Affinage

PHB2

Prohibitin-2 · UniProt Q99623

Length
299 aa
Mass
33.3 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    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

    PMID:10960470

    Open questions at the time
    • Did not establish in vivo physiological relevance
    • Mechanism of how repression is enzymatically achieved unresolved
  2. 2005 High

    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

    PMID:15713652

    Open questions at the time
    • Embryonic lethality precluded analysis of homozygous adult function
    • Did not separate nuclear corepressor role from mitochondrial functions
  3. 2007 High

    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

    PMID:17656096

    Open questions at the time
    • Direct molecular target protecting cohesin from Plk1 not identified
    • Subcellular pool of PHB2 responsible unclear
  4. 2009 Medium

    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

    PMID:19496786

    Open questions at the time
    • Single lab
    • Did not identify the import machinery (resolved later)
  5. 2015 Medium

    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

    PMID:26052702

    Open questions at the time
    • Redundancy among KPNA1/5/6 not fully dissected
    • Single lab
  6. 2017 High

    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)

    PMID:28220775

    Open questions at the time
    • How inner-membrane PHB2 becomes accessible to LC3 only partially defined
    • Upstream regulation of receptor activity not yet mapped
  7. 2018 Medium

    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

    PMID:29416008

    Open questions at the time
    • Single study
    • Relative contribution of p62 versus direct LC3 binding unresolved
  8. 2019 High

    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

    PMID:31177901

    Open questions at the time
    • Direct biochemical control of PARL by PHB2 not reconstituted
    • Order of events relative to LC3 binding incompletely resolved
  9. 2022 High

    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

    PMID:36379251

    Open questions at the time
    • Stoichiometry and dynamics in vivo unknown
    • Deubiquitinase counteracting this modification not identified
  10. 2022 High

    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

    PMID:36406767 PMID:37781037 PMID:39285950

    Open questions at the time
    • Interplay between S91 and Y121 modification not jointly tested
    • Kinase/phosphatase balance under physiological stress incompletely mapped
  11. 2023 Medium

    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

    PMID:36658121 PMID:37451140

    Open questions at the time
    • Structural basis of Complex I stabilization unresolved
    • Whether scaffold and receptor roles are mechanistically coupled unknown
  12. 2024 Medium

    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

    PMID:35152003 PMID:39737891

    Open questions at the time
    • Direct E3 ligase(s) for PHB2 in each context not fully defined
    • Single-lab findings per modification
  13. 2024 Medium

    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

    PMID:33537079 PMID:36200440 PMID:38200519 PMID:39375512

    Open questions at the time
    • These cytoplasmic interactions are each single-study
    • Relationship to PHB2's mitochondrial pool unclear
  14. 2024 Medium

