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PHLDA2 (Pleckstrin homology-like domain, family A, member 2)

Written2020-10Renan Gomes do Nascimento, Flavia Rotea Mangone Ana Carolina Pavanelli, Maria Aparecida Nagai
Disciplina de Oncologia, Departamento de Radiologia e Oncologia, Faculdade de Medicina, Universidade de São Paulo, 01246-903, São Paulo, Brasil (RGN, NMA), Laboratório de Genética Molecular, Centro de Investiga&ccdil;ão Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo (ICESP), 01246-000, São Paulo, Brasil; (RGN, FRM, ACP, NMA) nagai@usp.br.

Abstract Review of the PHLDA2 gene, with data on DNA, the protein encoded by this gene, and biological and pathological implications.

Keywords PHLDA2; genomic imprinting; glycogen storage; apoptosis; cell-cycle; epithelial-mesenchymal transition

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)TSSC3
IPL
BWR1C
BRW1C
HLDA2
HGNC (Hugo) PHLDA2
HGNC Alias symbIPL
BWR1C
HLDA2
HGNC Previous nameTSSC3
HGNC Previous name"tumor suppressing subtransferable candidate 3
 pleckstrin homology-like domain, family A, member 2"
LocusID (NCBI) 7262
Atlas_Id 41708
Location 11p15.4  [Link to chromosome band 11p15]
Location_base_pair Starts at 2928273 and ends at 2929420 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PHLDA2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note PHLDA2 gene was mapped on human chromosome 11p15.5, considered an important region comprising human tumor suppressor genes (Qian et al., 1997; Hu et al., 1997). This gene exhibits a monoallelic expression by genomic imprinting with preferential expression of the maternal allele (Lee & Feinberg, 1998). Phylogenetic analyses classify PHLDA2 as a member of the pleckstrin homology superfamily (PHL), including PHLDA1 and PHLDA3 (Frank et al., 1999; Saxena et al., 2002). The PHLDA2 gene consists of 1,148 base pairs, 2 exons, and 1 intron, encodes a 9.2 kb mRNA with a coding region of 458 bp. 

DNA/RNA

Description DNA size: 1,148 kb, 2 exons.
Transcription mRNA size 920 pb NM_003311.4. Only one transcript variant encoding PHLDA2 have been described. NM_003311 - Homo sapiens pleckstrin homology-like domain, family A, member 2 (PHLDA2), mRNA -> Transcript size: 920 bp. NP_003302.1. (https://www.ncbi.nlm.nih.gov/nuccore/NM_003311; http://www.ensembl.org/id/ENST00000314222.5).

