{"gene":"PHB2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2017,"finding":"PHB2 was identified as an inner mitochondrial membrane mitophagy receptor that interacts with lipidated LC3 (MAP1LC3B) via an LC3-interacting region (LIR) motif, enabling autophagosome recognition of damaged mitochondria after outer membrane rupture.","method":"Mechanistic cell biology; the finding is reviewed/summarized in this commentary citing the original Wei et al. discovery paper","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — discovery independently replicated across multiple labs and organisms; referenced as foundational in numerous subsequent papers","pmids":["28220775"],"is_preprint":false},{"year":2019,"finding":"PHB2 promotes PINK1-Parkin-dependent mitophagy via the PARL-PGAM5-PINK1 axis: PHB2 depletion destabilizes PINK1 at mitochondria by activating the inner membrane protease PARL, blocking PRKN/Parkin recruitment and ubiquitin/OPTN accumulation; PHB2 overexpression directly induces Parkin recruitment.","method":"siRNA knockdown, overexpression, immunofluorescence, Co-IP; genetic epistasis with PARL and PGAM5 in mouse embryo fibroblasts and cancer cell lines","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, epistasis, multiple cell models, single lab with several orthogonal methods","pmids":["31177901"],"is_preprint":false},{"year":2018,"finding":"PHB2 directly binds the autophagosomal protein LC3 via an LIR domain upon mitochondrial damage, and also forms a ternary complex with SQSTM1 (p62) and LC3, promoting LC3 loading onto damaged mitochondria during cholestasis-induced mitophagy in hepatocytes.","method":"Co-immunoprecipitation, domain mapping, cell-based mitophagy assays in hepatocytes treated with bile acids; in vivo biliary atresia liver samples","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and domain analysis in single lab, mechanistic follow-up limited to one study","pmids":["29416008"],"is_preprint":false},{"year":2022,"finding":"Parkin (PRKN) directly binds PHB2 through its RING1 domain and promotes K11- and K33-linked ubiquitination on PHB2 K142/K200 residues, enhancing PHB2–LC3B interaction and efficient mitophagy; this establishes inner mitochondrial membrane ubiquitination as a step in Parkin-mediated mitophagy.","method":"Molecular, cellular, and biochemical approaches including domain-deletion mutagenesis, ubiquitination assays specifying linkage type and sites, Co-IP, and LC3B binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination assay with site mutagenesis, domain mapping, multiple orthogonal methods in single study","pmids":["36379251"],"is_preprint":false},{"year":2022,"finding":"PGAM5 (mitochondrial Ser/Thr phosphatase) dephosphorylates PHB2 on Ser91; phosphodefective PHB2-S91A impairs mitochondrial quality surveillance (fission/fusion, mitophagy, biogenesis) under hyperglycemia, whereas phosphomimetic PHB2-S91D is protective, establishing PHB2 Ser91 phosphorylation as critical for mitochondrial homeostasis in diabetic cardiomyopathy.","method":"Co-immunoprecipitation, phosphodefective/phosphomimetic PHB2 mutant transfection in cardiomyocytes, cardiomyocyte-specific Pgam5 knockout mice, PHB2-S91D knockin mice","journal":"Research (Washington, D.C.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis combined with in vivo knockin mouse model and multiple cellular assays in single rigorous study","pmids":["39285950"],"is_preprint":false},{"year":2022,"finding":"PHB2 maintains the contractile phenotype of vascular smooth muscle cells (VSMCs) by directly interacting (via its C-terminus) with hnRNPA1, a key modulator of PKM1/2 mRNA splicing, thereby suppressing PKM2 expression and glycolysis; PHB2 deficiency shifts PKM splicing toward PKM2, enhancing glycolysis and promoting the synthetic VSMC phenotype and neointima formation.","method":"RNA-seq, protein interactome analysis, Co-immunoprecipitation, mammalian 2-hybrid assay, carotid artery injury model, collagen gel contraction and wire myography assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mammalian 2-hybrid, in vivo model, multiple orthogonal methods in single study","pmids":["36200440"],"is_preprint":false},{"year":2023,"finding":"PHB2 directly interacts with NDUFS1 (Complex I subunit) in mitochondria and facilitates NDUFS1 binding to NDUFV1, stabilizing Complex I activity and enhancing oxidative phosphorylation to promote CRC cell proliferation.","method":"Co-immunoprecipitation, mass spectrometry, co-localization (immunofluorescence), siRNA knockdown, PHB2 overexpression with Complex I activity assays in CRC and normal intestinal epithelial cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + MS identification + functional rescue, single lab","pmids":["36658121"],"is_preprint":false},{"year":2023,"finding":"PHB2 interacts with NDUFV2 (mitochondrial Complex I subunit V2) via Co-IP; PHB2 promotes NDUFV2 stabilization, and PHB2 deficiency impairs mitochondrial bioenergetics and oxidative phosphorylation in doxorubicin-challenged hearts.","method":"Proteomic profiling, bioinformatic analysis, Co-immunoprecipitation, pulldown assays, cardiac-specific PHB2 conditional knockout mice","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proteomic screen + Co-IP validation + in vivo KO phenotype, single lab","pmids":["37451140"],"is_preprint":false},{"year":2009,"finding":"BIG3 (ARFGEF3) traps PHB2/REA in the cytoplasm, preventing its estrogen-stimulated nuclear translocation; when BIG3 is knocked down, estradiol causes PHB2/REA translocation to the nucleus where it interacts with ERα and suppresses ERα transcriptional activity.","method":"siRNA knockdown of BIG3, Co-immunoprecipitation, immunoblotting of nuclear/cytoplasmic fractions, ERα transcriptional activity assays in breast cancer cells","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + fractionation + transcriptional reporter, single lab","pmids":["19496786"],"is_preprint":false},{"year":2013,"finding":"PHB2 released from BIG3 by the cell-permeable peptide ERAP directly binds both nuclear and membrane-associated ERα, inhibiting multiple ERα-signalling pathways (genomic and non-genomic ERα activation and ERα phosphorylation) and suppressing tamoxifen resistance in ERα-positive breast cancer cells in vitro and in vivo.","method":"Cell-permeable peptide inhibitor (ERAP), Co-immunoprecipitation, Western blot for ERα signalling intermediates, in vitro proliferation assays, xenograft in vivo models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical tool + Co-IP + in vitro and in vivo validation, single lab but multiple orthogonal methods","pmids":["24051437"],"is_preprint":false},{"year":2015,"finding":"PHB2 nuclear import upon estradiol stimulation is mediated by karyopherin alpha proteins KPNA1, KPNA5, and KPNA6; BIG3 blocks the KPNA-binding region(s) of PHB2 to prevent this nuclear translocation.","method":"siRNA knockdown of individual KPNAs, Co-immunoprecipitation, subcellular fractionation, immunofluorescence in breast cancer cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple Co-IP + siRNA epistasis, single lab","pmids":["26052702"],"is_preprint":false},{"year":2000,"finding":"REA (PHB2) binds the ligand-binding domain (E domain) of ERα via a region in the C-terminal half of REA; this interaction competes with coactivator SRC-1 for ER binding; the LXXLL motif near REA N-terminus is required for competitive binding with SRC-1 but not for direct ER binding; loss of LXXLL impairs optimal repression of ER activity.","method":"GST pull-down assays, deletion mutant mapping, antisense RNA knockdown, transactivation assays with estrogen response element reporters","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro pull-down with systematic mutagenesis/deletion mapping + functional reporter assays, multiple orthogonal methods in single study","pmids":["10960470"],"is_preprint":false},{"year":2007,"finding":"EZH2 (histone methyltransferase) associates with REA/PHB2 (Co-immunoprecipitation); EZH2 represses estrogen-dependent transcription and this repression is mutually dependent on REA, suggesting EZH2 is recruited to estrogen-regulated target genes via its interaction with the ER corepressor REA.","method":"Co-immunoprecipitation, luciferase reporter assays for estrogen-dependent transcription, siRNA knockdown","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + reporter assays, single lab, single study","pmids":["17453341"],"is_preprint":false},{"year":2009,"finding":"REA/PHB2 directly interacts with TRPM6 (at the 6th, 7th, and 8th β-sheets of TRPM6's α-kinase domain), inhibits TRPM6 channel activity in a phosphorylation-dependent manner (no effect on kinase-dead K1804R TRPM6), and this interaction is dynamically disrupted by short-term 17β-estradiol treatment, leading to increased TRPM6-mediated Mg2+ current.","method":"Co-immunoprecipitation, electrophysiology (channel activity assays), site-directed mutagenesis (K1804R), PKC activation/inhibition, estradiol treatment in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis, Co-IP domain mapping, pharmacological dissection, multiple orthogonal methods in one study","pmids":["19329436"],"is_preprint":false},{"year":2007,"finding":"PHB2 depletion by RNAi in HeLa cells causes premature sister-chromatid separation and defects in chromosome congression with mitotic arrest; cohesin is dissociated from centromeres during early mitosis in the absence of PHB2, even though centromeric shugoshin localization is preserved, indicating PHB2 protects centromeric cohesion against Plk1-mediated phosphorylation.","method":"RNAi knockdown in HeLa cells, immunofluorescence for cohesin and shugoshin localization, chromosome segregation analysis, spindle checkpoint activation assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean RNAi with defined molecular phenotype (cohesin localization) and epistasis with shugoshin pathway, well-controlled single study","pmids":["17656096"],"is_preprint":false},{"year":2008,"finding":"Akt2 (but not Akt1) specifically binds PHB2/REA (Co-immunoprecipitation of endogenous proteins, Akt2-REA complex does not contain PHB1); Akt2 promotes myogenic differentiation inversely correlated with PHB2 levels; Akt2 overexpression reduces PHB2 protein and siRNA knockdown of Akt2 increases PHB2/REA levels.","method":"Co-immunoprecipitation of endogenous proteins, siRNA silencing of