    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

    PMID:30779914 PMID:33754036 PMID:38077250

    Open questions at the time
    • Quantitative contribution of each transcription factor in normal physiology unknown
    • Cross-regulation between transcriptional and post-translational control unmapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 4 GO:0005829 cytosol 4
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9612973 Autophagy 4 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 1
Partners
BIG3ESR1MAP1LC3BNDUFS1NDUFV2PARLPGAM5PRKN
Complex memberships
Mitochondrial respiratory Complex IPHB1/PHB2 prohibitin complexPHB2/STOML2 complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 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. Mechanistic cell biology; the finding is reviewed/summarized in this commentary citing the original Wei et al. discovery paper Cell research High 28220775
2019 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. siRNA knockdown, overexpression, immunofluorescence, Co-IP; genetic epistasis with PARL and PGAM5 in mouse embryo fibroblasts and cancer cell lines Autophagy High 31177901
2018 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. Co-immunoprecipitation, domain mapping, cell-based mitophagy assays in hepatocytes treated with bile acids; in vivo biliary atresia liver samples Cell death & disease Medium 29416008
2022 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. Molecular, cellular, and biochemical approaches including domain-deletion mutagenesis, ubiquitination assays specifying linkage type and sites, Co-IP, and LC3B binding assays The Journal of biological chemistry High 36379251
2022 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. Co-immunoprecipitation, phosphodefective/phosphomimetic PHB2 mutant transfection in cardiomyocytes, cardiomyocyte-specific Pgam5 knockout mice, PHB2-S91D knockin mice Research (Washington, D.C.) High 39285950
2022 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. RNA-seq, protein interactome analysis, Co-immunoprecipitation, mammalian 2-hybrid assay, carotid artery injury model, collagen gel contraction and wire myography assays Circulation research High 36200440
2023 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. Co-immunoprecipitation, mass spectrometry, co-localization (immunofluorescence), siRNA knockdown, PHB2 overexpression with Complex I activity assays in CRC and normal intestinal epithelial cells Cell death & disease Medium 36658121
2023 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. Proteomic profiling, bioinformatic analysis, Co-immunoprecipitation, pulldown assays, cardiac-specific PHB2 conditional knockout mice Redox biology Medium 37451140
2009 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. siRNA knockdown of BIG3, Co-immunoprecipitation, immunoblotting of nuclear/cytoplasmic fractions, ERα transcriptional activity assays in breast cancer cells Cancer science Medium 19496786
2013 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. Cell-permeable peptide inhibitor (ERAP), Co-immunoprecipitation, Western blot for ERα signalling intermediates, in vitro proliferation assays, xenograft in vivo models Nature communications Medium 24051437
2015 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. siRNA knockdown of individual KPNAs, Co-immunoprecipitation, subcellular fractionation, immunofluorescence in breast cancer cells PloS one Medium 26052702
2000 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. GST pull-down assays, deletion mutant mapping, antisense RNA knockdown, transactivation assays with estrogen response element reporters The Journal of biological chemistry High 10960470
2007 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. Co-immunoprecipitation, luciferase reporter assays for estrogen-dependent transcription, siRNA knockdown Breast cancer research and treatment Medium 17453341
2009 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. Co-immunoprecipitation, electrophysiology (channel activity assays), site-directed mutagenesis (K1804R), PKC activation/inhibition, estradiol treatment in HEK293 cells The Journal of biological chemistry High 19329436
2007 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. RNAi knockdown in HeLa cells, immunofluorescence for cohesin and shugoshin localization, chromosome segregation analysis, spindle checkpoint activation assays Current biology : CB High 17656096
2008 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. Co-immunoprecipitation of endogenous proteins, siRNA silencing of Akt1 vs. Akt2, overexpression in C2 myoblasts and fibroblasts, immunofluorescence colocalization Journal of cellular physiology Medium 17565718
2008 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. Yeast two-hybrid, Co-immunoprecipitation, RNF2 deletion mutant mapping, luciferase reporter assays Molecular and cellular biochemistry Medium 18629613
2022 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. Mass spectrometry, Co-immunoprecipitation, ubiquitination assays, Tipe1 conditional knockout mice, siRNA knockdown of PHB2 for rescue experiments Redox biology Medium 35152003
2020 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. Domain deletion assay, Co-immunoprecipitation, immunofluorescence, BI1 transgenic mice, siRNA knockdown of PHB2 for rescue, mitochondrial fractionation Theranostics Medium 31903127