Protein

 
  Figure 1. Schematic representation of the modular structure of the PHLDA2 protein. The PHLDA2 protein structure consists of a single PHL domain (pleckstrin homology-like) from amino acid residues 7 to 99, flanked by short terminal extensions.
Description The protein encoded by the PHLDA2 gene consists of 152 amino acids, a molecular weight of 17.1 kDa, composed mainly of the PHL domain (93aa) (Frank et al., 1999). The PHL domain present in its structure has a moderate binding affinity to phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate (PIP3) (Frank et al., 2002; Saxena et al., 2002). NP_003302.1 (https://www.ncbi.nlm.nih.gov/protein/NP_003302)
Expression According to the integrative human mRNA and protein expression map, the PHLDA2 is remarkably expressed in placental tissue. Tissues of stomach, colon, prostate, duodenum, small intestine, and kidney are those of more abundant expression (Fagerberg et al., 2013). A monoallelic expression is observed in human fetal tissues such as the kidney, intestine, liver, heart, being the maternal allele preferentially expressed (Lee & Feinberg, 1998). It has been shown that PHLDA2 expression is down-regulated under hypoxia in human trophoblasts (Roh et al., 2005). PHLDA2 has been described as the first apoptotic related gene regulated by genomic imprinting (Lee & Feinberg, 1998). PHLDA2 expression is negatively regulated at the minimum by two different mechanisms, one by at least to miRNAs ( MIR214 MIR148A-5p) and by a methyltransferase called EZH2 (Lv et al., 2015; Idishi et al., 2018; Li et al., 2019).
Localisation The mature PHLDA2 protein subcellular localization is at the cytoplasm, cellular membrane, and also peripheral membrane protein (https://www.uniprot.org/uniprot/Q53GA4).
Function The PHLDA2 gene is one of several genes clustered at 11p15.5 domain, an important region for tumor suppressor genes. Changes in this chromosomal region have already been described in Beckwith-Wiedemann syndrome, hydatidiform mole, and different types of tumors (Hu et al., 1997, Weksberg et al., 2005, Feinberg, 1999).
The protein encoded by the PHLDA2 gene can play different biological roles depending on cell or tissue specificity (https://www.uniprot.org/uniprot/Q53GA4). In mouse models, PHLDA2 negatively controls glycogen storage during pregnancy, negatively regulates the expression of a variety of placental hormones through the spongiotrophoblast layer (Tunster et al., 2010; Tunster et al., 2016).
PHLDA2 (TSSC3) has been shown to induce apoptosis by increasing the intrinsic pro-apoptotic pathway members such as BAK1, BCL2L11 (BIM), CYCS (Cyt c), and the BAX: BCL2 ratio and downregulating anti-apoptotic proteins like BCL2 and FAS in human osteosarcoma cell lines (Dai et al., 2012; Huang et al., 2012). PHLDA2 has also been shown to have a role in anoikis resistance and metastasis through the interaction with RANBP9 and downregulation of the SRC -dependent Akt pathway in osteosarcoma cells (Dai et al., 2016).
Experimental evidence also associated increased expression of PHLDA2 in trophoblast cells with cell-cycle inhibition through the reduction of cyclin D1 and cyclin E ( CCND1 and CCNE1) arresting cells in G0/G1 phase of the cell cycle (Jin et al., 2015).
PHLDA2 increases epithelial-mesenchymal transition (EMT) of osteosarcoma cells by upregulating mesenchymal markers, such as CDH2 (N-cadherin), VIM (Vimentin), and SNAI1 (SNAIL), and inhibiting the epithelial markers like CDH1 (E-cadherin) (Dai et al., 2016, Lv et al., 2016). Additionally, PHLDA2 can inhibit Src/Akt pathway suppressing self-renewal in osteosarcoma stem cells (Yan et al., 2017), and this Src/Akt pathway inactivation prevents MTOR phosphorylation, that drives osteosarcoma cells to autophagy, contributing to the inhibition of tumorigenesis and metastasis (Zhao et al., 2018).
 
  Figure 2 - Schematic diagram of the modulators, effectors, and biological processes associated with PHLDA2 expression. Different stimuli can modulate PHLDA2 expression. Therefore, various biological processes are associated depending on the stimulus and cellular effectors.
Homology The human protein encoded by the PHLDA2 gene is highly conserved in vertebrates. Orthologs have been described in Pan troglodytes (chimpanzee); Macaca mulatta (Rhesus monkey); Bos taurus (cattle); Mus musculus (house mouse); Rattus norvegicus (Norway rat); Gallus gallus (chicken), Xenopus tropicalis (tropical clawed frog), Danio rerio (zebrafish) (https://www.ncbi.nlm.nih.gov/homologene/2482), among others also described at Ensembl genome browser (https://www.ensembl.org/ PHLDA2 ENSG00000181649, Ensembl release 100 - April 2020). Moreover, two protein paralogues are known: PHLDA1 (pleckstrin homology like domain, family A, member 1) e PHLDA3 (pleckstrin homology like domain, family A, member 3) (https://www.ensembl.org/ PHLDA2 ENSG00000181649)

Implicated in

Note The PHLDA2 gene is located in a chromosomal region considered an important center for imprinting and localizing tumor suppressor genes. Alterations in the expression of PHLDA2 has been reported in different types of tumors. However, the attribution of its oncogenic or suppressive functions in tumor development is under investigation (Dai et al., 2012; Hsu et al., 2017; Zhao et al., 2018).
  