Akt1 vs. Akt2, overexpression in C2 myoblasts and fibroblasts, immunofluorescence colocalization","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal endogenous Co-IP + siRNA phenotype, single lab","pmids":["17565718"],"is_preprint":false},{"year":2008,"finding":"PHB2 interacts with RNF2 (polycomb protein); RNF2 represses CP2c-stimulated transcription in a PHB2 dose-dependent manner; RNF2 residues 1–158 are sufficient for association with PHB2; PHB2 and CP2c bind to N- and C-termini of RNF2 respectively; the PHB2-RNF2 complex modulates CP2-mediated alpha-globin gene expression.","method":"Yeast two-hybrid, Co-immunoprecipitation, RNF2 deletion mutant mapping, luciferase reporter assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast 2-hybrid + Co-IP + functional reporter, single lab","pmids":["18629613"],"is_preprint":false},{"year":2022,"finding":"TIPE1 interacts with PHB2 (identified by mass spectrometry screening and confirmed by Co-immunoprecipitation) and promotes the ubiquitination and proteasomal degradation of PHB2, thereby impairing PHB2-dependent mitophagy and causing mitochondrial dysfunction in renal tubular epithelial cells under high glucose.","method":"Mass spectrometry, Co-immunoprecipitation, ubiquitination assays, Tipe1 conditional knockout mice, siRNA knockdown of PHB2 for rescue experiments","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification + Co-IP + ubiquitination assay + in vivo KO + rescue, single lab","pmids":["35152003"],"is_preprint":false},{"year":2020,"finding":"BI1 (Bax inhibitor-1) directly interacts with cytoplasmic PHB2 via its C-terminus and the PHB domain of PHB2, promoting PHB2 retention/import into mitochondria; PHB2 knockdown abolishes the mitochondrial-protective and renal-protective effects of BI1 in acute kidney injury.","method":"Domain deletion assay, Co-immunoprecipitation, immunofluorescence, BI1 transgenic mice, siRNA knockdown of PHB2 for rescue, mitochondrial fractionation","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping + Co-IP + in vivo transgenic + rescue with PHB2 siRNA, single lab","pmids":["31903127"],"is_preprint":false},{"year":2022,"finding":"PHB2 interaction with GOLPH3 (Golgi phosphorylation protein 3) recruits PHB2 and LC3-II to promote autophagy/mitophagy in glioma cells; PHB2 knockdown abolishes the GOLPH3-induced autophagy stimulation.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, autophagy flux assays in glioma cells and tissues","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP + knockdown phenotype, limited mechanistic follow-up, single lab","pmids":["34094672"],"is_preprint":false},{"year":2022,"finding":"The small molecule YL-939 binds PHB2 (identified by chemical proteomics); YL-939 binding to PHB2 promotes ferritin expression, reduces intracellular iron content, and thereby decreases susceptibility to ferroptosis via the PHB2/ferritin/iron axis.","method":"Chemical proteomics (target identification), Western blot for ferritin, iron content measurements, ferroptosis cell death assays, acute liver injury model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics target ID + functional validation in cells and in vivo, multiple assays, single lab","pmids":["36463308"],"is_preprint":false},{"year":2021,"finding":"FOXM1 transcriptionally regulates PHB2 expression by binding to the PHB2 promoter; PINT87aa peptide binds the DNA-binding domain of FOXM1 (verified by Co-IP and co-localization) and blocks FOXM1-mediated PHB2 transcription, reducing mitophagy and inducing cellular senescence in HCC.","method":"Co-immunoprecipitation, immunofluorescence co-localization, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, in vitro and in vivo tumor models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + luciferase + Co-IP + rescue assays, multiple orthogonal methods, single lab","pmids":["33754036"],"is_preprint":false},{"year":2022,"finding":"GALNT14 O-glycosylates PHB2 at serine-161 (identified by comparative lectin-capture glycoproteomics, confirmed by site-directed mutagenesis); this O-glycosylation is required for increased PHB2–IGFBP6 interaction and subsequent IGF1R-mediated signaling activation promoting HCC growth, migration, and drug resistance.","method":"Comparative lectin-capture glycoproteomic approach, site-directed mutagenesis (S161A), Co-immunoprecipitation, functional proliferation/migration assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — glycoproteomic identification + site mutagenesis + Co-IP + functional rescue, single lab","pmids":["36376274"],"is_preprint":false},{"year":2022,"finding":"c-Abl (nonreceptor tyrosine kinase) phosphorylates PHB2 at tyrosine Y121; phosphomimetic substitution Y121D of PHB2 impairs PHB2–LC3 interaction in vitro, blocking mitophagy; c-Abl activation increases interaction with PHB2 and reduces PHB2–LC3 co-localization in MPP+-treated cells.","method":"PHB2 tyrosine phosphorylation site mutagenesis (Y121D), Co-immunoprecipitation, immunofluorescence, c-Abl inhibitor STI571 in cell and mouse PD models","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — site mutagenesis establishing Y121 as key phosphorylation site affecting LC3 binding, single lab, partially validated in vivo","pmids":["36406767"],"is_preprint":false},{"year":2022,"finding":"Protein disulfide isomerase (PDI) directly interacts with PHB2 in mitochondria and competitively blocks the LC3II–PHB2 interaction, thereby inhibiting mitophagy signaling and reducing radio/chemo-sensitivity in colorectal cancer cells.","method":"Co-immunoprecipitation, competition binding assays, autophagy flux assays, colorectal cancer cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + competition assay + functional mitophagy readout, single lab","pmids":["36202782"],"is_preprint":false},{"year":2018,"finding":"PHB2 functions as a chaperone for the transcription factor Hes1 outside the nucleus; the small molecule JI051 binds PHB2 (identified by immunomagnetic isolation and LC-MS/MS) and stabilizes PHB2's interaction with Hes1, sequestering Hes1 outside the nucleus, inducing G2/M arrest and reducing cell growth.","method":"Immunomagnetic isolation + nanoscale LC-MS/MS (target ID), cell proliferation assays, G2/M cell cycle analysis, pancreatic tumor xenograft model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — chemical proteomics target identification + functional cell/in vivo validation, single lab","pmids":["29523683"],"is_preprint":false},{"year":2024,"finding":"ALDH2 lactylation at K52 promotes ubiquitination-dependent proteasomal degradation of PHB2 (interaction identified by immunoprecipitation-mass spectrometry); loss of PHB2 inhibits mitophagy and worsens mitochondrial dysfunction in AKI; ALDH2-K52R mutation or SIRT3 upregulation reduces ALDH2 lactylation, stabilizes PHB2, and restores mitophagy.","method":"IP-mass spectrometry (interaction), K52R mutagenesis, SIRT3 modulation, ubiquitination assays, mouse AKI model with adeno-associated virus","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS + site mutagenesis + in vivo mouse model + rescue, multiple methods, single lab","pmids":["39737891"],"is_preprint":false},{"year":2022,"finding":"PHB2 directly interacts with PHB domain of RACK1 in NSCLC cells (Co-immunoprecipitation + mass spectrometry), stabilizes RACK1 via posttranslational modification, and activates downstream Akt and FAK pathways to promote proliferation, migration, and invasion.","method":"Co-immunoprecipitation, mass spectrometry, siRNA knockdown, PHB2 overexpression, in vivo tumor model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + MS + functional rescue, single lab","pmids":["33537079"],"is_preprint":false},{"year":2024,"finding":"HKDC1 sequesters PHB2 in the cytoplasm (interaction demonstrated by Co-IP), disabling PHB2's suppressive effect on the transcription factor SP1 and promoting expression of pro-oncogenic genes; glucose depletion or HKDC1 knockout releases PHB2, suppressing cancer cell proliferation.","method":"Co-immunoprecipitation, genetic knockout, SP1 transcriptional assays, glucose-starvation experiments in cancer cell lines","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + KO + transcriptional readout, single lab","pmids":["39375512"],"is_preprint":false},{"year":2024,"finding":"PHB2 physically interacts with SHIP2 in the cytoplasm of gastric cancer cells; PHB2 promotes SHIP2 ubiquitination and degradation via the E3 ligase NEDD4, activating PI3K/Akt signaling and driving gastric cancer cell proliferation.","method":"Co-immunoprecipitation, GST pull-down, deletion mapping, cycloheximide chase, ubiquitination assays, in vivo GC xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP + GST pulldown + ubiquitination assay + in vivo, single lab","pmids":["38200519"],"is_preprint":false},{"year":2019,"finding":"Co-immunoprecipitation demonstrated a direct interaction between Nrf2 and PHB2 in brain tissue; MitoQ increases Nrf2 binding to PHB2 and elevates PHB2/OPA1 in the mitochondrial fraction, promoting mitochondrial fusion and reducing blood-brain barrier disruption after SAH; PHB2 siRNA reverses these effects.","method":"Co-immunoprecipitation, Western blot of mitochondrial fractions, PHB2 siRNA, Nrf2 inhibitor ML385, transmission electron microscopy in rat SAH model","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP interaction + in vivo siRNA rescue, single lab, animal model","pmids":["30779914"],"is_preprint":false},{"year":2024,"finding":"Yeast Phb1 and Phb2 (S. cerevisiae orthologs) function as Atg8 (LC3) receptors for mitophagy via a conserved AIM/LIR-like motif; both require complex formation with each other; they also negatively regulate Atg32 processing via the rhomboid protease Pcp1 (PARL ortholog).","method":"Genetic deletion/complementation, AIM/LIR motif mutagenesis, Co-immunoprecipitation with Atg8, mitochondrial co-localization, mitophagy flux assays in S. cerevisiae","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — motif mutagenesis + Co-IP + genetic epistasis with Yme1 and Pcp1 + functional mitophagy assay, multiple methods in single rigorous study","pmids":["38964378"],"is_preprint":false},{"year":2022,"finding":"PHB2 directly interacts with PGAM5 (confirmed by Co-IP and immunoblot); PGAM5 dephosphorylates PHB2, causing its cytosolic translocation from mitochondria; silencing Pgam5 or expressing phosphomimetic PHB2 mutant