2022 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. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, autophagy flux assays in glioma cells and tissues American journal of cancer research Low 34094672
2022 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. Chemical proteomics (target identification), Western blot for ferritin, iron content measurements, ferroptosis cell death assays, acute liver injury model Nature communications Medium 36463308
2021 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. Co-immunoprecipitation, immunofluorescence co-localization, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, in vitro and in vivo tumor models Theranostics Medium 33754036
2022 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. Comparative lectin-capture glycoproteomic approach, site-directed mutagenesis (S161A), Co-immunoprecipitation, functional proliferation/migration assays Cell death & disease Medium 36376274
2022 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. PHB2 tyrosine phosphorylation site mutagenesis (Y121D), Co-immunoprecipitation, immunofluorescence, c-Abl inhibitor STI571 in cell and mouse PD models Oxidative medicine and cellular longevity Medium 36406767
2022 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. Co-immunoprecipitation, competition binding assays, autophagy flux assays, colorectal cancer cell lines Cell death & disease Medium 36202782
2018 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. Immunomagnetic isolation + nanoscale LC-MS/MS (target ID), cell proliferation assays, G2/M cell cycle analysis, pancreatic tumor xenograft model The Journal of biological chemistry Medium 29523683
2024 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. IP-mass spectrometry (interaction), K52R mutagenesis, SIRT3 modulation, ubiquitination assays, mouse AKI model with adeno-associated virus Advanced science Medium 39737891
2022 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. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, PHB2 overexpression, in vivo tumor model Theranostics Medium 33537079
2024 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. Co-immunoprecipitation, genetic knockout, SP1 transcriptional assays, glucose-starvation experiments in cancer cell lines Cell death and differentiation Medium 39375512
2024 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. Co-immunoprecipitation, GST pull-down, deletion mapping, cycloheximide chase, ubiquitination assays, in vivo GC xenograft model Journal of experimental & clinical cancer research Medium 38200519
2019 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. Co-immunoprecipitation, Western blot of mitochondrial fractions, PHB2 siRNA, Nrf2 inhibitor ML385, transmission electron microscopy in rat SAH model Experimental neurology Medium 30779914
2024 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). Genetic deletion/complementation, AIM/LIR motif mutagenesis, Co-immunoprecipitation with Atg8, mitochondrial co-localization, mitophagy flux assays in S. cerevisiae Autophagy High 38964378
2022 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. Co-immunoprecipitation, immunoblot, PHB2 phosphomimetic mutant transfection, Pgam5 siRNA, cardiomyocyte-specific Pgam5 KO mice International journal of biological sciences Medium 37781037
2023 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. Co-immunoprecipitation of CPT1a with PHB2, CPT1a mutation (M593S), PARL overexpression via AAV, db/db mouse model, endothelial cell high glucose/FFA injury model Acta physiologica Medium 37042471
2020 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. Mass spectrometry, Co-immunoprecipitation, PHB2 siRNA knockdown, viral replication assays, autophagy flux assays Viruses Medium 32276428
2022 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. Co-immunoprecipitation, ubiquitination assays, PHB2 overexpression/knockdown, in vitro and in vivo tumor models Molecular carcinogenesis Medium 36342357
2005 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. Targeted gene disruption (homologous recombination), heterozygous mouse phenotyping, uterine gene expression analysis, estrogen challenge assays Molecular and cellular biology High 15713652
2009 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. siRNA knockdown of REA and ERα, chromatin immunoprecipitation (ChIP), cycloheximide experiment, transfection with ERα domain mutants, HDAC inhibitor TSA treatment International journal of cancer Medium 19117054
2007 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. Yeast two-hybrid screen, Western blot of REA levels in transgenic mammary glands, transgenic mouse phenotyping Molecular and cellular biology Medium 17785450
2015 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. siRNA knockdown, ChIP (REA binding to RORγT promoter ERE sites), ERα/REA complex Co-IP, Th17 differentiation assays in mouse splenocytes Journal of immunology Medium 25769926
2022 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. Knockdown experiments, Co-immunoprecipitation, OPA1/DELE1 cleavage assays, ovarian cancer cell lines and mouse subcutaneous tumor model International journal of molecular sciences Low 35163244
2024 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. Dual-luciferase reporter assay, Nrf2 overexpression in A549 cells, Western blot for mitochondrial vs. cytoplasmic PHB2, Nrf2 knockout mice MedComm Medium 38077250