Entity Placental and Fetal Development
Note Several reports in the literature have been shown the role played by PHLDA2 expression in placental development. Salas et al. (2004), using a transgenic model, demonstrated that loss of Phlda2 expression in animals with wild background causes placentomegaly and increased expression of this gene in the placenta causes a significant delay in placental growth. High expression of the PHLDA2 leads to decreased expression of genes associated with lipids production, regulated by spongiophoblasts, causing placental dwarfism and reduction in the accumulation of placental glycogen (Tunster et al., 2016). High expression of PHLDA2 was also significantly associated with decreased birth weight, showing that PHLDA2 can act to decrease body weight by reducing the size and function of the placenta (Apostolidou et al., 2007). The expression of PHLDA2 in the placenta was significantly correlated with decreased femur growth in fetuses between 19 and 34 weeks of gestation and later associated with a lower bone mineral content of the child at the age of four (Lewis et al., 2012).
PHLDA2 expression has been associated with hydatidiform mole disease, in which an increase in PHLDA2 expression was observed in trophoblast cells, possibly due to trisomy of the 11p15.5 chromosomal region (Fisher et al., 2004).
PHLDA2 expression has also been associated with the development of spontaneous abortions, where the increased expression of this gene was observed in placental and fetal samples in the first half of the interrupted pregnancy, showing that this gene may be a possible marker in fetal growth. In vitro studies, with trophoblast cells with overexpression of PHLDA2, showed inhibition of cell growth, migration, and invasion. On the other hand, PHLDA2 reduced expression showed the opposite effect, with an increase in migration and invasion, suggesting the involvement of PHLDA2 in the development of pre-eclampsia due to inhibition of proliferation, migration, and invasion of trophoblastic cells (Jin et al., 2015).
  
  
Entity Lung cancer
Note High expression of PHLDA2 was observed in samples of lung adenocarcinoma compared to adjacent normal tissue. Increased PHLDA2 expression was associated with poor patient survival, suggesting an oncogenic role of PHLDA2 in the development of lung cancer (Hsu e al., 2017). PHLDA2 was also identified as negatively regulated in lung cancer cell lines after inhibiting the EGFR/ ERBB2 pathway. In addition, PHLDA2 expression showed a direct correlation with the expression of p-AKT, suggesting that PHLDA2 may act in the regulation of oncogenic signaling pathways (Wang et al., 2018).
  
  
Entity Osteosarcoma
Note In osteosarcomas, PHLDA2 has been investigated and reported as a possible gene with tumor-suppressive activities. Osteosarcoma samples showed reduced expression of PHLDA2 when compared to adjacent normal tissue and were found to be associated with clinical-pathological data, such as high tumor grade, presence of metastasis, and tumor recurrence (Dai et al., 2012; Wang et al., 2016). PHLDA2 knockdown results in increased cell proliferation and colony formation decreased cell division and apoptosis, and increased tumor growth, which suggests that inactivation of the PHLDA2 protein may contribute to the development and progression of these tumors (Dai et al., 2012). Osteosarcoma cells with PHLDA2 overexpression show increased autophagy and reduced MTOR phosphorylation via SRC/AKT, leading to suppression of tumorigenesis and metastatic phenotype (Zhao et al., 2018). Recently, negative regulation of PHLDA2 expression has been associated with MIR214 expression, promoting resistance to radiotherapy, pulmonary metastasis, and activation of the AKT pathway, suggesting that PHLDA2/AKT may be a new radiotherapy target in osteosarcomas (Yi Li, et al. 2019).
  
