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PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, alpha)

Written2015-09Keli Lima, João Agostinho Machado-Neto
Department of Clinical Pathology, School of Medical Sciences, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil (KL); Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo, Brazil (JAMN); Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil (JAMN) jamachadoneto@gmail.com

Abstract PIP4K2A is a lipid kinase that phosphorylates phosphatidylinositol (PtdIns) 5P, generating PtdIns4,5P2, which is an important precursor to second messengers of the phosphoinositide signal transduction pathways. Recently, studies have indicated that PIP4K2A is involved in the regulation of important biological processes that participate in the malignant phenotype, including cell proliferation, clonogenicity and survival. The present review on PIP4K2A contains data on DNA/RNA, protein encoded and where the gene is implicated.

Keywords PIP4K2A; cell proliferation; clonogenicity; cell cycle; apoptosis; phosphatidylinositol signaling

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPIP5K2A
phosphatidylinositol-4-phosphate 5-kinase, type II, alpha
phosphatidylinositol-5-phosphate 4-kinase, type II, alpha
Alias_symbol (synonym)PIP5KIIA
PIP5KIIalpha
Other aliasPIPK
PI5P4KA
PIP5KII-alpha
HGNC (Hugo) PIP4K2A
LocusID (NCBI) 5305
Atlas_Id 43943
Location 10p12.2  [Link to chromosome band 10p12]
Location_base_pair Starts at 22534837 and ends at 22714108 bp from pter ( according to hg19-Feb_2009)  [Mapping PIP4K2A.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)
PIP4K2A (10p12.2) / ABLIM1 (10q25.3)PIP4K2A (10p12.2) / RPS6KC1 (1q32.3)PSMG2 (18p11.21) / PIP4K2A (10p12.2)
RIMKLB (12p13.31) / PIP4K2A (10p12.2)XRN1 (3q23) / PIP4K2A (10p12.2)

DNA/RNA

Description The entire PIP4K2A gene is about 179.7 Kb (start: 22534837 and end: 22714574 bp; orientation: Minus strand) and contains 10 exons. The PIP4K2A cDNA contains 3.8 Kb.

Protein

 
Description PIP4K2A protein consists of 406 aminoacids with a molecular weight of 53 kDa and has a conserved phosphatidylinositol phosphate kinase (PIPK) domain in the C-terminal region. The schematic representation of PIP4K2A protein is illustrated in Figure 1.
Expression Ubiquitous.
 
Localisation PIP4K2A is predominantly located in the cytoplasm. However, in some cell types PIP4K2A was found in both nucleus and cytoplasm (Figure 2).
 
Function PIP4K2A belongs to the class II of the phosphatidylinositol-5-phosphate 4-kinase family, and major function of these proteins is to recognize the phosphatidylinositol (PtdIns) phosphorylated at position five (PtdIns5P) and phosphorylate inositol ring in position four, to generate a new lipid messenger, the phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2) (Figure 3). The PtdIns4,5P2 plays an important role in phosphoinositide signaling, participating in several cell processes, including vesicle transport, cell proliferation, adhesion, apoptosis and nuclear events (revised in McCrea and De Camilli, 2009). The acknowledgment about the functions of PIP4K proteins in cellular mechanism is still under construction and recent findings suggest that this protein family is strongly involved in oxidative stress and cellular senescence (revised in Fiume, et al., 2015). In contrast, the specific functions of PIP4K2A are poorly elucidated, and seems to vary according to cell type and stimulus. For instance, PIP4K2A silencing reduces cell survival in THP1 cells (an acute myeloid leukemia cells) (Jude, et al., 2015), but not in K562 cells (a chronic myeloid leukemia cell line) (Peretti de Albuquerque Wobeto, et al., 2014), whereas its overexpression reduces clonogenicity and sensibility to oxidative stress in O2OS cells (Jones, et al., 2013). PIP4K2A was initially identified in erythrocytes (Ling, et al., 1989) and its expression was found to be upregulated during erythroid differentiation (Peretti de Albuquerque Wobeto, et al., 2014, Zaccariotto, et al., 2012), suggesting a potential participation in cell differentiation. Of note, among the PIP4K proteins, which include PIP4K2A, PIP4K2B and PIP4KC, PIP4K2A has been reported as having the highest kinase activity (Bultsma, et al., 2010). PIP4K2A might also form heterodimer with PIP4K2B and result in PIP4K2A nuclear translocation (Bultsma, et al., 2010, Wang, et al., 2010).
Homology PIP4K2A shares high homology with the other members of the PIP4K protein family, including PIP4K2B and PIP4K2C. PIP4K2A also shares high homology among different species (Table 1).
Table 1. Comparative identity of human PIP4K2A with other species