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nature communications 403 24710105
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 342 31177901
2019 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. Stroke 148 30890112
2020 Bax inhibitor 1 preserves mitochondrial homeostasis in acute kidney injury through promoting mitochondrial retention of PHB2. Theranostics 123 31903127
2000 Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity (REA) and the regulation of estrogen receptor transcriptional activity by REA. The Journal of biological chemistry 109 10960470
1999 Listeria monocytogenes in pork slaughtering and cutting plants. Use of RAPD, PFGE and PCR-REA for tracing and molecular epidemiology. International journal of food microbiology 107 10634704
2021 Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2. Theranostics 104 33754036
2015 Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter. Journal of immunology (Baltimore, Md. : 1950) 98 25769926
2022 Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy. Redox biology 96 35152003
2022 PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing. Circulation research 86 36200440
2005 Genetic deletion of the repressor of estrogen receptor activity (REA) enhances the response to estrogen in target tissues in vivo. Molecular and cellular biology 82 15713652
2018 PHB2 interacts with LC3 and SQSTM1 is required for bile acids-induced mitophagy in cholestatic liver. Cell death & disease 69 29416008
2023 PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation. Cell death & disease 67 36658121
2013 Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells. Nature communications 66 24051437
2007 23,24-Dihydrocucurbitacin B induces G2/M cell-cycle arrest and mitochondria-dependent apoptosis in human breast cancer cells (Bcap37). Cancer letters 65 17681423
2008 Cell growth inhibition, G2/M cell cycle arrest, and apoptosis induced by chloroquine in human breast cancer cell line Bcap-37. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 61 19088425
2014 Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions. Scientific reports 60 25483453
2009 Regulation of the epithelial Mg2+ channel TRPM6 by estrogen and the associated repressor protein of estrogen receptor activity (REA). The Journal of biological chemistry 57 19329436
2009 Activation of an estrogen/estrogen receptor signaling by BIG3 through its inhibitory effect on nuclear transport of PHB2/REA in breast cancer. Cancer science 54 19496786
2013 Changes in acromegaly treatment over four decades in Spain: analysis of the Spanish Acromegaly Registry (REA). Pituitary 52 22481632
2013 Anticancer mechanisms of temporin-1CEa, an amphipathic α-helical antimicrobial peptide, in Bcap-37 human breast cancer cells. Life sciences 52 23583573
2022 Non-classical ferroptosis inhibition by a small molecule targeting PHB2. Nature communications 51 36463308
2009 Presence, characterization, and genotype profiles of Mycobacterium avium subspecies paratuberculosis from unpasteurized individual and pooled milk, commercial pasteurized milk, and milk products in India by culture, PCR, and PCR-REA methods. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 51 19576834
2019 Mitoquinone attenuates blood-brain barrier disruption through Nrf2/PHB2/OPA1 pathway after subarachnoid hemorrhage in rats. Experimental neurology 50 30779914
2022 MicroRNA-24-3p alleviates cardiac fibrosis by suppressing cardiac fibroblasts mitophagy via downregulating PHB2. Pharmacological research 49 35149188
2017 PHB2/prohibitin 2: An inner membrane mitophagy receptor. Cell research 49 28220775
2023 L-carnitine alleviates cardiac microvascular dysfunction in diabetic cardiomyopathy by enhancing PINK1-Parkin-dependent mitophagy through the CPT1a-PHB2-PARL pathways. Acta physiologica (Oxford, England) 47 37042471
2024 Aldehyde Dehydrogenase 2 Lactylation Aggravates Mitochondrial Dysfunction by Disrupting PHB2 Mediated Mitophagy in Acute Kidney Injury. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 45 39737891
2022 The interaction between E3 ubiquitin ligase Parkin and mitophagy receptor PHB2 links inner mitochondrial membrane ubiquitination to efficient mitophagy. The Journal of biological chemistry 45 36379251
1993 Further characterization of 19 cases of rea(21q21q) and delineation as isochromosomes or Robertsonian translocations in Down syndrome. American journal of medical genetics 44 7904793
2023 PHB2 ameliorates Doxorubicin-induced cardiomyopathy through interaction with NDUFV2 and restoration of mitochondrial complex I function. Redox biology 43 37451140
2022 Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy. Acta pharmacologica Sinica 41 35948750
2022 PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance. Research (Washington, D.C.) 41 39285950
2021 PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer. Theranostics 40 33537079