  
Entity Pancreatic adenocarcinoma
Note Pancreatic adenocarcinoma is one of the most lethal cancers, in which only 5% of patients have recurrence-free survival in 5 years. Low expression of PHLDA2, directly modulated by MIR148A-5p, inhibits proliferation, migration, and invasion and increases apoptosis in PANC-1 cells, which are derived from pancreatic carcinoma (Idich et al., 2018).
  
  
Entity Colorectal cancer
Note A recent study found that colorectal tumors showed higher expression of PHLDA2 (transcripts and proteins) when compared to adjacent normal tissues. The inactivation of these proteins in colorectal cancer-derived lineage promoted inhibition of cell growth, migration and invasion, and reduced expression of proteins related to the epithelium-mesenchymal transition, and induction of autophagy through the PI3K/AKT signaling pathway, suggesting that PHLDA2 may play a role in the development and progression of colorectal cancer (Zhan Ma et al., 2020).
  
  
Entity Breast cancer
Note There are few studies in the literature addressing the expression of PHLDA2 in breast cancer. Moon et al. (2015), using patient-derived xenograft (PDX) technique, sought to investigate the prognostic role and a gene signature in breast tumors of the triple-negative subtype. PHLDA2 was shown to be positively regulated in cells of the triple negative breast cancer subtype, and its silencing led to a reduction in invasion and proliferation of MDA-MB-231 cells, suggesting the involvement of PHLDA2 in the breast cancer.
  

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Citation

This paper should be referenced as such :
Gomes do Nascimento R, Mangone FR, Pavanelli C, Nagai MA
PHLDA2 (Pleckstrin homology-like domain, family A, member 2);
Atlas Genet Cytogenet Oncol Haematol. in press


