PHB2

Summary

PHB2 (prohibitin 2, HGNC:30306) is a protein-coding gene on chromosome 12p13.31, encoding Prohibitin-2 (Q99623). 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 t…. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

Enables amide binding activity; protein dimerization activity; and sphingolipid binding activity. Involved in several processes, including RIG-I signaling pathway; positive regulation of cell cycle phase transition; and regulation of DNA-templated transcription. Located in several cellular components, including cell surface; mitochondrial membrane; and nuclear matrix. Part of mitochondrial prohibitin complex.

Source: NCBI Gene 11331 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 39 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_001144831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30306
Approved symbol	PHB2
Name	prohibitin 2
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	REA, BCAP37, Bap37, p22
Ensembl gene	ENSG00000215021
Ensembl biotype	protein_coding
OMIM	610704
Entrez	11331

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 9 protein_coding, 8 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000399433, ENST00000440277, ENST00000535923, ENST00000536316, ENST00000537646, ENST00000542294, ENST00000542912, ENST00000543465, ENST00000544134, ENST00000544888, ENST00000545167, ENST00000545555, ENST00000546111, ENST00000546217, ENST00000676496, ENST00000676893, ENST00000677354, ENST00000678000, ENST00000678829, ENST00000678983, ENST00000925249

RefSeq mRNA: 2 — MANE Select: NM_001144831 NM_001144831, NM_001267700

CCDS: CCDS53741, CCDS58207

Canonical transcript exons

ENST00000535923 — 10 exons

Exon	Start	End
ENSE00001538309	6967676	6967779
ENSE00002249177	6970417	6970664
ENSE00003496959	6967171	6967248
ENSE00003500254	6965911	6965916
ENSE00003540339	6965327	6965712
ENSE00003697170	6970196	6970280
ENSE00003698564	6969498	6969577
ENSE00003701196	6968411	6968595
ENSE00003784191	6966424	6966500
ENSE00003786812	6967892	6968021

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 204.5258 / max 2054.2322, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129224	196.7901	1827
129223	7.2424	1552
129222	0.4137	210
129221	0.0797	27

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mammalian vulva	UBERON:0000997	99.18	gold quality
nipple	UBERON:0002030	99.17	gold quality
upper arm skin	UBERON:0004263	99.17	gold quality
vastus lateralis	UBERON:0001379	99.16	gold quality
triceps brachii	UBERON:0001509	99.15	gold quality
quadriceps femoris	UBERON:0001377	99.12	gold quality
left ovary	UBERON:0002119	99.07	gold quality
jejunal mucosa	UBERON:0000399	99.04	gold quality
upper leg skin	UBERON:0004262	99.02	gold quality
thymus	UBERON:0002370	99.01	gold quality
gluteal muscle	UBERON:0002000	98.97	gold quality
jejunum	UBERON:0002115	98.95	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.95	gold quality
right ovary	UBERON:0002118	98.91	gold quality
penis	UBERON:0000989	98.90	gold quality
colonic mucosa	UBERON:0000317	98.89	gold quality
embryo	UBERON:0000922	98.89	gold quality
body of tongue	UBERON:0011876	98.88	gold quality
biceps brachii	UBERON:0001507	98.86	gold quality
pharyngeal mucosa	UBERON:0000355	98.85	gold quality
body of pancreas	UBERON:0001150	98.85	gold quality
parotid gland	UBERON:0001831	98.85	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.85	gold quality
mucosa of transverse colon	UBERON:0004991	98.85	gold quality
transverse colon	UBERON:0001157	98.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.82	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.81	gold quality
ileal mucosa	UBERON:0000331	98.80	gold quality
skeletal muscle tissue	UBERON:0001134	98.80	gold quality
superior surface of tongue	UBERON:0007371	98.79	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	14.21
E-MTAB-7606	no	543.36
E-MTAB-6524	no	261.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
ARNT	Repression
BTG2	Repression