2007 PHB2 protects sister-chromatid cohesion in mitosis. Current biology : CB 40 17656096
2007 EZH2 regulates the transcription of estrogen-responsive genes through association with REA, an estrogen receptor corepressor. Breast cancer research and treatment 39 17453341
2008 Emodin-induced apoptosis in human breast cancer BCap-37 cells through the mitochondrial signaling pathway. Archives of pharmacal research 38 18563356
2006 Haploinsufficiency of the corepressor of estrogen receptor activity (REA) enhances estrogen receptor function in the mammary gland. Proceedings of the National Academy of Sciences of the United States of America 37 17065319
2004 Characterization of Listeria monocytogenes and Listeria innocua from a vegetable processing plant by RAPD and REA. International journal of food microbiology 37 14751689
2008 Akt2 is implicated in skeletal muscle differentiation and specifically binds Prohibitin2/REA. Journal of cellular physiology 36 17565718
2022 GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells. Cell death & disease 35 36376274
1998 Identification and clustering of dairy propionibacteria by RAPD-PCR and CGE-REA methods. Journal of applied microbiology 34 9871315
2022 The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer. International journal of molecular sciences 30 35163244
2011 Antiproliferation and cell apoptosis inducing bioactivities of constituents from Dysosma versipellis in PC3 and Bcap-37 cell lines. Cell division 28 21676247
2020 PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels. Biomedicines 27 32290388
2020 Prohibitin 2/PHB2 in Parkin-Mediated Mitophagy: A Potential Therapeutic Target for Non-Small Cell Lung Carcinoma. Medical science monitor : international medical journal of experimental and clinical research 27 32320388
1993 Characterization of bovine Haemophilus somnus by biotyping, plasmid profiling, REA-patterns and ribotyping. Zentralblatt fur Bakteriologie : international journal of medical microbiology 27 7690273
2022 Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity. Cell death & disease 26 36202782
2011 Repressor of estrogen receptor activity (REA) is essential for mammary gland morphogenesis and functional activities: studies in conditional knockout mice. Endocrinology 26 21862609
2023 Essential Protein PHB2 and Its Regulatory Mechanisms in Cancer. Cells 24 37190120
2018 Small-molecule screening yields a compound that inhibits the cancer-associated transcription factor Hes1 via the PHB2 chaperone. The Journal of biological chemistry 24 29523683
1993 Comparison of multilocus enzyme electrophoresis (MEE), ribotyping, restriction enzyme analysis (REA) and phage typing for typing of Listeria monocytogenes. Epidemiology and infection 24 7688694
2015 BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells. PloS one 23 26052702
2003 A novel polygalacturonic acid bioflocculant REA-11 produced by Corynebacterium glutamicum: a proposed biosynthetic pathway and experimental confirmation. Applied microbiology and biotechnology 23 12827320
2018 Bcl-2 promotes metastasis through the epithelial-to-mesenchymal transition in the BCap37 medullary breast cancer cell line. Oncology letters 22 29844816
2009 Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor-alpha and the REA corepressor. International journal of cancer 21 19117054
2023 Rutin Attenuates Oxidative Stress Via PHB2-Mediated Mitophagy in MPP+-Induced SH-SY5Y Cells. Neurotoxicity research 20 36738374
2020 Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection. Viruses 20 32276428
1987 A phase I clinical evaluation of 1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]-1-nitrosou rea (TCNU). European journal of cancer & clinical oncology 20 3436347
2024 Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer. Cancer letters 18 39181433
2023 Pgam5-mediated PHB2 dephosphorylation contributes to endotoxemia-induced myocardial dysfunction by inhibiting mitophagy and the mitochondrial unfolded protein response. International journal of biological sciences 18 37781037
2008 PHB2 interacts with RNF2 and represses CP2c-stimulated transcription. Molecular and cellular biochemistry 18 18629613
2023 Nrf2/PHB2 alleviates mitochondrial damage and protects against Staphylococcus aureus-induced acute lung injury. MedComm 17 38077250
2022 Formononetin Inhibits Hepatic I/R-Induced Injury through Regulating PHB2/PINK1/Parkin Pathway. Oxidative medicine and cellular longevity 17 36506934
2021 GOLPH3 promotes glioma progression by enhancing PHB2-mediated autophagy. American journal of cancer research 17 34094672
2021 Folate receptor α increases chemotherapy resistance through stabilizing MDM2 in cooperation with PHB2 that is overcome by MORAb-202 in gastric cancer. Clinical and translational medicine 17 34185411
2013 The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization. Endocrinology 17 23392257