% Identity for: Homo sapiens PIP4K2A

Symbol

Protein

DNA

vs. P. troglodytes

PIP4K2A

100

99.9

vs. M. mulatta

PIP4K2A

100

98.7

vs. C. lupus

PIP4K2A

100

91.8

vs. B. taurus

PIP4K2A

99.3

92.6

vs. M. musculus

Pip4k2a

98.3

89.5

vs. R. norvegicus

Pip4k2a

97.5

87.9

vs. G. gallus

PIP4K2A

93.6

84.5

vs. X. tropicalis

pip4k2b

93.2

80.9

vs. D. rerio

pip4k2aa

87.6

76.8


(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic Recurrent mutations in the PIP4K2A gene are rare, 68 substitution missense, 1 substitution nonsense, 19 substitution synonymous, 2 insertion frameshift and 4 deletion frameshift mutations are reported in COSMIC (Catalogue of somatic mutations in cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic).

Implicated in

Note
  
Entity Acute Leukemia
Note Wobeto and colleagues (Peretti de Albuquerque Wobeto, et al., 2014) reported that PIP4K2A is a nuclear and cytoplasm protein widely expressed in myeloid leukemia cell lines, and that PIP4K2A inhibition induces hemoglobin production and slightly decreases cell proliferation, but does not modulate apoptosis in K562 cells. Using a targeted knockdown screen for phosphoinositide modulator genes as approach, Jude and colleagues (Jude, et al., 2015) identified PIP4K2A as an important gene for proliferation, clonogenicity and survival of acute myeloid leukemia cells. In this work, the sensibility to PIP4K2A inhibition was modulated by CDKN1A (p21) and mTOR activation. Szczepanek and colleagues (Szczepanek, et al., 2012), using ex vivo drug sensitivity experiments and DNA microarray analysis in childhood acute lymphoblastic leukemia cells, found that PIP4K2A gene signature was associated with drug resistance for vincristine, thioguanine, melphalan and doxorubicin. Recently, our research group (Lima, et al., 2015) observed that PIP4K2A expression was reduced in a panel of myeloid and lymphoid leukemia cells when compared with normal leukocytes. Similar PIP4K2A expression prolife was observed in acute lymphoblastic leukemia patients compared with healthy donors. In our study, HEL cells, a myeloid leukemia cell line that presents very low levels of p21, and Namalwa cells, a lymphoid leukemia cell line, that presents constitutive PI3K/AKT activation, did not show any modulation regarding cell proliferation, clonogenicity and apoptosis upon PIP4K2A silencing (Lima, et al., 2015).
  
  
Entity Myelodysplastic syndromes
Note In a cohort of 54 untreated patients with myelodysplastic syndromes (MDS) was observed a reduction of PIP4K2A expression in ≥5% bone marrow blats MDS patients group and an association between low expression of PIP4K2A and high blast percentage. Interestingly, MDS patients with low levels of PIP4K2A (stratified by tertiles) presented reduced overall survival by univariate analysis (Lima, et al., 2015).
  
  
Entity Breast cancer
Note Emerling and colleagues (Emerling, et al., 2013), using immunohistochemistry and western blot, reported that PIP4K2A is highly expressed in primary samples and cell lines from breast cancer. In this study, PIP4K2A plus PIP4K2B silencing reduced cell proliferation and tumor growth and induced cell senescence of null, but not of p53 wild type, breast cancer cell lines. Of note that triple knockout mice for PIP4K2A, PIP4K2B and TP53 presented reduced tumor burden and increased tumor free survival compared with Tp53 knockout mice (Emerling, et al., 2013).
  
  
Entity Osteosarcoma
Note Using the osteosarcoma cell line, U2OS cells, Jones and colleagues (Jones, et al., 2013) observed that induction of oxidative stress inhibits PIP4K2A activity and PIP4K2A overexpression reduces clonogenic cell growth. In contrast, PIP4K2A overexpression increased cell viability in response to oxidative stress in U2OS cells (Jones, et al., 2013).
  

To be noted

PIP4K2A knockout has been reported in several organisms, including fly, worm, fish and mouse, and different phenotypes has been described. In Drosophila and zebrafish, PIP4K2A orthologue protein knockout resulted in strong defective development (Gupta, et al., 2013, Elouarrat, et al., 2013). In Caenorhabditis elegans, PIP4K2A orthologue protein knockout did not lead to developmental defects, but increased oxidative stress (Fiume, et al., 2015). In mice, Pip4k2a knockout did not present any aberrant phenotype (Emerling, et al., 2013).