Upstream regulators (CollecTRI, top): AHR, MEF2A, MYOD1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• REA has a role as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases (PMID:15140878)
• mammalian PHB2 has roles in mitochondria and its nuclear translocation is estrogen receptor-dependent (PMID:17008324)
• EZH2 regulates the transcription of estrogen-responsive genes through association with REA, an estrogen receptor corepressor (PMID:17453341)
• Findings suggest that, in addition to the shugoshin, PHB2 is also required to protect the centromeric cohesion from phosphorylation by Plk1 during early mitosis and that its function is essential for proper mitotic progression. (PMID:17656096)
• SKP2 variant Skp2B interacts with the repressor of estrogen receptor activity (REA) and that overexpression of Skp2B leads to a reduction in REA levels. (PMID:17785450)
• Results demonstrate that the repressor of estrogen receptor activity (REA), a protein related to PHB, interacts with PHB, to form heteromers and enhance the protein stability of both corepressors. (PMID:17932104)
• Phb1 and Phb2 are novel phosphoproteins up-regulated during T cell activation that function to maintain mitochondrial integrity (PMID:18086671)
• a novel mechanism by which RNF2 and PHB2 modulate the CP2-mediated transcriptional pathway. (PMID:18629613)
• Estradiol downregulation of the tumor suppressor gene BTG2 requires estrogen receptor-alpha and the REA corepressor (PMID:19117054)
• Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex of PHB1 and PHB2 involved in mitochondrial biogenesis and intracellular signaling (PMID:19640993)
• results point to binding of the Phb1/Phb2 complex to the Env-CT as being of importance for replicative spread in nonpermissive cells, possibly by modulating critical Phb-dependent cellular process(es) (PMID:19906925)
• Prohibitin 1 and 2 are required for cancer cell proliferation and adhesion. (PMID:20856874)
• PHBs are localized on the human platelet membrane and are involved in PAR1-mediated platelet aggregation. (PMID:22212092)
• Casein kinase 1 proteomics reveal prohibitin 2 function in molecular clock (PMID:22384121)
• REA physiologically restrains endometrial stromal cell decidualization, controlling the timing and magnitude of decidualization to coordinate uterine differentiation with concurrent embryo development that is essential for implantation and fertility. (PMID:23392257)
• ASURA specifically binds to chromatin when Scc1 is associated with chromatin. (PMID:23548868)
• PHB2 in hepatocellular carcinoma supports the development and progression of hepatocellular malignancy. (PMID:23661548)
• Data demonstrate that PHB2 is essential for metabolic activation of mitochondria and, as a consequence, for function and survival of beta-cells. (PMID:23863811)
• Data indicate that IGFBP-6 binds to prohibitin-2 on the cell membrane, and knockdown of the latter abrogates IGFBP-6-induced migration. (PMID:24003225)
• BIG3(WRD5)-PHB2 interaction is critical for the tamoxifen resistance of breast cancer cells; its targeting reverses the resistance. (PMID:24051437)
• prohibitin and prohibiton (PHB2) contribute to PIG3-mediated apoptosis by binding to the PIG3 promoter (TGYCC)15 motif (PMID:24388982)
• Prohibitin 2 acts as a nuclear AKT substrate during all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells (PMID:24522204)