prevents mitochondrial PHB2 loss and activates mitophagy/UPRmt in LPS-challenged cardiomyocytes.","method":"Co-immunoprecipitation, immunoblot, PHB2 phosphomimetic mutant transfection, Pgam5 siRNA, cardiomyocyte-specific Pgam5 KO mice","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + phosphomimetic mutagenesis + in vivo KO, multiple methods, single lab","pmids":["37781037"],"is_preprint":false},{"year":2023,"finding":"L-carnitine enhances PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction; CPT1a (activated by L-carnitine) directly binds PHB2 (Co-IP) and modulates the PHB2-PARL interaction; PARL overexpression inhibits mitophagy and abolishes L-carnitine's protective effects on cardiac microvascular function in diabetic cardiomyopathy.","method":"Co-immunoprecipitation of CPT1a with PHB2, CPT1a mutation (M593S), PARL overexpression via AAV, db/db mouse model, endothelial cell high glucose/FFA injury model","journal":"Acta physiologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + site mutagenesis + in vivo mouse model + rescue, single lab","pmids":["37042471"],"is_preprint":false},{"year":2020,"finding":"EV-A71 VP1 C-terminus (aa 251-297) interacts with PHB2 (identified by mass spectrometry, verified by Co-IP); PHB2 knockdown reduces EV-A71 replication, viral particle release, and viral protein synthesis, and inhibits autophagy, indicating PHB2 is required for VP1-induced autophagy and viral infectivity.","method":"Mass spectrometry, Co-immunoprecipitation, PHB2 siRNA knockdown, viral replication assays, autophagy flux assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MS + Co-IP + siRNA rescue, single lab","pmids":["32276428"],"is_preprint":false},{"year":2022,"finding":"PHB2 promotes DHA-inhibited RCHY1 upregulation: PHB2 interacts with and stabilizes RCHY1 (E3 ubiquitin ligase), leading to p53 and p21 downregulation in colon cancer; DHA degrades PHB2 via ubiquitylation-dependent pathway, blocking PHB2-RCHY1-p53 axis.","method":"Co-immunoprecipitation, ubiquitination assays, PHB2 overexpression/knockdown, in vitro and in vivo tumor models","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP + ubiquitination assay + in vivo tumor model, single lab","pmids":["36342357"],"is_preprint":false},{"year":2005,"finding":"Genetic deletion of both REA/PHB2 alleles in mice is embryonic lethal; REA heterozygous animals have half normal REA protein levels and display greater uterine weight gain, epithelial hyperproliferation in response to estradiol, and substantially enhanced stimulation of estrogen-upregulated genes, as well as loss of estrogen-mediated gene repression, demonstrating REA is a significant physiological modulator of estrogen responsiveness in vivo.","method":"Targeted gene disruption (homologous recombination), heterozygous mouse phenotyping, uterine gene expression analysis, estrogen challenge assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic deletion with defined molecular and physiological phenotype, gene-dosage effect demonstrated, replicated in subsequent papers","pmids":["15713652"],"is_preprint":false},{"year":2009,"finding":"REA/PHB2 corepressor is required for estradiol-mediated downregulation of the tumor suppressor gene BTG2: ERα interacts with the BTG2 promoter in a ligand-independent manner, and depletion of REA by siRNA significantly abrogates E2-mediated BTG2 repression; ERα's DNA- and ligand-binding domains and HDAC activity are required for this regulation.","method":"siRNA knockdown of REA and ERα, chromatin immunoprecipitation (ChIP), cycloheximide experiment, transfection with ERα domain mutants, HDAC inhibitor TSA treatment","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP + siRNA epistasis + domain mutagenesis, single lab","pmids":["19117054"],"is_preprint":false},{"year":2007,"finding":"Skp2B (an F-box protein) interacts with REA/PHB2 (identified by two-hybrid screen) and overexpression of Skp2B reduces REA protein levels in mammary glands of MMTV-Skp2B transgenic mice, inducing lobuloalveolar development in virgin females identical to that of REA heterozygote mice.","method":"Yeast two-hybrid screen, Western blot of REA levels in transgenic mammary glands, transgenic mouse phenotyping","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — 2-hybrid + in vivo transgenic model, limited biochemical mechanistic detail on how Skp2B reduces REA, single lab","pmids":["17785450"],"is_preprint":false},{"year":2015,"finding":"Estradiol activates ERα to recruit REA/PHB2 forming an ERα/REA complex that binds three estrogen response element (ERE) half-sites on the Rorγt promoter region, suppressing Rorγt expression and inhibiting Th17 differentiation; siRNA knockdown of Rea enhances Rorγt expression and Th17 differentiation.","method":"siRNA knockdown, ChIP (REA binding to RORγT promoter ERE sites), ERα/REA complex Co-IP, Th17 differentiation assays in mouse splenocytes","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + Co-IP + siRNA + functional differentiation assay, single lab","pmids":["25769926"],"is_preprint":false},{"year":2022,"finding":"OMA1 protease activity is regulated by the PHB2/STOML2 complex in ovarian cancer mitochondria; PHB2/STOML2 modulates OMA1-mediated cleavage of OPA1 and DELE1 during chemotherapy response.","method":"Knockdown experiments, Co-immunoprecipitation, OPA1/DELE1 cleavage assays, ovarian cancer cell lines and mouse subcutaneous tumor model","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP + knockdown, limited mechanistic detail on PHB2/STOML2 regulation of OMA1 in abstract, single lab","pmids":["35163244"],"is_preprint":false},{"year":2024,"finding":"Nrf2 directly binds the PHB2 promoter (confirmed by bioinformatic analysis and dual-luciferase reporter assay), increasing PHB2 transcription; PHB2 overexpression in SA-ALI elevates PHB2 on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division.","method":"Dual-luciferase reporter assay, Nrf2 overexpression in A549 cells, Western blot for mitochondrial vs. cytoplasmic PHB2, Nrf2 knockout mice","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — luciferase reporter (transcriptional regulation) + in vivo Nrf2 KO, single lab","pmids":["38077250"],"is_preprint":false}],"current_model":"PHB2 is a highly conserved inner mitochondrial membrane scaffold protein with multiple location-dependent functions: in mitochondria it acts as a direct mitophagy receptor by binding lipidated LC3 via an LIR motif (this interaction is enhanced by Parkin-mediated K11/K33 ubiquitination on K142/K200) and regulates the PINK1-Parkin pathway through a PARL-PGAM5-PINK1 axis; its mitochondrial retention and activity are governed by post-translational modifications including PGAM5-mediated dephosphorylation (at Ser91), c-Abl-mediated phosphorylation (at Y121), GALNT14-mediated O-glycosylation (at Ser161), and ubiquitin-proteasomal degradation; it stabilizes respiratory Complex I by binding NDUFS1/NDUFV2 to support oxidative phosphorylation; and it regulates mitochondrial morphology partly via OPA1; in the nucleus PHB2 functions as a corepressor of ERα (binding its ligand-binding domain in competition with SRC-1) and is regulated by the BIG3-KPNA-dependent nuclear import pathway, by EZH2 association, and by transcription factor interactions including FOXM1-driven transcription of PHB2 itself; in the cytoplasm it modulates signaling (hnRNPA1/PKM splicing, RACK1/Akt/FAK, SHIP2/NEDD4/PI3K-Akt, HKDC1/SP1) and is required for normal cell division by protecting centromeric cohesin from Plk1-mediated phosphorylation."},"narrative":{"mechanistic_narrative":"PHB2 is a highly conserved inner mitochondrial membrane scaffold protein that acts as a direct mitophagy receptor, binding lipidated LC3 (MAP1LC3B) through an LC3-interacting region (LIR) motif to mark damaged mitochondria for autophagosomal engulfment after outer-membrane rupture [PMID:28220775, PMID:29416008]; this receptor function is conserved to the yeast Phb1/Phb2 complex, which engages Atg8 via an analogous AIM/LIR motif and requires heterocomplex formation [PMID:38964378]. PHB2 is integral to the PINK1-Parkin axis: its presence stabilizes PINK1 by restraining the inner-membrane protease PARL and licenses Parkin recruitment, while Parkin reciprocally binds PHB2 and deposits K11/K33-linked ubiquitin on K142/K200 to strengthen the PHB2-LC3B interaction [PMID:31177901, PMID:36379251]. The receptor activity of PHB2 is tightly gated by post-translational modification at the inner membrane—PGAM5-mediated dephosphorylation controls its mitochondrial retention versus cytosolic translocation [PMID:39285950, PMID:37781037], c-Abl phosphorylation at Y121 blocks LC3 binding [PMID:36406767], and competitive binders such as protein disulfide isomerase displace LC3 from PHB2 [PMID:36202782]—and its abundance is set by ubiquitin-proteasomal turnover driven by multiple interactors [PMID:35152003, PMID:39737891]. Independently of mitophagy, PHB2 supports oxidative phosphorylation by binding the Complex I subunits NDUFS1 and NDUFV2 to stabilize Complex I assembly and activity [PMID:36658121, PMID:37451140]. In a spatially distinct role, PHB2 (originally identified as the repressor of estrogen activity, REA) is a corepressor of ERα: it binds the ERα ligand-binding domain via its C-terminal region and an N-terminal LXXLL motif, competing with the coactivator SRC-1 to repress estrogen-responsive transcription [PMID:10960470], a function established in vivo where REA gene dosage governs uterine estrogen responsiveness [PMID:15713652]. Its nuclear corepressor activity is controlled by cytoplasmic sequestration through BIG3 and karyopherin-dependent import [PMID:19496786, PMID:26052702]. PHB2 is also required for faithful chromosome segregation, protecting centromeric cohesin from premature Plk1-dependent dissociation during mitosis [PMID:17656096].","teleology":[{"year":2000,"claim":"Established PHB2/REA as a direct transcriptional corepressor of estrogen receptor alpha, defining its earliest molecular function in the nucleus.","evidence":"GST pull-down, deletion mapping, antisense knockdown, and ERE reporter assays delineating C-terminal ERα-binding region and N-terminal LXXLL motif","pmids":["10960470"],"confidence":"High","gaps":["Did not establish in vivo physiological relevance","Mechanism of how repression is enzymatically achieved unresolved"]},{"year":2005,"claim":"Demonstrated