Bibliography

PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha
Bultsma Y, Keune WJ, Divecha N
Biochem J 2010 Sep 1;430(2):223-35
PMID 20583997
 
Role of phosphatidylinositol 5-phosphate 4-kinase α in zebrafish development
Elouarrat D, van der Velden YU, Jones DR, Moolenaar WH, Divecha N, Haramis AP
Int J Biochem Cell Biol 2013 Jul;45(7):1293-301
PMID 23542014
 
Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors
Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R, Wulf GM, Bell EL, Shim HS, Lamia KA, Rameh LE, Bellinger G, Sasaki AT, Asara JM, Yuan X, Bullock A, Denicola GM, Song J, Brown V, Signoretti S, Cantley LC
Cell 2013 Nov 7;155(4):844-57
PMID 24209622
 
PIP4K and the role of nuclear phosphoinositides in tumour suppression
Fiume R, Stijf-Bultsma Y, Shah ZH, Keune WJ, Jones DR, Jude JG, Divecha N
Biochim Biophys Acta 2015 Jun;1851(6):898-910
PMID 25728392
 
Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) regulates TOR signaling and cell growth during Drosophila development
Gupta A, Toscano S, Trivedi D, Jones DR, Mathre S, Clarke JH, Divecha N, Raghu P
Proc Natl Acad Sci U S A 2013 Apr 9;110(15):5963-8
PMID 23530222
 
PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation
Jones DR, Foulger R, Keune WJ, Bultsma Y, Divecha N
FASEB J 2013 Apr;27(4):1644-56
PMID 23241309
 
A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival
Jude JG, Spencer GJ, Huang X, Somerville TD, Jones DR, Divecha N, Somervaille TC
Oncogene 2015 Mar 5;34(10):1253-62
PMID 24681948
 
Differential profile of PIP4K2A expression in hematological malignancies
Lima K, Ribeiro DM, Campos Pde M, Costa FF, Traina F, Saad ST, Sonati Mde F, Machado-Neto JA
Blood Cells Mol Dis 2015 Oct;55(3):228-35
PMID 26227852
 
Characterization and purification of membrane-associated phosphatidylinositol-4-phosphate kinase from human red blood cells
Ling LE, Schulz JT, Cantley LC
J Biol Chem 1989 Mar 25;264(9):5080-8
PMID 2538472
 
Mutations in phosphoinositide metabolizing enzymes and human disease
McCrea HJ, De Camilli P
Physiology (Bethesda) 2009 Feb;24:8-16
PMID 19196647
 
PIPKII is widely expressed in hematopoietic-derived cells and may play a role in the expression of alpha- and gamma-globins in K562 cells
Peretti de Albuquerque Wobeto V, Machado-Neto JA, Zaccariotto TR, Ribeiro DM, da Silva Santos Duarte A, Saad ST, Costa FF, de Fatima Sonati M
Mol Cell Biochem 2014 Aug;393(1-2):145-53
PMID 24788727
 
Gene expression signatures and ex vivo drug sensitivity profiles in children with acute lymphoblastic leukemia
Szczepanek J, Jarzab M, Oczko-Wojciechowska M, Kowalska M, Tretyn A, Haus O, Pogorzala M, Wysocki M, Jarzab B, Styczynski J
J Appl Genet 2012 Feb;53(1):83-91
PMID 22038456
 
Genomic tagging reveals a random association of endogenous PtdIns5P 4-kinases IIalpha and IIbeta and a partial nuclear localization of the IIalpha isoform
Wang M, Bond NJ, Letcher AJ, Richardson JP, Lilley KS, Irvine RF, Clarke JH
Biochem J 2010 Sep 1;430(2):215-21
PMID 20569199
 
Expression profiles of phosphatidylinositol phosphate kinase genes during normal human in vitro erythropoiesis
Zaccariotto TR, Lanaro C, Albuquerque DM, Santos MN, Bezerra MA, Cunha FG, Lorand-Metze I, Araujo AS, Costa FF, Sonati MF
Genet Mol Res 2012 Nov 12;11(4):3861-8
PMID 23212325
 

Citation

This paper should be referenced as such :
Lima K, Machado-Neto JA
PIP4K2A (phosphatidylinositol-5-phosphate 4-kinase, type II, alpha);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/PIP4K2AID43943ch10p12.html


