Prohibitin-2 (PHB2)
The protein contains 299 amino acids for an estimated molecular weight of 33296 Da.
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 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:20959514, PubMed:11302691). Binding to sphingoid 1-phosphate (SPP) modulates its regulator activity (PubMed:20959514, PubMed:11302691). Has a key role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (PubMed:28017329). Involved in mitochondrial-mediated antiviral innate immunity, activates DDX58/RIG-I-mediated signal transduction and production of IFNB1 and proinflammatory 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 (updated: Aug. 12, 2020)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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Biological Process
Activation of phospholipase C activity
Activation of protein kinase C activity
Antiviral innate immune response
B cell activation
CD40 signaling pathway
Cell migration
Cellular response to hypoxia
Cellular response to retinoic acid
Immunoglobulin production
Induction by virus of host autophagy
Mammary gland alveolus development
Mammary gland branching involved in thelarche
Mitochondrial calcium ion transmembrane transport
Mitochondrion organization
Mitophagy
Negative regulation of apoptotic process
Negative regulation of DNA-binding transcription factor activity
Negative regulation of intracellular estrogen receptor signaling pathway
Negative regulation of mammary gland epithelial cell proliferation
Negative regulation of transcription, DNA-templated
Positive regulation of cell cycle G1/S phase transition
Positive regulation of DNA-binding transcription factor activity
Positive regulation of ERK1 and ERK2 cascade
Positive regulation of exit from mitosis
Positive regulation of immunoglobulin production
Positive regulation of NIK/NF-kappaB signaling
Protein import into nucleus
Protein stabilization
Regulation of branching involved in mammary gland duct morphogenesis
Regulation of cardiolipin metabolic process
Regulation of cytochrome-c oxidase activity
Response to wounding
RIG-I signaling pathway
Sister chromatid cohesion
Cellular Component
Axon
Cell periphery
Cell surface
Cytoplasm
GABA-ergic synapse
Glutamatergic synapse
Mitochondrial inner membrane
Mitochondrial outer membrane
Mitochondrial prohibitin complex
Mitochondrion
Nuclear matrix
Nucleus
Plasma membrane
Postsynaptic density
Presynaptic active zone
Protein-containing complex
The reference OMIM entry for this protein is 610704
Prohibitin 2; phb2
Repressor of estrogen receptor activity; rea
CLONING
Using the C-terminal EF domains of a dominant-negative estrogen receptor (ER)-alpha (ESR1; 133430) mutant as bait in a yeast 2-hybrid screen of a breast cancer cell line cDNA library, followed by EST database analysis, Montano et al. (1999) cloned PHB2, which the called REA. The deduced 299-amino acid protein contains 4 potential phosphorylation sites, a nuclear receptor interaction box, and a nuclear localization motif.GENE FUNCTION
Montano et al. (1999) showed that REA enhanced the potency of a dominant-negative ER-alpha mutant and antiestrogens as suppressors of ER-alpha activity in Chinese hamster ovary cells. When coexpressed with wildtype ER-alpha or ER-beta (ESR2; 601663), REA suppressed activation of a reporter gene in a dose-dependent manner. REA had no effect on reporter activity in the absence of liganded ER, and it had no effect on the transcriptional activities of other hormone receptors. Mutation analysis showed that an N-terminal domain and a central domain of REA were required for its repressor activity. REA interacted directly with ER-alpha in an in vitro pull-down assay. REA did not interfere with the ability of ER-alpha to bind to estrogen response element DNA, but it competed with the coactivator SRC1 (NCOA1; 602691) for modulation of ER-alpha transcriptional activity. By gel filtration, mass spectrometry, coimmunoprecipitation, and Western blot analysis of HeLa cells, Da Cruz et al. (2008) showed that prohibitin-1 (PHB; 176705) and prohibitin-2 interacted in a 250-kD complex with SLP2 (STOML2; 608292). Knockdown of SLP2 in HeLa cells or mouse embryonic fibroblasts via RNA interference led to increased proteolysis of the prohibitins and other mitochondrial proteins. Using coimmunoprecipitation analysis, Christie et al. (2011) confirmed that SLP2 interacted with PHB1 and PHB2. Elevated SLP2 content increased the association of PHB1 with mitochondrial membranes.MAPPING
Hartz (2013) mapped the PHB2 gene to chromosome 12p13.31 based on an alignment of the PHB2 sequence (GenBank GENBANK AF150962) with the genomic sequence (GRCh37).ANIMAL MODEL
Mussi et al. (2006) reported that Rea deletion in mice was embryonic lethal. They found that, compared with wildtype mice, virgin Rea +/- mice exhibited faster mammary ductal elongation, and Rea +/- mice showed increased lobuloalveolar development during pregnancy and delayed mammary gland involution after weaning. These phenotypes of Rea +/- mice were associated with significantly increased cell proliferation and ER transcriptional activities. Rea repressed ER transcriptional activity in mouse mammary gland under natural conditions, as well as following ovariectomy and after estrogen replacement. Using conditional gene targeting, Merkwirth et al. (2008) restricted expression of mouse Phb2 to mitochondria and identified processing of the dynamin (see 602377)-like GTPase Opa1 (605290), an essential component of the mitochondrial fusion machinery, as the central cellular process controlled by prohibitins. Deletion of Phb2 led to selective loss of long isoforms of Opa1, resulting in aberrant cristae morphogenesis, impaired cellular proliferation, and resistance to apoptosis. Expression of a long Opa1 isoform in Phb2-deficient cells suppressed these defects, identifying impaired Opa1 processing as the primary cellular defect in the absence of prohibitins. Merkwirth et al. (2008) concluded that prohibitins are essential for formation ... More on the omim web site
Aug. 24, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 610704 was added.
April 25, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
June 7, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).