that REA/PHB2 is an essential gene and a dose-dependent physiological modulator of estrogen responsiveness in vivo, validating its corepressor role at the organismal level.","evidence":"Targeted gene disruption in mice; heterozygote phenotyping with uterine estrogen challenge and gene-expression analysis","pmids":["15713652"],"confidence":"High","gaps":["Embryonic lethality precluded analysis of homozygous adult function","Did not separate nuclear corepressor role from mitochondrial functions"]},{"year":2007,"claim":"Revealed a mitochondria-independent requirement for PHB2 in mitosis, showing it protects centromeric cohesion during chromosome segregation.","evidence":"RNAi in HeLa cells with immunofluorescence of cohesin/shugoshin and segregation analysis","pmids":["17656096"],"confidence":"High","gaps":["Direct molecular target protecting cohesin from Plk1 not identified","Subcellular pool of PHB2 responsible unclear"]},{"year":2009,"claim":"Defined the cytoplasmic sequestration mechanism controlling PHB2 nuclear access, explaining how its corepressor activity is regulated by estrogen signaling.","evidence":"siRNA of BIG3, Co-IP, nuclear/cytoplasmic fractionation and ERα reporter assays in breast cancer cells","pmids":["19496786"],"confidence":"Medium","gaps":["Single lab","Did not identify the import machinery (resolved later)"]},{"year":2015,"claim":"Identified the karyopherin-alpha import pathway delivering PHB2 to the nucleus, completing the spatial-control model for its corepressor function.","evidence":"siRNA of individual KPNAs, Co-IP, fractionation and immunofluorescence","pmids":["26052702"],"confidence":"Medium","gaps":["Redundancy among KPNA1/5/6 not fully dissected","Single lab"]},{"year":2017,"claim":"Identified PHB2 as the inner-membrane mitophagy receptor binding LC3, transforming understanding of how ruptured mitochondria are recognized by autophagosomes.","evidence":"Mechanistic cell biology defining a LIR motif mediating LC3 binding (foundational discovery)","pmids":["28220775"],"confidence":"High","gaps":["How inner-membrane PHB2 becomes accessible to LC3 only partially defined","Upstream regulation of receptor activity not yet mapped"]},{"year":2018,"claim":"Extended the LC3-receptor mechanism by showing PHB2 forms a ternary complex with SQSTM1/p62 and LC3 to drive mitophagy in a disease context.","evidence":"Co-IP, domain mapping and mitophagy assays in bile-acid-treated hepatocytes plus biliary atresia samples","pmids":["29416008"],"confidence":"Medium","gaps":["Single study","Relative contribution of p62 versus direct LC3 binding unresolved"]},{"year":2019,"claim":"Placed PHB2 mechanistically within the PINK1-Parkin pathway via a PARL-PGAM5-PINK1 axis, linking the receptor to canonical mitophagy signaling.","evidence":"siRNA/overexpression, immunofluorescence, Co-IP and genetic epistasis with PARL/PGAM5 in MEFs and cancer lines","pmids":["31177901"],"confidence":"High","gaps":["Direct biochemical control of PARL by PHB2 not reconstituted","Order of events relative to LC3 binding incompletely resolved"]},{"year":2022,"claim":"Showed that Parkin ubiquitinates PHB2 itself (K11/K33 on K142/K200), establishing inner-membrane ubiquitination as a step that enhances the receptor's LC3 binding.","evidence":"In vitro ubiquitination assays with linkage/site specification, domain mapping, Co-IP and LC3B binding assays","pmids":["36379251"],"confidence":"High","gaps":["Stoichiometry and dynamics in vivo unknown","Deubiquitinase counteracting this modification not identified"]},{"year":2022,"claim":"Defined phosphorylation as a master switch for PHB2 mitochondrial retention and receptor activity through PGAM5 dephosphorylation and c-Abl phosphorylation.","evidence":"Phosphodefective/phosphomimetic mutants (S91, Y121), Co-IP, knockin and KO mouse models in cardiomyocytes and PD models","pmids":["39285950","37781037","36406767"],"confidence":"High","gaps":["Interplay between S91 and Y121 modification not jointly tested","Kinase/phosphatase balance under physiological stress incompletely mapped"]},{"year":2023,"claim":"Established a direct bioenergetic role for PHB2 in stabilizing respiratory Complex I, distinct from its mitophagy receptor function.","evidence":"Co-IP, mass spectrometry, co-localization, knockdown/overexpression with Complex I activity assays and cardiac conditional KO mice for NDUFS1/NDUFV2 binding","pmids":["36658121","37451140"],"confidence":"Medium","gaps":["Structural basis of Complex I stabilization unresolved","Whether scaffold and receptor roles are mechanistically coupled unknown"]},{"year":2024,"claim":"Showed PHB2 abundance is governed by post-translational modification-coupled degradation, identifying lactylation-driven and other ubiquitin-dependent routes that tune mitophagy capacity.","evidence":"IP-MS, site mutagenesis (ALDH2-K52R), ubiquitination assays, TIPE1 KO and SIRT3 modulation in AKI mouse models","pmids":["39737891","35152003"],"confidence":"Medium","gaps":["Direct E3 ligase(s) for PHB2 in each context not fully defined","Single-lab findings per modification"]},{"year":2024,"claim":"Mapped diverse cytoplasmic signaling roles in which PHB2 sequestration or interaction reprograms metabolism and growth signaling in cancer and vascular cells.","evidence":"Co-IP/MS, domain mapping, ubiquitination assays, and in vivo models for hnRNPA1/PKM splicing, RACK1/Akt-FAK, SHIP2/NEDD4/PI3K-Akt, and HKDC1/SP1 axes","pmids":["36200440","33537079","38200519","39375512"],"confidence":"Medium","gaps":["These cytoplasmic interactions are each single-study","Relationship to PHB2's mitochondrial pool unclear"]},{"year":2024,"claim":"Demonstrated transcriptional control of PHB2 itself by FOXM1 and Nrf2, defining how cellular stress sets PHB2 levels and mitophagy capacity.","evidence":"ChIP, dual-luciferase reporter assays, Co-IP and Nrf2/FOXM1 modulation in tumor and lung-injury models","pmids":["33754036","38077250","30779914"],"confidence":"Medium","gaps":["Quantitative contribution of each transcription factor in normal physiology unknown","Cross-regulation between transcriptional and post-translational control unmapped"]},{"year":null,"claim":"How PHB2's distinct pools—inner-membrane mitophagy receptor, Complex I scaffold, nuclear ERα corepressor, mitotic cohesion factor, and cytoplasmic signaling adaptor—are coordinated within a single cell and whether they share an underlying structural mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking the location-dependent functions","Determinants partitioning PHB2 among compartments not defined","Whether functions are mutually regulated is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,36,37,39]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,13,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,6,7,31]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,6,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,10,11,36]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,27,28,29]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,36,37,39]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,27,29]}],"complexes":["PHB1/PHB2 prohibitin complex","Mitochondrial respiratory Complex I","PHB2/STOML2 complex"],"partners":["MAP1LC3B","PRKN","PGAM5","PARL","NDUFS1","NDUFV2","ESR1","BIG3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99623","full_name":"Prohibitin-2","aliases":["B-cell receptor-associated protein BAP37","D-prohibitin","Repressor of estrogen receptor activity"],"length_aa":299,"mass_kda":33.3,"function":"Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors and sex steroid hormones in the nucleus In the mitochondria, together with PHB, forms large ring complexes (prohibitin complexes) in the inner mitochondrial membrane (IMM) and functions as a chaperone protein that stabilizes mitochondrial respiratory enzymes and maintains mitochondrial integrity in the IMM, which is required for mitochondrial morphogenesis, neuronal survival, and normal lifespan (Probable). The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner (By similarity). Also regulates cytochrome-c oxidase assembly (COX) and mitochondrial respiration (PubMed:11302691, PubMed:20959514). Binding to sphingoid 1-phosphate (SPP) modulates its regulator activity (PubMed:11302691, PubMed:20959514). Has a key role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (PubMed:28017329). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117) In the nucleus, serves as transcriptional co-regulator (Probable). Acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases. Functions as an estrogen receptor (ER)-selective coregulator that potentiates the inhibitory activities of antiestrogens and represses the activity of estrogens. Competes with NCOA1 for modulation of ER transcriptional activity (By similarity) In the plasma membrane, is involved in IGFBP6-induced cell migration (PubMed:24003225). Cooperates with CD86 to mediate CD86-signaling in B lymphocytes that regulates the level of IgG1 produced through the activation of distal signaling intermediates. Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity) (Microbial infection) Involved in human enterovirus 71/EV-71 infection by enhancing the autophagy mechanism during the infection","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q99623/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PHB2","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PHGDH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHB2","total_profiled":1310},"omim":[{"mim_id":"617411","title":"ADP-RIBOSYLATION FACTOR GUANINE NUCLEOTIDE EXCHANGE FACTOR 3; ARFGEF3","url":"https://www.omim.org/entry/617411"},{"mim_id":"617081","title":"OMA1 ZINC METALLOPEPTIDASE; OMA1","url":"https://www.omim.org/entry/617081"},{"mim_id":"616254","title":"CASEINOLYTIC PEPTIDASE B; CLPB","url":"https://www.omim.org/entry/616254"},{"mim_id":"615642","title":"SMALL CAJAL BODY-SPECIFIC RNA 12; SCARNA12","url":"https://www.omim.org/entry/615642"},{"mim_id":"614461","title":"UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX ASSEMBLY FACTOR 2; UQCC2","url":"https://www.omim.org/entry/614461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHB2"},"hgnc":{"alias_symbol":["REA","BCAP37","Bap37","p22"],"prev_symbol":[]},"alphafold":{"accession":"Q99623","domains":[{"cath_id":"3.30.479.30","chopping":"85-189","consensus_level":"high","plddt":92.853,"start":85,"end":189},{"cath_id":"-","chopping":"221-296","consensus_level":"medium","plddt":81.9688,"start":221,"end":296},{"cath_id":"2.30.30","chopping":"40-84","consensus_level":"medium","plddt":86.644,"start":40,"end":84}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99623","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99623-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99623-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHB2","jax_strain_url":"https://www.jax.org/strain/search?query=PHB2"},"sequence":{"accession":"Q99623","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99623.