• BIG3 (ARFGEF3) is predicted to interact with its partner PHB2 through an ARM-type alpha-helical structure. (PMID:24997568)
• Data indicate that the up-regulated expression of prohibitin promoted acute promyelocytic leukemia cell line NB4-R1 cell apoptosis. (PMID:25200157)
• These results demonstrate that estradiol upregulates REA expression and recruits REA via ERalpha to the EREs on the RORgammaT promoter region, thus inhibiting RORgammaT expression and Th17 differentiation. (PMID:25769926)
• Functional analysis of selected regulated proteins revealed that knockdown of HNRPD, PHB2 and UB2V2 can increase HCMV replication, while knockdown of A4 and KSRP resulted in decreased HCMV replication. (PMID:25910425)
• results show that PHB2 binds to the ligand binding domain of ERalpha with a conformational change in the helix 12 of ERalpha (PMID:26049107)
• BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2. (PMID:26052702)
• analysis of LGALS3, PHB2, MUC1, and GK2 expression with CA15-3 in early-stage breast cancer (PMID:26289852)
• Fluorizoline bind to prohibitin, inducing mitochondrial apoptotic pathway through NOXA and BIM upregulation. (PMID:26497683)
• REA modulates cross talk among multiple cell types in the uterine tissue and host background, serving as a brake on the estradiol-ER axis and restraining multiple aspects that contribute to the pathologic progression of endometriosis. (PMID:26653759)
• the present study suggested that PHB2 may promote Prostate cancer cell migration by inhibiting the expression of AKT2. These results provide information regarding the role of PHB2 in Prostate cancer migration and malignancy (PMID:29207197)
• Taken together, the results indicate that PHB2 plays a central role in p21 upregulation following GGCT knockdown and as such may promote deregulated proliferation of cancer cells by suppressing p21. (PMID:29307834)
• High PHB2 expression is associated with high ribosomal RNA transcription and facilitation of cell proliferation in rhabdomyosarcoma. (PMID:29367618)
• PHB2 forms a ternary protein complex with sequestosome 1 (SQSTM1) and LC3, leading to loading of LC3 onto the damaged mitochondria. (PMID:29416008)
• we found that LOC283070 can bind to PHB2 located in the nucleus and inhibit its effect, and this is one of the mechanisms by which LOC283070 is involved in the transition of LNCaP cells into androgen-independent cells (PMID:29956684)
• Prohibitin 2-mediated mitophagy attenuates renal tubular epithelial cells injury by regulating mitochondrial dysfunction and NLRP3 inflammasome activation. (PMID:30539655)
• during cell stress, Bif-1 regulates mitochondrial inner membrane by interacting with prohibitin-2 to disrupt prohibitin complexes and induce OPA1 proteolysis and inactivation. (PMID:31126972)
• Cytoplasmic sequestration of the RhoA effector mDiaphanous1 by Prohibitin2 promotes muscle differentiation. (PMID:31165762)
• PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. (PMID:31177901)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	phb2b	ENSDARG00000017728
danio_rerio	phb2a	ENSDARG00000045297
mus_musculus	Phb2	ENSMUSG00000004264
rattus_norvegicus	Phb2	ENSRNOG00000012999
drosophila_melanogaster	Phb2	FBGN0010551
caenorhabditis_elegans		WBGENE00004015