2012 Uterine development and fertility are dependent on gene dosage of the nuclear receptor coregulator REA. Endocrinology 17 22585830
2015 Identification of a panel of complex autoantigens (LGALS3, PHB2, MUC1, and GK2) in combination with CA15-3 for the diagnosis of early-stage breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 16 26289852
2014 Expression of PHB2 in rat brain cortex following traumatic brain injury. International journal of molecular sciences 16 24566151
2012 Effect of norcantharidin on the human breast cancer Bcap-37 cells. Connective tissue research 16 22606958
2006 An evaluation of the apxIVA based PCR-REA method for differentiation of Actinobacillus pleuropneumoniae. Veterinary microbiology 16 17169508
2024 Oxidative stress suppresses PHB2-mediated mitophagy in β-cells via the Nrf2/PHB2 pathway. Journal of diabetes investigation 15 38260951
2015 Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer. Cancer science 15 25736224
2007 Skp2B stimulates mammary gland development by inhibiting REA, the repressor of the estrogen receptor. Molecular and cellular biology 15 17785450
2024 High glucose- or AGE-induced oxidative stress inhibits hippocampal neuronal mitophagy through the Keap1-Nrf2-PHB2 pathway in diabetic encephalopathy. Scientific reports 14 39402106
2022 Nonreceptor Tyrosine Kinase c-Abl-Mediated PHB2 Phosphorylation Aggravates Mitophagy Disorder in Parkinson's Disease Model. Oxidative medicine and cellular longevity 14 36406767
2022 Artemisinin Alleviates Cerebral Ischemia/Reperfusion-Induced Oxidative Damage via Regulating PHB2-Mediated Autophagy in the Human Neuroblastoma SH-SY5Y Cell Line. Oxidative medicine and cellular longevity 14 36567858
2021 The survival and proliferation of osteosarcoma cells are dependent on the mitochondrial BIG3-PHB2 complex formation. Cancer science 14 34363714
2024 Prohibitins, Phb1 and Phb2, function as Atg8 receptors to support yeast mitophagy and also play a negative regulatory role in Atg32 processing. Autophagy 13 38964378
2024 Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway. iScience 13 39091464
2022 PHB2 affects the virulence of Vip3Aa to Sf9 cells through internalization and mitochondrial stability. Virulence 13 35400294
2018 The novel long noncoding RNA LOC283070 is involved in the transition of LNCaP cells into androgen-independent cells via its interaction with PHB2. Asian journal of andrology 13 29956684
2015 Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis. Endocrinology 13 26653759
2011 Vaccine platforms combining circumsporozoite protein and potent immune modulators, rEA or EAT-2, paradoxically result in opposing immune responses. PloS one 13 21912619
2023 LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets. Journal of translational medicine 12 36782197
2004 Diffuse cutaneous candidiasis in a dog. Diagnosis by PCR-REA. Revista iberoamericana de micologia 12 15709788
2003 [The inhibitory effect of saponins from Tribulus terrestris on Bcap-37 breast cancer cell line in vitro]. Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials 12 12795220
1990 Application of small fragment restriction endonuclease analysis (SF-REA) to the epidemiological fingerprinting of Staphylococcus aureus. Journal of medical microbiology 12 1700127
1984 On telomere replication and fusion in eukaryotes: apropos of a case of 45,X/46,X,ter rea(X;X)(p22.3;p22.3). Cytogenetics and cell genetics 12 6705562
2022 Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2-RCHY1 mediated signaling pathway. Molecular carcinogenesis 11 36342357
2022 Identification of PHB2 as a Potential Biomarker of Luminal A Breast Cancer Cells Using a Cell-Specific Aptamer. ACS applied materials & interfaces 11 36346944
2021 The expression of PHB2 in the cochlea: Possible relation to age-related hearing loss. Cell biology international 11 34435719
1991 Epidemiological fingerprinting of Klebsiella pneumoniae by small-fragment-restriction-endonuclease-analysis (SF-REA). Scandinavian journal of infectious diseases 11 1815337
2024 PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer. Journal of experimental & clinical cancer research : CR 10 38200519
2024 Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice. European journal of medicinal chemistry 10 38422699
2024 HKDC1 functions as a glucose sensor and promotes metabolic adaptation and cancer growth via interaction with PHB2. Cell death and differentiation 9 39375512
2023 A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease. Neural regeneration research 9 38103250
2020 Lamprey PHB2 maintains mitochondrial stability by tanslocation to the mitochondria under oxidative stress. Fish & shellfish immunology 9 32592929
1995 Typing of coagulase-negative staphylococci from peritonitis in CAPD-patients by the PhP-CS system and REA. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 9 7488390

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