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99623/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99623"}},"corpus_meta":[{"pmid":"24710105","id":"PMC_24710105","title":"CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24710105","citation_count":403,"is_preprint":false},{"pmid":"31177901","id":"PMC_31177901","title":"PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31177901","citation_count":342,"is_preprint":false},{"pmid":"30890112","id":"PMC_30890112","title":"Mitophagy Reduces Oxidative Stress Via Keap1 (Kelch-Like Epichlorohydrin-Associated Protein 1)/Nrf2 (Nuclear Factor-E2-Related Factor 2)/PHB2 (Prohibitin 2) Pathway After Subarachnoid Hemorrhage in Rats.","date":"2019","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/30890112","citation_count":148,"is_preprint":false},{"pmid":"31903127","id":"PMC_31903127","title":"Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31903127","citation_count":123,"is_preprint":false},{"pmid":"10960470","id":"PMC_10960470","title":"Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity (REA) and the regulation of estrogen receptor transcriptional activity by REA.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10960470","citation_count":109,"is_preprint":false},{"pmid":"10634704","id":"PMC_10634704","title":"Listeria monocytogenes in pork slaughtering and cutting plants. 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the finding is reviewed/summarized in this commentary citing the original Wei et al. discovery paper\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — discovery independently replicated across multiple labs and organisms; referenced as foundational in numerous subsequent papers\",\n      \"pmids\": [\"28220775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHB2 promotes PINK1-Parkin-dependent mitophagy via the PARL-PGAM5-PINK1 axis: PHB2 depletion destabilizes PINK1 at mitochondria by activating the inner membrane protease PARL, blocking PRKN/Parkin recruitment and ubiquitin/OPTN accumulation; PHB2 overexpression directly induces Parkin recruitment.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence, Co-IP; genetic epistasis with PARL and PGAM5 in mouse embryo fibroblasts and cancer cell lines\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, epistasis, multiple cell models, single lab with several orthogonal methods\",\n      \"pmids\": [\"31177901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHB2 directly binds the autophagosomal protein LC3 via an LIR domain upon mitochondrial damage, and also forms a ternary complex with SQSTM1 (p62) and LC3, promoting LC3 loading onto damaged mitochondria during cholestasis-induced mitophagy in hepatocytes.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, cell-based mitophagy assays in hepatocytes treated with bile acids; in vivo biliary atresia liver samples\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and domain analysis in single lab, mechanistic follow-up limited to one study\",\n      \"pmids\": [\"29416008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Parkin (PRKN) directly binds PHB2 through its RING1 domain and promotes K11- and K33-linked ubiquitination on PHB2 K142/K200 residues, enhancing PHB2–LC3B interaction and efficient mitophagy; this establishes inner mitochondrial membrane ubiquitination as a step in Parkin-mediated mitophagy.\",\n      \"method\": \"Molecular, cellular, and biochemical approaches including domain-deletion mutagenesis, ubiquitination assays specifying linkage type and sites, Co-IP, and LC3B binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination assay with site mutagenesis, domain mapping, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36379251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PGAM5 (mitochondrial Ser/Thr phosphatase) dephosphorylates PHB2 on Ser91; phosphodefective PHB2-S91A impairs mitochondrial quality surveillance (fission/fusion, mitophagy, biogenesis) under hyperglycemia, whereas phosphomimetic PHB2-S91D is protective, establishing PHB2 Ser91 phosphorylation as critical for mitochondrial homeostasis in diabetic cardiomyopathy.\",\n      \"method\": \"Co-immunoprecipitation, phosphodefective/phosphomimetic PHB2 mutant transfection in cardiomyocytes, cardiomyocyte-specific Pgam5 knockout mice, PHB2-S91D knockin mice\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis combined with in vivo knockin mouse model and multiple cellular assays in single rigorous study\",\n      \"pmids\": [\"39285950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHB2 maintains the contractile phenotype of vascular smooth muscle cells (VSMCs) by directly interacting (via its C-terminus) with hnRNPA1, a key modulator of PKM1/2 mRNA splicing, thereby suppressing PKM2 expression and glycolysis; PHB2 deficiency shifts PKM splicing toward PKM2, enhancing glycolysis and promoting the synthetic VSMC phenotype and neointima formation.\",\n      \"method\": \"RNA-seq, protein interactome analysis, Co-immunoprecipitation, mammalian 2-hybrid assay, carotid artery injury model, collagen gel contraction and wire myography assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mammalian 2-hybrid, in vivo model, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36200440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHB2 directly interacts with NDUFS1 (Complex I subunit) in mitochondria and facilitates NDUFS1 binding to NDUFV1, stabilizing Complex I activity and enhancing oxidative phosphorylation to promote CRC cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, co-localization (immunofluorescence), siRNA knockdown, PHB2 overexpression with Complex I activity assays in CRC and normal intestinal epithelial cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + MS identification + functional rescue, single lab\",\n      \"pmids\": [\"36658121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHB2 interacts with NDUFV2 (mitochondrial Complex I subunit V2) via Co-IP; PHB2 promotes NDUFV2 stabilization, and PHB2 deficiency impairs mitochondrial bioenergetics and oxidative phosphorylation in doxorubicin-challenged hearts.\",\n      \"method\": \"Proteomic profiling, bioinformatic analysis, Co-immunoprecipitation, pulldown assays, cardiac-specific PHB2 conditional knockout mice\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proteomic screen + Co-IP validation + in vivo KO phenotype, single lab\",\n      \"pmids\": [\"37451140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BIG3 (ARFGEF3) traps PHB2/REA in the cytoplasm, preventing its estrogen-stimulated nuclear translocation; when BIG3 is knocked down, estradiol causes PHB2/REA translocation to the nucleus where it interacts with ERα and suppresses ERα transcriptional activity.\",\n      \"method\": \"siRNA knockdown of BIG3, Co-immunoprecipitation, immunoblotting of nuclear/cytoplasmic fractions, ERα transcriptional activity assays in breast cancer cells\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + fractionation + transcriptional reporter, single lab\",\n      \"pmids\": [\"19496786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHB2 released from BIG3 by the cell-permeable peptide ERAP directly binds both nuclear and membrane-associated ERα, inhibiting multiple ERα-signalling pathways (genomic and non-genomic ERα activation and ERα phosphorylation) and suppressing tamoxifen resistance in ERα-positive breast cancer cells in vitro and in vivo.\",\n      \"method\": \"Cell-permeable peptide inhibitor (ERAP), Co-immunoprecipitation, Western blot for ERα signalling intermediates, in vitro proliferation assays, xenograft in vivo models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical tool + Co-IP + in vitro and in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24051437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PHB2 nuclear import upon estradiol stimulation is mediated by karyopherin alpha proteins KPNA1, KPNA5, and KPNA6; BIG3 blocks the KPNA-binding region(s) of PHB2 to prevent this nuclear translocation.\",\n      \"method\": \"siRNA knockdown of individual KPNAs, Co-immunoprecipitation, subcellular fractionation, immunofluorescence in breast cancer cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple Co-IP + siRNA epistasis, single lab\",\n      \"pmids\": [\"26052702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"REA (PHB2) binds the ligand-binding domain (E domain) of ERα via a region in the C-terminal half of REA; this interaction competes with coactivator SRC-1 for ER binding; the LXXLL motif near REA N-terminus is required for competitive binding with SRC-1 but not for direct ER binding; loss of LXXLL impairs optimal repression of ER activity.\",\n      \"method\": \"GST pull-down assays, deletion mutant mapping, antisense RNA knockdown, transactivation assays with estrogen response element reporters\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro pull-down with systematic mutagenesis/deletion mapping + functional reporter assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"10960470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EZH2 (histone methyltransferase) associates with REA/PHB2 (Co-immunoprecipitation); EZH2 represses estrogen-dependent transcription and this repression is mutually dependent on REA, suggesting EZH2 is recruited to estrogen-regulated target genes via its interaction with the ER corepressor REA.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays for estrogen-dependent transcription, siRNA knockdown\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + reporter assays, single lab, single study\",\n      \"pmids\": [\"17453341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"REA/PHB2 directly interacts with TRPM6 (at the 6th, 7th, and 8th β-sheets of TRPM6's α-kinase domain), inhibits TRPM6 channel activity in a phosphorylation-dependent manner (no effect on kinase-dead K1804R TRPM6), and this interaction is dynamically disrupted by short-term 17β-estradiol treatment, leading to increased TRPM6-mediated Mg2+ current.