Paralogs (1): PHB1 (ENSG00000167085)

Protein

Protein identifiers

Prohibitin-2 — Q99623 (reviewed: Q99623)

Alternative names: B-cell receptor-associated protein BAP37, D-prohibitin, Repressor of estrogen receptor activity

All UniProt accessions (10): A0A3G2KQ93, A0A7I2V5F0, Q99623, F5GWA7, F5GY37, F5H0C5, F5H2D2, F5H3X6, J3KPX7, U3KPZ5

UniProt curated annotations — full annotation on UniProt →

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. The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner. Also regulates cytochrome-c oxidase assembly (COX) and mitochondrial respiration. Binding to sphingoid 1-phosphate (SPP) modulates its regulator activity. Has a key role of mitophagy receptor involved in targeting mitochondria for autophagic degradation. Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6. In the nucleus, serves as transcriptional co-regulator. 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. In the plasma membrane, is involved in IGFBP6-induced cell migration. 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. (Microbial infection) Involved in human enterovirus 71/EV-71 infection by enhancing the autophagy mechanism during the infection.

Subunit / interactions. The mitochondrial prohibitin complex consists of two subunits (PHB1 and PHB2), assembled into a membrane-associated ring-shaped supercomplex of approximately 1 mDa. Interacts with ESR1, HDAC1 and HDAC5. Interacts with ZNF703. Interacts with STOML2. Interacts with ARFGEF3. Interacts with SPHK2. Interacts with COX4I1; the interaction associates PHB2 with COX. Interacts with MAP1LC3B (membrane-bound form LC3-II); the interaction is direct and upon mitochondrial depolarization and proteasome-dependent outer membrane rupture. Interacts with IGFBP6 (via C-terminal domain). Interacts with CLPB. Interacts with CD86 (via cytoplasmic domain); the interactions increases after priming with CD40. Interacts with AFG3L2. Interacts with DNAJC19. Interacts with AKT2; this interaction may be important for myogenic differentiation. (Microbial infection) Interacts with SARS coronavirus/SARS-CoV nsp2 protein. (Microbial infection) Interacts with human enterovirus 71/EV-71 capsid protein VP1; the interaction is required for induction of autophagy and the infectivity of EV-71. (Microbial infection) Interaction with human immunodeficiency virus type 1/HIV-1 envelope glycoprotein GP160.

Subcellular location. Mitochondrion inner membrane. Cytoplasm. Nucleus. Cell membrane Mitochondrion inner membrane Mitochondrion inner membrane.

Tissue specificity. Expressed in myoblasts.

Post-translational modifications. Phosphorylated. Tyrosine phosphorylation is indirectly stimulated by IGFBP6.

Domain organisation. LC3-interaction region (LIR) is required for interaction with MAP1LC3B/LC3-II and for Parkin-mediated mitophagy.

Induction. Expression increases approximately 3-fold upon entry into G1 phase compared to other phases of the cell cycle. Also induced following inhibition of mitochondrial protein synthesis by thiamphenicol.

Similarity. Belongs to the prohibitin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99623-1	1, V1	yes
Q99623-2	2, V3

RefSeq proteins (2): NP_001138303, NP_001254629 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000163	Prohibitin	Family
IPR001107	Band_7	Domain
IPR036013	Band_7/SPFH_dom_sf	Homologous_superfamily

Pfam: PF01145

UniProt features (21 total): modified residue 8, mutagenesis site 5, region of interest 3, initiator methionine 1, chain 1, splice variant 1, helix 1, coiled-coil region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6IQE	X-RAY DIFFRACTION	1.7
9O9Z	ELECTRON MICROSCOPY	2.4
9UNL	ELECTRON MICROSCOPY	2.8
9OA0	ELECTRON MICROSCOPY	3.1
8RRH	ELECTRON MICROSCOPY	16.3
9O6S	ELECTRON MICROSCOPY	21
9O6T	ELECTRON MICROSCOPY	22
8J4I	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99623-F1	85.36	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 200, 236, 250, 262, 2, 128, 147, 151

Mutagenesis-validated functional residues (5):

Position	Phenotype
77	no effect on interaction with map1lc3b.
121–124	abolishes interaction with map1lc3b. no effect on interaction with phb. no effect on mitochondrial location. abolishes r
175–178	decreases interaction with map1lc3b.
225	reduces helicity. decreases homodimerization and interaction with phb. disrupts mitochondrial dynamics. disrupts mitocho
229–233	no effect on homodimerization or interaction with phb. decreases mitochondrial dynamics. disrupts mitochondrial-mediated

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8949664	Processing of SMDT1
R-HSA-9840373	Cellular response to mitochondrial stress

MSigDB gene sets: 404 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_CHROMOSOME_ORGANIZATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_MAMMARY_GLAND_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, CCAWYNNGAAR_UNKNOWN, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_B_CELL_ACTIVATION, MODULE_151