External links

Nomenclature
HGNC (Hugo)PHLDA2   12385
LRG (Locus Reference Genomic)LRG_1043
Cards
AtlasPHLDA2ID41708ch11p15
Entrez_Gene (NCBI)PHLDA2    pleckstrin homology like domain family A member 2
AliasesBRW1C; BWR1C; HLDA2; IPL; 
TSSC3
GeneCards (Weizmann)PHLDA2
Ensembl hg19 (Hinxton)ENSG00000181649 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000181649 [Gene_View]  ENSG00000181649 [Sequence]  chr11:2928273-2929420 [Contig_View]  PHLDA2 [Vega]
ICGC DataPortalENSG00000181649
TCGA cBioPortalPHLDA2
AceView (NCBI)PHLDA2
Genatlas (Paris)PHLDA2
SOURCE (Princeton)PHLDA2
Genetics Home Reference (NIH)PHLDA2
Genomic and cartography
GoldenPath hg38 (UCSC)PHLDA2  -     chr11:2928273-2929420 -  11p15.4   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PHLDA2  -     11p15.4   [Description]    (hg19-Feb_2009)
GoldenPathPHLDA2 - 11p15.4 [CytoView hg19]  PHLDA2 - 11p15.4 [CytoView hg38]
ImmunoBaseENSG00000181649
genome Data Viewer NCBIPHLDA2 [Mapview hg19]  
OMIM602131   
Gene and transcription
Genbank (Entrez)AF001294 AF019953 AF035444 AI659266 AK223027
RefSeq transcript (Entrez)NM_003311
RefSeq genomic (Entrez)NC_000011 NG_009266 NT_187585
Consensus coding sequences : CCDS (NCBI)PHLDA2
Alternative Splicing GalleryENSG00000181649
Gene ExpressionPHLDA2 [ NCBI-GEO ]   PHLDA2 [ EBI - ARRAY_EXPRESS ]   PHLDA2 [ SEEK ]   PHLDA2 [ MEM ]
Gene Expression Viewer (FireBrowse)PHLDA2 [ Firebrowse - Broad ]
GenevisibleExpression of PHLDA2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7262
GTEX Portal (Tissue expression)PHLDA2
Human Protein AtlasENSG00000181649-PHLDA2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ53GA4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ53GA4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ53GA4
Splice isoforms : SwissVarQ53GA4
PhosPhoSitePlusQ53GA4
Domains : Interpro (EBI)PH-like_dom_sf    PH_domain    PHLA1/2/3    PHLA2/3_PH   
Domain families : Pfam (Sanger)PH_15 (PF17339)   
Domain families : Pfam (NCBI)pfam17339   
Domain families : Smart (EMBL)PH (SM00233)  
Conserved Domain (NCBI)PHLDA2
Blocks (Seattle)PHLDA2
SuperfamilyQ53GA4
Human Protein Atlas [tissue]ENSG00000181649-PHLDA2 [tissue]
Peptide AtlasQ53GA4
HPRD03679
IPIIPI00019551   
Protein Interaction databases
DIP (DOE-UCLA)Q53GA4
IntAct (EBI)Q53GA4
BioGRIDPHLDA2
STRING (EMBL)PHLDA2
ZODIACPHLDA2
Ontologies - Pathways
QuickGOQ53GA4
Ontology : AmiGOplacenta development  cytoplasm  apoptotic process  animal organ morphogenesis  regulation of gene expression  membrane  regulation of cell migration  positive regulation of apoptotic process  regulation of spongiotrophoblast cell proliferation  regulation of glycogen metabolic process  phosphatidylinositol phosphate binding  regulation of growth hormone activity  
Ontology : EGO-EBIplacenta development  cytoplasm  apoptotic process  animal organ morphogenesis  regulation of gene expression  membrane  regulation of cell migration  positive regulation of apoptotic process  regulation of spongiotrophoblast cell proliferation  regulation of glycogen metabolic process  phosphatidylinositol phosphate binding  regulation of growth hormone activity  
NDEx NetworkPHLDA2
Atlas of Cancer Signalling NetworkPHLDA2
Wikipedia pathwaysPHLDA2
Orthology - Evolution
OrthoDB7262
GeneTree (enSembl)ENSG00000181649
Phylogenetic Trees/Animal Genes : TreeFamPHLDA2
HOGENOMQ53GA4
Homologs : HomoloGenePHLDA2
Homology/Alignments : Family Browser (UCSC)PHLDA2
Gene fusions - Rearrangements
Fusion : Fusion_HubFSCN1--PHLDA2    HNRNPK--PHLDA2   
Fusion : QuiverPHLDA2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPHLDA2 [hg38]
dbVarPHLDA2
ClinVarPHLDA2
MonarchPHLDA2
1000_GenomesPHLDA2 
Exome Variant ServerPHLDA2
GNOMAD BrowserENSG00000181649
Varsome BrowserPHLDA2
Genomic Variants (DGV)PHLDA2 [DGVbeta]
DECIPHERPHLDA2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPHLDA2 
Mutations
ICGC Data PortalPHLDA2 
TCGA Data PortalPHLDA2 
Broad Tumor PortalPHLDA2
OASIS PortalPHLDA2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPHLDA2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPHLDA2
Mutations and Diseases : HGMDPHLDA2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PHLDA2
DgiDB (Drug Gene Interaction Database)PHLDA2
DoCM (Curated mutations)PHLDA2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PHLDA2 (select a term)
intoGenPHLDA2
NCG6 (London) select PHLDA2
Cancer3DPHLDA2(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602131   
Orphanet
DisGeNETPHLDA2
MedgenPHLDA2
Genetic Testing Registry PHLDA2
NextProtQ53GA4 [Medical]
GENETestsPHLDA2
Target ValidationPHLDA2
Huge Navigator PHLDA2 [HugePedia]
ClinGenPHLDA2 (curated)
Clinical trials, drugs, therapy
MyCancerGenomePHLDA2
Protein Interactions : CTD
Pharm GKB GenePA37053
PharosQ53GA4
Clinical trialPHLDA2
Miscellaneous
canSAR (ICR)PHLDA2 (select the gene name)
HarmonizomePHLDA2
DataMed IndexPHLDA2
Probes
Litterature
PubMed43 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXPHLDA2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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