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology (channel activity assays), site-directed mutagenesis (K1804R), PKC activation/inhibition, estradiol treatment in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis, Co-IP domain mapping, pharmacological dissection, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19329436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PHB2 depletion by RNAi in HeLa cells causes premature sister-chromatid separation and defects in chromosome congression with mitotic arrest; cohesin is dissociated from centromeres during early mitosis in the absence of PHB2, even though centromeric shugoshin localization is preserved, indicating PHB2 protects centromeric cohesion against Plk1-mediated phosphorylation.\",\n      \"method\": \"RNAi knockdown in HeLa cells, immunofluorescence for cohesin and shugoshin localization, chromosome segregation analysis, spindle checkpoint activation assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi with defined molecular phenotype (cohesin localization) and epistasis with shugoshin pathway, well-controlled single study\",\n      \"pmids\": [\"17656096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Akt2 (but not Akt1) specifically binds PHB2/REA (Co-immunoprecipitation of endogenous proteins, Akt2-REA complex does not contain PHB1); Akt2 promotes myogenic differentiation inversely correlated with PHB2 levels; Akt2 overexpression reduces PHB2 protein and siRNA knockdown of Akt2 increases PHB2/REA levels.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, siRNA silencing of Akt1 vs. Akt2, overexpression in C2 myoblasts and fibroblasts, immunofluorescence colocalization\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal endogenous Co-IP + siRNA phenotype, single lab\",\n      \"pmids\": [\"17565718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PHB2 interacts with RNF2 (polycomb protein); RNF2 represses CP2c-stimulated transcription in a PHB2 dose-dependent manner; RNF2 residues 1–158 are sufficient for association with PHB2; PHB2 and CP2c bind to N- and C-termini of RNF2 respectively; the PHB2-RNF2 complex modulates CP2-mediated alpha-globin gene expression.\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, RNF2 deletion mutant mapping, luciferase reporter assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast 2-hybrid + Co-IP + functional reporter, single lab\",\n      \"pmids\": [\"18629613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIPE1 interacts with PHB2 (identified by mass spectrometry screening and confirmed by Co-immunoprecipitation) and promotes the ubiquitination and proteasomal degradation of PHB2, thereby impairing PHB2-dependent mitophagy and causing mitochondrial dysfunction in renal tubular epithelial cells under high glucose.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, ubiquitination assays, Tipe1 conditional knockout mice, siRNA knockdown of PHB2 for rescue experiments\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification + Co-IP + ubiquitination assay + in vivo KO + rescue, single lab\",\n      \"pmids\": [\"35152003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BI1 (Bax inhibitor-1) directly interacts with cytoplasmic PHB2 via its C-terminus and the PHB domain of PHB2, promoting PHB2 retention/import into mitochondria; PHB2 knockdown abolishes the mitochondrial-protective and renal-protective effects of BI1 in acute kidney injury.\",\n      \"method\": \"Domain deletion assay, Co-immunoprecipitation, immunofluorescence, BI1 transgenic mice, siRNA knockdown of PHB2 for rescue, mitochondrial fractionation\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping + Co-IP + in vivo transgenic + rescue with PHB2 siRNA, single lab\",\n      \"pmids\": [\"31903127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHB2 interaction with GOLPH3 (Golgi phosphorylation protein 3) recruits PHB2 and LC3-II to promote autophagy/mitophagy in glioma cells; PHB2 knockdown abolishes the GOLPH3-induced autophagy stimulation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, autophagy flux assays in glioma cells and tissues\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP + knockdown phenotype, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"34094672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The small molecule YL-939 binds PHB2 (identified by chemical proteomics); YL-939 binding to PHB2 promotes ferritin expression, reduces intracellular iron content, and thereby decreases susceptibility to ferroptosis via the PHB2/ferritin/iron axis.\",\n      \"method\": \"Chemical proteomics (target identification), Western blot for ferritin, iron content measurements, ferroptosis cell death assays, acute liver injury model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics target ID + functional validation in cells and in vivo, multiple assays, single lab\",\n      \"pmids\": [\"36463308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXM1 transcriptionally regulates PHB2 expression by binding to the PHB2 promoter; PINT87aa peptide binds the DNA-binding domain of FOXM1 (verified by Co-IP and co-localization) and blocks FOXM1-mediated PHB2 transcription, reducing mitophagy and inducing cellular senescence in HCC.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, in vitro and in vivo tumor models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + luciferase + Co-IP + rescue assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33754036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GALNT14 O-glycosylates PHB2 at serine-161 (identified by comparative lectin-capture glycoproteomics, confirmed by site-directed mutagenesis); this O-glycosylation is required for increased PHB2–IGFBP6 interaction and subsequent IGF1R-mediated signaling activation promoting HCC growth, migration, and drug resistance.\",\n      \"method\": \"Comparative lectin-capture glycoproteomic approach, site-directed mutagenesis (S161A), Co-immunoprecipitation, functional proliferation/migration assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — glycoproteomic identification + site mutagenesis + Co-IP + functional rescue, single lab\",\n      \"pmids\": [\"36376274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"c-Abl (nonreceptor tyrosine kinase) phosphorylates PHB2 at tyrosine Y121; phosphomimetic substitution Y121D of PHB2 impairs PHB2–LC3 interaction in vitro, blocking mitophagy; c-Abl activation increases interaction with PHB2 and reduces PHB2–LC3 co-localization in MPP+-treated cells.\",\n      \"method\": \"PHB2 tyrosine phosphorylation site mutagenesis (Y121D), Co-immunoprecipitation, immunofluorescence, c-Abl inhibitor STI571 in cell and mouse PD models\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — site mutagenesis establishing Y121 as key phosphorylation site affecting LC3 binding, single lab, partially validated in vivo\",\n      \"pmids\": [\"36406767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Protein disulfide isomerase (PDI) directly interacts with PHB2 in mitochondria and competitively blocks the LC3II–PHB2 interaction, thereby inhibiting mitophagy signaling and reducing radio/chemo-sensitivity in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, competition binding assays, autophagy flux assays, colorectal cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + competition assay + functional mitophagy readout, single lab\",\n      \"pmids\": [\"36202782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHB2 functions as a chaperone for the transcription factor Hes1 outside the nucleus; the small molecule JI051 binds PHB2 (identified by immunomagnetic isolation and LC-MS/MS) and stabilizes PHB2's interaction with Hes1, sequestering Hes1 outside the nucleus, inducing G2/M arrest and reducing cell growth.\",\n      \"method\": \"Immunomagnetic isolation + nanoscale LC-MS/MS (target ID), cell proliferation assays, G2/M cell cycle analysis, pancreatic tumor xenograft model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — chemical proteomics target identification + functional cell/in vivo validation, single lab\",\n      \"pmids\": [\"29523683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALDH2 lactylation at K52 promotes ubiquitination-dependent proteasomal degradation of PHB2 (interaction identified by immunoprecipitation-mass spectrometry); loss of PHB2 inhibits mitophagy and worsens mitochondrial dysfunction in AKI; ALDH2-K52R mutation or SIRT3 upregulation reduces ALDH2 lactylation, stabilizes PHB2, and restores mitophagy.\",\n      \"method\": \"IP-mass spectrometry (interaction), K52R mutagenesis, SIRT3 modulation, ubiquitination assays, mouse AKI model with adeno-associated virus\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS + site mutagenesis + in vivo mouse model + rescue, multiple methods, single lab\",\n      \"pmids\": [\"39737891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHB2 directly interacts with PHB domain of RACK1 in NSCLC cells (Co-immunoprecipitation + mass spectrometry), stabilizes RACK1 via posttranslational modification, and activates downstream Akt and FAK pathways to promote proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, siRNA knockdown, PHB2 overexpression, in vivo tumor model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + MS + functional rescue, single lab\",\n      \"pmids\": [\"33537079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HKDC1 sequesters PHB2 in the cytoplasm (interaction demonstrated by Co-IP), disabling PHB2's suppressive effect on the transcription factor SP1 and promoting expression of pro-oncogenic genes; glucose depletion or HKDC1 knockout releases PHB2, suppressing cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockout, SP1 transcriptional assays, glucose-starvation experiments in cancer cell lines\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + KO + transcriptional readout, single lab\",\n      \"pmids\": [\"39375512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PHB2 physically interacts with SHIP2 in the cytoplasm of gastric cancer cells; PHB2 promotes SHIP2 ubiquitination and degradation via the E3 ligase NEDD4, activating PI3K/Akt signaling and driving gastric cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, deletion mapping, cycloheximide chase, ubiquitination assays, in vivo GC xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP + GST pulldown + ubiquitination assay + in vivo, single lab\",\n      \"pmids\": [\"38200519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Co-immunoprecipitation demonstrated a direct interaction between Nrf2 and PHB2 in brain tissue; MitoQ increases Nrf2 binding to PHB2 and elevates PHB2/OPA1 in the mitochondrial fraction, promoting mitochondrial fusion and reducing blood-brain barrier disruption after SAH; PHB2 siRNA reverses these effects.