GO Biological Process (26): mitophagy (GO:0000423), positive regulation of immunoglobulin production (GO:0002639), protein import into nucleus (GO:0006606), mitochondrion organization (GO:0007005), sister chromatid cohesion (GO:0007062), cell migration (GO:0016477), estrogen receptor signaling pathway (GO:0030520), negative regulation of intracellular estrogen receptor signaling pathway (GO:0033147), mammary gland epithelial cell proliferation (GO:0033598), negative regulation of mammary gland epithelial cell proliferation (GO:0033600), RIG-I signaling pathway (GO:0039529), B cell activation (GO:0042113), negative regulation of apoptotic process (GO:0043066), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), negative regulation of DNA-templated transcription (GO:0045892), protein stabilization (GO:0050821), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), mammary gland branching involved in thelarche (GO:0060744), mammary gland alveolus development (GO:0060749), regulation of branching involved in mammary gland duct morphogenesis (GO:0060762), positive regulation of ERK1 and ERK2 cascade (GO:0070374), antiviral innate immune response (GO:0140374), regulation of cardiolipin metabolic process (GO:1900208), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), regulation of cytochrome-c oxidase activity (GO:1904959), RNA processing (GO:0006396)

GO Molecular Function (7): nuclear estrogen receptor binding (GO:0030331), obsolete amide binding (GO:0033218), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), sphingolipid binding (GO:0046625), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), plasma membrane (GO:0005886), cell surface (GO:0009986), nuclear matrix (GO:0016363), protein-containing complex (GO:0032991), mitochondrial prohibitin complex (GO:0035632), cell periphery (GO:0071944), nucleolus (GO:0005730), membrane (GO:0016020), inner mitochondrial membrane protein complex (GO:0098800)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Mitochondrial calcium ion transport	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
branching involved in mammary gland duct morphogenesis	2
protein dimerization activity	2
intracellular membrane-bounded organelle	2
mitochondrial membrane	2
nuclear lumen	2
autophagy of mitochondrion	1
macroautophagy	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
organelle organization	1
cell cycle process	1
chromosome organization	1
cell motility	1
nuclear receptor-mediated steroid hormone signaling pathway	1
estrogen receptor signaling pathway	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of intracellular estrogen receptor signaling pathway	1
epithelial cell proliferation	1
mammary gland epithelium development	1
mammary gland epithelial cell proliferation	1
regulation of mammary gland epithelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
negative regulation of multicellular organismal process	1
cytoplasmic pattern recognition receptor signaling pathway	1
lymphocyte activation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of protein stability	1
thelarche	1
anatomical structure development	1

Protein interactions and networks

STRING

3946 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHB2	PHB1	P35232	988
PHB2	ESR1	P03372	915
PHB2	MFN1	Q8IWA4	903
PHB2	OPA1	O60313	885
PHB2	ARFGEF3	Q5TH69	863
PHB2	HDAC1	Q13547	845
PHB2	DNAJC19	Q96DA6	830
PHB2	FUNDC1	Q8IVP5	819
PHB2	PARL	Q9H300	818
PHB2	A0A1W2PP11	A0A1W2PP11	815
PHB2	DNMT3A	Q9Y6K1	784
PHB2	DCAF7	P61962	758
PHB2	CYCS	P00001	725
PHB2	PINK1	Q9BXM7	718
PHB2	NCOR2	Q9Y618	714

IntAct

303 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
RAB11A	EVI5	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
rep	PHB1	psi-mi:“MI:0914”(association)	0.640
rep	EIF4E2	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
PHB1	PHB2	psi-mi:“MI:0915”(physical association)	0.590
DUSP6	PHB2	psi-mi:“MI:0915”(physical association)	0.560
PHB2	PCDHGC3	psi-mi:“MI:0915”(physical association)	0.560
	PHB2	psi-mi:“MI:0915”(physical association)	0.560
PHB2	XIAP	psi-mi:“MI:0914”(association)	0.530
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
	PHB2	psi-mi:“MI:0915”(physical association)	0.520

