 co-localization, and multinucleation quantification\",\n      \"pmids\": [\"20946871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise abscission step affected not defined\", \"Relationship to other midbody trafficking factors unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a physiological secretory role and a separate DNA-damage-related function: TPD52 drives apical endolysosomal secretion in acinar cells and acts as a negative regulator of ATM protein levels.\",\n      \"evidence\": \"Adenoviral gain-of-function with S136 mutagenesis and amylase/LAMP1 secretion assays; GST pull-down, reciprocal co-IP, domain mapping, and clonogenic radiation assays\",\n      \"pmids\": [\"23868405\", \"23974097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ATM downregulation (degradation route) not defined\", \"ATM finding from a single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a lipid-metabolic function, showing TPD52 promotes triglyceride synthesis and lipid droplet formation through direct, isoform-specific binding to ADRP/PLIN2 at the Golgi.\",\n      \"evidence\": \"Stable expression, fatty acid incorporation, subcellular fractionation, yeast two-hybrid, and GST pull-down in 3T3 cells\",\n      \"pmids\": [\"26183179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic step in triglyceride synthesis affected unknown\", \"Physiological relevance in vivo not tested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded the interactome with PLP2 and RAB5C binding to a region distinct from the coiled-coil, reinforcing an endosomal-trafficking role.\",\n      \"evidence\": \"Yeast two-hybrid screen, GST pull-down, and interaction domain mapping\",\n      \"pmids\": [\"24604726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PLP2/RAB5C binding not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked a specific TPD52 isoform to prostate cancer phenotype, showing isoform 1 (PC-1) drives IL-6-enhanced neuroendocrine transdifferentiation.\",\n      \"evidence\": \"Inducible overexpression with NE marker immunostaining and IL-6 treatment in LNCaP\",\n      \"pmids\": [\"26846108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting PC-1 to NE program unknown\", \"Isoform-specific partners not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established post-transcriptional control and an oncogenic signaling axis: TIA-1/TIAR stabilize TPD52 mRNA via the 3'-UTR, while TPD52 binds NF-κB p65 to drive STAT3 cross-talk, invasion, and EMT.\",\n      \"evidence\": \"RIP, biotin pull-down, 3'-UTR reporter and mRNA-stability assays; co-IP with NF-κB p65 plus MMP-9/EMT readouts in LNCaP\",\n      \"pmids\": [\"28298474\", \"28466782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect NF-κB binding not fully resolved\", \"Growth-factor regulation of TIA-1/TIAR binding mechanism partial\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined oxidative-stress and trafficking-route mechanisms: TPD52 binds PRDX1 at its C-terminal PEST domain to enhance peroxidase activity, and reaches lipid droplets via a microtubule-dependent TGN route.\",\n      \"evidence\": \"TAP, GST pull-down, co-IP, domain mapping and peroxidase/dimerization assays; BFA time-course, nocodazole, and N-terminal deletion mutant localization\",\n      \"pmids\": [\"30981892\", \"31278300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TPD52 enhances PRDX1 catalysis structurally unknown\", \"TGN-to-LD transfer machinery not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TPD52 to autophagy regulation by two routes: direct HSPA8 binding enhances chaperone-mediated autophagy under acetylation control (KAT2B/HDAC2 at K163), and hypoxia-stabilized TPD52 inhibits autophagy by lowering p62.\",\n      \"evidence\": \"Co-IP, in vitro acetylation, K163 mutagenesis and xenografts; hypoxia mRNA-stability and HIF-epistasis assays with TIA-1/TIAR binding\",\n      \"pmids\": [\"34034634\", \"34217360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent dual autophagy roles (CMA-enhancing vs autophagy-inhibiting) not reconciled\", \"Substrate selectivity of TPD52-HSPA8 CMA not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified TPD52 as a direct negative regulator of energy-stress AMPK signaling, with metabolic consequences in vivo.\",\n      \"evidence\": \"TAP-MS, co-IP, in vitro kinase assay, and TPD52 transgenic mice with metabolic phenotyping\",\n      \"pmids\": [\"35666017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which binding inhibits AMPKα catalysis unclear\", \"Relationship to LKB1 axis not integrated here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the AMPK axis upstream, showing TPD52 binds LKB1 to suppress LKB1 autophosphorylation and AMPK activation, with AMPK reciprocally downregulating TPD52 via GSK3β.\",\n      \"evidence\": \"Co-IP, MD simulation, AICAR and LiCl pharmacology, and pLKB1/pAMPK immunoblotting in prostate cancer cells\",\n      \"pmids\": [\"37040029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LKB1 kinase inhibition not demonstrated in vitro\", \"Single lab; computational interaction model unconfirmed structurally\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a context-dependent tumor-suppressor role and degradation pathway: TPD52 promotes S2P-mediated ATF6 cleavage to couple ER stress/UPR to chaperone machinery, and is targeted for proteolysis by APC/C-Cdc20.\",\n      \"evidence\": \"Co-IP (ATF6, Cdc20), ubiquitination assays, UPR signaling, rescue experiments, and in vivo tumor models in bladder cancer\",\n      \"pmids\": [\"39401430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tumor-suppressor vs oncogenic role reconciliation across tissues unresolved\", \"Cdc20 degron on TPD52 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TPD52's many partner interactions and post-translational controls are integrated into a single coherent regulatory logic—and what determines its opposing oncogenic versus tumor-suppressive outputs across tissues—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of any TPD52 complex\", \"Determinants of tissue-specific tumor-suppressor vs oncogene behavior unknown\", \"Interplay among S136 phosphorylation, K163 acetylation, and Cdc20 ubiquitination not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 9, 16, 17, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 16, 18, 19]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [9, 21]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [9, 21]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 18, 19]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAL2\", \"ANXA6\", \"PLIN2\", \"PLP2\", \"RAB5C\", \"ATM\", \"HSPA8\", \"PRDX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}