\",\n      \"method\": \"Co-immunoprecipitation, Western blot of mitochondrial fractions, PHB2 siRNA, Nrf2 inhibitor ML385, transmission electron microscopy in rat SAH model\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP interaction + in vivo siRNA rescue, single lab, animal model\",\n      \"pmids\": [\"30779914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Yeast Phb1 and Phb2 (S. cerevisiae orthologs) function as Atg8 (LC3) receptors for mitophagy via a conserved AIM/LIR-like motif; both require complex formation with each other; they also negatively regulate Atg32 processing via the rhomboid protease Pcp1 (PARL ortholog).\",\n      \"method\": \"Genetic deletion/complementation, AIM/LIR motif mutagenesis, Co-immunoprecipitation with Atg8, mitochondrial co-localization, mitophagy flux assays in S. cerevisiae\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — motif mutagenesis + Co-IP + genetic epistasis with Yme1 and Pcp1 + functional mitophagy assay, multiple methods in single rigorous study\",\n      \"pmids\": [\"38964378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHB2 directly interacts with PGAM5 (confirmed by Co-IP and immunoblot); PGAM5 dephosphorylates PHB2, causing its cytosolic translocation from mitochondria; silencing Pgam5 or expressing phosphomimetic PHB2 mutant prevents mitochondrial PHB2 loss and activates mitophagy/UPRmt in LPS-challenged cardiomyocytes.\",\n      \"method\": \"Co-immunoprecipitation, immunoblot, PHB2 phosphomimetic mutant transfection, Pgam5 siRNA, cardiomyocyte-specific Pgam5 KO mice\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + phosphomimetic mutagenesis + in vivo KO, multiple methods, single lab\",\n      \"pmids\": [\"37781037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"L-carnitine enhances PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction; CPT1a (activated by L-carnitine) directly binds PHB2 (Co-IP) and modulates the PHB2-PARL interaction; PARL overexpression inhibits mitophagy and abolishes L-carnitine's protective effects on cardiac microvascular function in diabetic cardiomyopathy.\",\n      \"method\": \"Co-immunoprecipitation of CPT1a with PHB2, CPT1a mutation (M593S), PARL overexpression via AAV, db/db mouse model, endothelial cell high glucose/FFA injury model\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + site mutagenesis + in vivo mouse model + rescue, single lab\",\n      \"pmids\": [\"37042471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EV-A71 VP1 C-terminus (aa 251-297) interacts with PHB2 (identified by mass spectrometry, verified by Co-IP); PHB2 knockdown reduces EV-A71 replication, viral particle release, and viral protein synthesis, and inhibits autophagy, indicating PHB2 is required for VP1-induced autophagy and viral infectivity.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, PHB2 siRNA knockdown, viral replication assays, autophagy flux assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MS + Co-IP + siRNA rescue, single lab\",\n      \"pmids\": [\"32276428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PHB2 promotes DHA-inhibited RCHY1 upregulation: PHB2 interacts with and stabilizes RCHY1 (E3 ubiquitin ligase), leading to p53 and p21 downregulation in colon cancer; DHA degrades PHB2 via ubiquitylation-dependent pathway, blocking PHB2-RCHY1-p53 axis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, PHB2 overexpression/knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP + ubiquitination assay + in vivo tumor model, single lab\",\n      \"pmids\": [\"36342357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Genetic deletion of both REA/PHB2 alleles in mice is embryonic lethal; REA heterozygous animals have half normal REA protein levels and display greater uterine weight gain, epithelial hyperproliferation in response to estradiol, and substantially enhanced stimulation of estrogen-upregulated genes, as well as loss of estrogen-mediated gene repression, demonstrating REA is a significant physiological modulator of estrogen responsiveness in vivo.\",\n      \"method\": \"Targeted gene disruption (homologous recombination), heterozygous mouse phenotyping, uterine gene expression analysis, estrogen challenge assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic deletion with defined molecular and physiological phenotype, gene-dosage effect demonstrated, replicated in subsequent papers\",\n      \"pmids\": [\"15713652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"REA/PHB2 corepressor is required for estradiol-mediated downregulation of the tumor suppressor gene BTG2: ERα interacts with the BTG2 promoter in a ligand-independent manner, and depletion of REA by siRNA significantly abrogates E2-mediated BTG2 repression; ERα's DNA- and ligand-binding domains and HDAC activity are required for this regulation.\",\n      \"method\": \"siRNA knockdown of REA and ERα, chromatin immunoprecipitation (ChIP), cycloheximide experiment, transfection with ERα domain mutants, HDAC inhibitor TSA treatment\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP + siRNA epistasis + domain mutagenesis, single lab\",\n      \"pmids\": [\"19117054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Skp2B (an F-box protein) interacts with REA/PHB2 (identified by two-hybrid screen) and overexpression of Skp2B reduces REA protein levels in mammary glands of MMTV-Skp2B transgenic mice, inducing lobuloalveolar development in virgin females identical to that of REA heterozygote mice.\",\n      \"method\": \"Yeast two-hybrid screen, Western blot of REA levels in transgenic mammary glands, transgenic mouse phenotyping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — 2-hybrid + in vivo transgenic model, limited biochemical mechanistic detail on how Skp2B reduces REA, single lab\",\n      \"pmids\": [\"17785450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Estradiol activates ERα to recruit REA/PHB2 forming an ERα/REA complex that binds three estrogen response element (ERE) half-sites on the Rorγt promoter region, suppressing Rorγt expression and inhibiting Th17 differentiation; siRNA knockdown of Rea enhances Rorγt expression and Th17 differentiation.\",\n      \"method\": \"siRNA knockdown, ChIP (REA binding to RORγT promoter ERE sites), ERα/REA complex Co-IP, Th17 differentiation assays in mouse splenocytes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + Co-IP + siRNA + functional differentiation assay, single lab\",\n      \"pmids\": [\"25769926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OMA1 protease activity is regulated by the PHB2/STOML2 complex in ovarian cancer mitochondria; PHB2/STOML2 modulates OMA1-mediated cleavage of OPA1 and DELE1 during chemotherapy response.\",\n      \"method\": \"Knockdown experiments, Co-immunoprecipitation, OPA1/DELE1 cleavage assays, ovarian cancer cell lines and mouse subcutaneous tumor model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP + knockdown, limited mechanistic detail on PHB2/STOML2 regulation of OMA1 in abstract, single lab\",\n      \"pmids\": [\"35163244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nrf2 directly binds the PHB2 promoter (confirmed by bioinformatic analysis and dual-luciferase reporter assay), increasing PHB2 transcription; PHB2 overexpression in SA-ALI elevates PHB2 on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division.\",\n      \"method\": \"Dual-luciferase reporter assay, Nrf2 overexpression in A549 cells, Western blot for mitochondrial vs. cytoplasmic PHB2, Nrf2 knockout mice\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — luciferase reporter (transcriptional regulation) + in vivo Nrf2 KO, single lab\",\n      \"pmids\": [\"38077250\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHB2 is a highly conserved inner mitochondrial membrane scaffold protein with multiple location-dependent functions: in mitochondria it acts as a direct mitophagy receptor by binding lipidated LC3 via an LIR motif (this interaction is enhanced by Parkin-mediated K11/K33 ubiquitination on K142/K200) and regulates the PINK1-Parkin pathway through a PARL-PGAM5-PINK1 axis; its mitochondrial retention and activity are governed by post-translational modifications including PGAM5-mediated dephosphorylation (at Ser91), c-Abl-mediated phosphorylation (at Y121), GALNT14-mediated O-glycosylation (at Ser161), and ubiquitin-proteasomal degradation; it stabilizes respiratory Complex I by binding NDUFS1/NDUFV2 to support oxidative phosphorylation; and it regulates mitochondrial morphology partly via OPA1; in the nucleus PHB2 functions as a corepressor of ERα (binding its ligand-binding domain in competition with SRC-1) and is regulated by the BIG3-KPNA-dependent nuclear import pathway, by EZH2 association, and by transcription factor interactions including FOXM1-driven transcription of PHB2 itself; in the cytoplasm it modulates signaling (hnRNPA1/PKM splicing, RACK1/Akt/FAK, SHIP2/NEDD4/PI3K-Akt, HKDC1/SP1) and is required for normal cell division by protecting centromeric cohesin from Plk1-mediated phosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHB2 is a highly conserved inner mitochondrial membrane scaffold protein that acts as a direct mitophagy receptor, binding lipidated LC3 (MAP1LC3B) through an LC3-interacting region (LIR) motif to mark damaged mitochondria for autophagosomal engulfment after outer-membrane rupture [#0, #2]; this receptor function is conserved to the yeast Phb1/Phb2 complex, which engages Atg8 via an analogous AIM/LIR motif and requires heterocomplex formation [#31]. PHB2 is integral to the PINK1-Parkin axis: its presence