BioGRID (797): PHB2 (Affinity Capture-MS), PHB2 (Protein-peptide), PHB2 (Affinity Capture-MS), PHB2 (Affinity Capture-MS), PHB2 (Affinity Capture-MS), PHB2 (Affinity Capture-MS), PHB2 (Affinity Capture-MS), PHB2 (Affinity Capture-MS), XIAP (Affinity Capture-MS), NMRAL1 (Affinity Capture-MS), PHB2 (Affinity Capture-MS), PHB2 (Affinity Capture-RNA), PHB2 (Affinity Capture-MS), ATP6V1C1 (Co-fractionation), CCDC47 (Co-fractionation)

ESM2 similar proteins: A3QMC6, A9UMS3, H1VAN0, H1VPS8, H2FLJ1, O04331, O08917, O13127, O35129, O49460, O60121, O61491, O75477, O75955, O94550, P16148, P24156, P26659, P27105, P40961, P50085, P50093, P54116, P72655, P77306, Q28DX1, Q2HJ97, Q32LL2, Q4FZT0, Q54GI9, Q54Q31, Q5RB19, Q5RBL4, Q5RCJ9, Q5XIH7, Q5ZMN3, Q7YR41, Q8TAV4, Q91X78, Q99623

Diamond homologs: A9UMS3, H1VAN0, H1VPS8, O04331, O35129, O49460, O94550, P24156, P35232, P40961, P50085, P50093, P67778, P67779, P84173, P86220, Q2HJ97, Q3T165, Q54GI9, Q54Q31, Q5RB19, Q5XIH7, Q5ZMN3, Q99623, Q9BKU4, Q9FFH5, Q9LK25, Q9LY99, Q9P7H3, Q9SIL6, Q9ZNT7

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CAMK4	down-regulates	PHB2	phosphorylation
PRKCA	“down-regulates activity”	PHB2	phosphorylation
AKT	down-regulates	PHB2	binding
PHB2	down-regulates	MEF2A	binding
PHB2	down-regulates	MYOD1	binding
AKT1	down-regulates	PHB2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHOQ GTPase cycle	7	9.6×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein ubiquitination	8	10.9×	1e-03
mitochondrion organization	8	7.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

39 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1479 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6965708:TGTCA:T	acceptor_gain	1.0000
12:6965710:TCA:T	acceptor_gain	1.0000
12:6965711:CA:C	acceptor_gain	1.0000
12:6965711:CAC:C	acceptor_gain	1.0000
12:6965713:C:A	acceptor_loss	1.0000
12:6965713:C:CC	acceptor_gain	1.0000
12:6965715:G:C	acceptor_gain	1.0000
12:6965942:C:CT	acceptor_gain	1.0000
12:6965943:A:T	acceptor_gain	1.0000
12:6965949:C:CT	acceptor_gain	1.0000
12:6965950:A:T	acceptor_gain	1.0000
12:6966419:CTCA:C	donor_loss	1.0000
12:6966421:CACCT:C	donor_loss	1.0000
12:6966497:CGAT:C	acceptor_gain	1.0000
12:6966499:ATC:A	acceptor_loss	1.0000
12:6966500:TC:T	acceptor_loss	1.0000
12:6966501:C:CC	acceptor_gain	1.0000
12:6966501:CTAC:C	acceptor_loss	1.0000
12:6966509:C:CT	acceptor_gain	1.0000
12:6966510:A:T	acceptor_gain	1.0000
12:6967249:G:GC	acceptor_gain	1.0000
12:6967259:T:TC	acceptor_gain	1.0000
12:6967631:AGGTG:A	donor_gain	1.0000
12:6967890:A:AC	donor_gain	1.0000
12:6967890:AC:A	donor_gain	1.0000
12:6967891:C:CC	donor_gain	1.0000
12:6967891:CC:C	donor_gain	1.0000
12:6967891:CCCA:C	donor_gain	1.0000
12:6967894:A:AC	donor_gain	1.0000
12:6967895:C:CC	donor_gain	1.0000

AlphaMissense

1927 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6967191:C:G	A257P	1.000
12:6967194:C:G	A256P	1.000
12:6967687:C:G	A234P	1.000
12:6967693:C:G	A232P	1.000
12:6967705:C:G	A228P	1.000
12:6967738:C:G	A217P	1.000
12:6967759:C:G	A210P	1.000
12:6967761:C:G	R209P	1.000
12:6967768:C:G	A207P	1.000
12:6967892:C:G	A203P	1.000
12:6967899:T:A	K200N	1.000
12:6967899:T:G	K200N	1.000
12:6967904:C:G	A199P	1.000
12:6967912:G:T	A196D	1.000
12:6967913:C:G	A196P	1.000
12:6967921:T:C	Y193C	1.000
12:6967922:A:G	Y193H	1.000
12:6967932:A:C	F189L	1.000
12:6967932:A:T	F189L	1.000
12:6967933:A:C	F189C	1.000
12:6967933:A:G	F189S	1.000
12:6967934:A:G	F189L	1.000
12:6967948:A:T	I184N	1.000
12:6967957:T:A	D181V	1.000
12:6967958:C:G	D181H	1.000
12:6967974:G:C	F175L	1.000
12:6967974:G:T	F175L	1.000
12:6967976:A:G	F175L	1.000
12:6967984:G:T	A172D	1.000
12:6967996:A:G	L168P	1.000

dbSNP variants (sampled 300 via entrez): RS1001818135 (12:6969935 C>G), RS1003756868 (12:6971006 A>C,G), RS1004234904 (12:6971408 G>T), RS1004400034 (12:6971727 G>A), RS1005069125 (12:6971957 T>C,G), RS1005764929 (12:6968678 C>T), RS1006174159 (12:6967281 T>A), RS1007038736 (12:6969402 G>A), RS1007787763 (12:6968199 C>T), RS1008341745 (12:6970484 G>A,C,T), RS1009095157 (12:6969198 T>G), RS1009787164 (12:6965212 C>T), RS1009851213 (12:6970703 C>A,G,T), RS1010855412 (12:6972020 T>C,G), RS1011729535 (12:6966659 C>A,T)

Disease associations

OMIM: gene MIM:610704 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002712_10	Red blood cell fatty acid levels	3.000000e-30
GCST002712_13	Red blood cell fatty acid levels	3.000000e-49
GCST007954_19	Glycated hemoglobin levels	4.000000e-08
GCST010002_206	Refractive error	3.000000e-62

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006807	linoleic acid measurement
EFO:0006810	oleic acid measurement
EFO:0004541	HbA1c measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295931 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11064477	PHB2		0.00	0

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	Kd	68.56	nM	CHEMBL5653589
7.16	ED50	68.56	nM	CHEMBL5653589
5.13	Kd	7376	nM	CHEMBL3752910
5.13	ED50	7376	nM	CHEMBL3752910
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 152 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148995: Binding affinity to human PHB2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0686	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148995: Binding affinity to human PHB2 incubated for 45 mins by Kinobead based pull down assay	kd	7.3760	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178917: Inhibition of PHB2 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
bisphenol A	decreases expression	2
arsenite	affects binding, increases reaction, increases expression, decreases reaction	2
sodium arsenite	increases abundance, increases expression, decreases expression	2
Estradiol	decreases expression, increases expression, affects binding, decreases reaction	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	decreases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Fulvestrant	increases expression, decreases expression, decreases reaction	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	increases abundance, increases expression	1
Aspirin	decreases expression	1
Cadmium	decreases reaction, increases expression	1
Capsaicin	affects binding, increases localization	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1

ChEMBL screening assays

32 unique, capped per target: 32 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4272317	Binding	Induction of PHB2-mediated melanogenesis in human HBL cells assessed as pigmentation at 1 uM after 10 days relative to control	Targeting prohibitin with small molecules to promote melanogenesis and apoptosis in melanoma cells. — Eur J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.