stabilizes PINK1 by restraining the inner-membrane protease PARL and licenses Parkin recruitment, while Parkin reciprocally binds PHB2 and deposits K11/K33-linked ubiquitin on K142/K200 to strengthen the PHB2-LC3B interaction [#1, #3]. The receptor activity of PHB2 is tightly gated by post-translational modification at the inner membrane\\u2014PGAM5-mediated dephosphorylation controls its mitochondrial retention versus cytosolic translocation [#4, #32], c-Abl phosphorylation at Y121 blocks LC3 binding [#23], and competitive binders such as protein disulfide isomerase displace LC3 from PHB2 [#24]\\u2014and its abundance is set by ubiquitin-proteasomal turnover driven by multiple interactors [#17, #26]. Independently of mitophagy, PHB2 supports oxidative phosphorylation by binding the Complex I subunits NDUFS1 and NDUFV2 to stabilize Complex I assembly and activity [#6, #7]. In a spatially distinct role, PHB2 (originally identified as the repressor of estrogen activity, REA) is a corepressor of ER\\u03b1: it binds the ER\\u03b1 ligand-binding domain via its C-terminal region and an N-terminal LXXLL motif, competing with the coactivator SRC-1 to repress estrogen-responsive transcription [#11], a function established in vivo where REA gene dosage governs uterine estrogen responsiveness [#36]. Its nuclear corepressor activity is controlled by cytoplasmic sequestration through BIG3 and karyopherin-dependent import [#8, #10]. PHB2 is also required for faithful chromosome segregation, protecting centromeric cohesin from premature Plk1-dependent dissociation during mitosis [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established PHB2/REA as a direct transcriptional corepressor of estrogen receptor alpha, defining its earliest molecular function in the nucleus.\",\n      \"evidence\": \"GST pull-down, deletion mapping, antisense knockdown, and ERE reporter assays delineating C-terminal ER\\u03b1-binding region and N-terminal LXXLL motif\",\n      \"pmids\": [\"10960470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo physiological relevance\", \"Mechanism of how repression is enzymatically achieved unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that REA/PHB2 is an essential gene and a dose-dependent physiological modulator of estrogen responsiveness in vivo, validating its corepressor role at the organismal level.\",\n      \"evidence\": \"Targeted gene disruption in mice; heterozygote phenotyping with uterine estrogen challenge and gene-expression analysis\",\n      \"pmids\": [\"15713652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Embryonic lethality precluded analysis of homozygous adult function\", \"Did not separate nuclear corepressor role from mitochondrial functions\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a mitochondria-independent requirement for PHB2 in mitosis, showing it protects centromeric cohesion during chromosome segregation.\",\n      \"evidence\": \"RNAi in HeLa cells with immunofluorescence of cohesin/shugoshin and segregation analysis\",\n      \"pmids\": [\"17656096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target protecting cohesin from Plk1 not identified\", \"Subcellular pool of PHB2 responsible unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the cytoplasmic sequestration mechanism controlling PHB2 nuclear access, explaining how its corepressor activity is regulated by estrogen signaling.\",\n      \"evidence\": \"siRNA of BIG3, Co-IP, nuclear/cytoplasmic fractionation and ER\\u03b1 reporter assays in breast cancer cells\",\n      \"pmids\": [\"19496786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not identify the import machinery (resolved later)\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the karyopherin-alpha import pathway delivering PHB2 to the nucleus, completing the spatial-control model for its corepressor function.\",\n      \"evidence\": \"siRNA of individual KPNAs, Co-IP, fractionation and immunofluorescence\",\n      \"pmids\": [\"26052702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy among KPNA1/5/6 not fully dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified PHB2 as the inner-membrane mitophagy receptor binding LC3, transforming understanding of how ruptured mitochondria are recognized by autophagosomes.\",\n      \"evidence\": \"Mechanistic cell biology defining a LIR motif mediating LC3 binding (foundational discovery)\",\n      \"pmids\": [\"28220775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How inner-membrane PHB2 becomes accessible to LC3 only partially defined\", \"Upstream regulation of receptor activity not yet mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the LC3-receptor mechanism by showing PHB2 forms a ternary complex with SQSTM1/p62 and LC3 to drive mitophagy in a disease context.\",\n      \"evidence\": \"Co-IP, domain mapping and mitophagy assays in bile-acid-treated hepatocytes plus biliary atresia samples\",\n      \"pmids\": [\"29416008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Relative contribution of p62 versus direct LC3 binding unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed PHB2 mechanistically within the PINK1-Parkin pathway via a PARL-PGAM5-PINK1 axis, linking the receptor to canonical mitophagy signaling.\",\n      \"evidence\": \"siRNA/overexpression, immunofluorescence, Co-IP and genetic epistasis with PARL/PGAM5 in MEFs and cancer lines\",\n      \"pmids\": [\"31177901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical control of PARL by PHB2 not reconstituted\", \"Order of events relative to LC3 binding incompletely resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that Parkin ubiquitinates PHB2 itself (K11/K33 on K142/K200), establishing inner-membrane ubiquitination as a step that enhances the receptor's LC3 binding.\",\n      \"evidence\": \"In vitro ubiquitination assays with linkage/site specification, domain mapping, Co-IP and LC3B binding assays\",\n      \"pmids\": [\"36379251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics in vivo unknown\", \"Deubiquitinase counteracting this modification not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined phosphorylation as a master switch for PHB2 mitochondrial retention and receptor activity through PGAM5 dephosphorylation and c-Abl phosphorylation.\",\n      \"evidence\": \"Phosphodefective/phosphomimetic mutants (S91, Y121), Co-IP, knockin and KO mouse models in cardiomyocytes and PD models\",\n      \"pmids\": [\"39285950\", \"37781037\", \"36406767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between S91 and Y121 modification not jointly tested\", \"Kinase/phosphatase balance under physiological stress incompletely mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a direct bioenergetic role for PHB2 in stabilizing respiratory Complex I, distinct from its mitophagy receptor function.\",\n      \"evidence\": \"Co-IP, mass spectrometry, co-localization, knockdown/overexpression with Complex I activity assays and cardiac conditional KO mice for NDUFS1/NDUFV2 binding\",\n      \"pmids\": [\"36658121\", \"37451140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of Complex I stabilization unresolved\", \"Whether scaffold and receptor roles are mechanistically coupled unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PHB2 abundance is governed by post-translational modification-coupled degradation, identifying lactylation-driven and other ubiquitin-dependent routes that tune mitophagy capacity.\",\n      \"evidence\": \"IP-MS, site mutagenesis (ALDH2-K52R), ubiquitination assays, TIPE1 KO and SIRT3 modulation in AKI mouse models\",\n      \"pmids\": [\"39737891\", \"35152003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct E3 ligase(s) for PHB2 in each context not fully defined\", \"Single-lab findings per modification\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped diverse cytoplasmic signaling roles in which PHB2 sequestration or interaction reprograms metabolism and growth signaling in cancer and vascular cells.\",\n      \"evidence\": \"Co-IP/MS, domain mapping, ubiquitination assays, and in vivo models for hnRNPA1/PKM splicing, RACK1/Akt-FAK, SHIP2/NEDD4/PI3K-Akt, and HKDC1/SP1 axes\",\n      \"pmids\": [\"36200440\", \"33537079\", \"38200519\", \"39375512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"These cytoplasmic interactions are each single-study\", \"Relationship to PHB2's mitochondrial pool unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated transcriptional control of PHB2 itself by FOXM1 and Nrf2, defining how cellular stress sets PHB2 levels and mitophagy capacity.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter assays, Co-IP and Nrf2/FOXM1 modulation in tumor and lung-injury models\",\n      \"pmids\": [\"33754036\", \"38077250\", \"30779914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each transcription factor in normal physiology unknown\", \"Cross-regulation between transcriptional and post-translational control unmapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHB2's distinct pools\\u2014inner-membrane mitophagy receptor, Complex I scaffold, nuclear ER\\u03b1 corepressor, mitotic cohesion factor, and cytoplasmic signaling adaptor\\u2014are coordinated within a single cell and whether they share an underlying structural mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking the location-dependent functions\", \"Determinants partitioning PHB2 among compartments not defined\", \"Whether functions are mutually regulated is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 36, 37, 39]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 13, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 6, 7, 31]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0, 3, 4, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 10, 11, 36]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 27, 28, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 36, 37, 39]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 27, 29]}\n    ],\n    \"complexes\": [\n      \"PHB1/PHB2 prohibitin complex\",\n      \"Mitochondrial respiratory Complex I\",\n      \"PHB2/STOML2 complex\"\n    ],\n    \"partners\": [\n      \"MAP1LC3B\",\n      \"PRKN\",\n      \"PGAM5\",\n      \"PARL\",\n      \"NDUFS1\",\n      \"NDUFV2\",\n      \"ESR1\",\n      \"BIG3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}