External links

Nomenclature
HGNC (Hugo)PIP4K2A   8997
Cards
AtlasPIP4K2AID43943ch10p12
Entrez_Gene (NCBI)PIP4K2A  5305  phosphatidylinositol-5-phosphate 4-kinase type 2 alpha
AliasesPI5P4KA; PIP5K2A; PIP5KII-alpha; PIP5KIIA; 
PIPK
GeneCards (Weizmann)PIP4K2A
Ensembl hg19 (Hinxton)ENSG00000150867 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000150867 [Gene_View]  chr10:22534837-22714108 [Contig_View]  PIP4K2A [Vega]
ICGC DataPortalENSG00000150867
TCGA cBioPortalPIP4K2A
AceView (NCBI)PIP4K2A
Genatlas (Paris)PIP4K2A
WikiGenes5305
SOURCE (Princeton)PIP4K2A
Genetics Home Reference (NIH)PIP4K2A
Genomic and cartography
GoldenPath hg38 (UCSC)PIP4K2A  -     chr10:22534837-22714108 -  10p12.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PIP4K2A  -     10p12.2   [Description]    (hg19-Feb_2009)
EnsemblPIP4K2A - 10p12.2 [CytoView hg19]  PIP4K2A - 10p12.2 [CytoView hg38]
Mapping of homologs : NCBIPIP4K2A [Mapview hg19]  PIP4K2A [Mapview hg38]
OMIM603140   
Gene and transcription
Genbank (Entrez)AK023329 AK294817 AK294867 BC018034 DB504104
RefSeq transcript (Entrez)NM_001330062 NM_005028
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PIP4K2A
Cluster EST : UnigeneHs.57079 [ NCBI ]
CGAP (NCI)Hs.57079
Alternative Splicing GalleryENSG00000150867
Gene ExpressionPIP4K2A [ NCBI-GEO ]   PIP4K2A [ EBI - ARRAY_EXPRESS ]   PIP4K2A [ SEEK ]   PIP4K2A [ MEM ]
Gene Expression Viewer (FireBrowse)PIP4K2A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5305
GTEX Portal (Tissue expression)PIP4K2A
Human Protein AtlasENSG00000150867-PIP4K2A [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP48426   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP48426  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP48426
Splice isoforms : SwissVarP48426
Catalytic activity : Enzyme2.7.1.149 [ Enzyme-Expasy ]   2.7.1.1492.7.1.149 [ IntEnz-EBI ]   2.7.1.149 [ BRENDA ]   2.7.1.149 [ KEGG ]   
PhosPhoSitePlusP48426
Domaine pattern : Prosite (Expaxy)PIPK (PS51455)   
Domains : Interpro (EBI)PInositol-4-P-5-kinase    PInositol-4-P-5-kinase_C    PInositol-4-P-5-kinase_core    PInositol-4-P-5-kinase_N   
Domain families : Pfam (Sanger)PIP5K (PF01504)   
Domain families : Pfam (NCBI)pfam01504   
Domain families : Smart (EMBL)PIPKc (SM00330)  
Conserved Domain (NCBI)PIP4K2A
DMDM Disease mutations5305
Blocks (Seattle)PIP4K2A
PDB (SRS)2YBX   
PDB (PDBSum)2YBX   
PDB (IMB)2YBX   
PDB (RSDB)2YBX   
Structural Biology KnowledgeBase2YBX   
SCOP (Structural Classification of Proteins)2YBX   
CATH (Classification of proteins structures)2YBX   
SuperfamilyP48426
Human Protein Atlas [tissue]ENSG00000150867-PIP4K2A [tissue]
Peptide AtlasP48426
HPRD11931
IPIIPI00009688   IPI01014663   IPI00908895   IPI00553149   IPI00645598   
Protein Interaction databases
DIP (DOE-UCLA)P48426
IntAct (EBI)P48426
FunCoupENSG00000150867
BioGRIDPIP4K2A
STRING (EMBL)PIP4K2A
ZODIACPIP4K2A
Ontologies - Pathways
QuickGOP48426
Ontology : AmiGOATP binding  cellular_component  nucleoplasm  autophagosome  cytosol  plasma membrane  phospholipid metabolic process  phosphatidylinositol biosynthetic process  regulation of autophagy  regulation of phosphatidylinositol 3-kinase signaling  1-phosphatidylinositol-4-phosphate 5-kinase activity  1-phosphatidylinositol-5-phosphate 4-kinase activity  1-phosphatidylinositol-5-phosphate 4-kinase activity  megakaryocyte development  phosphatidylinositol phosphorylation  1-phosphatidylinositol-3-phosphate 4-kinase activity  positive regulation of autophagosome assembly  
Ontology : EGO-EBIATP binding  cellular_component  nucleoplasm  autophagosome  cytosol  plasma membrane  phospholipid metabolic process  phosphatidylinositol biosynthetic process  regulation of autophagy  regulation of phosphatidylinositol 3-kinase signaling  1-phosphatidylinositol-4-phosphate 5-kinase activity  1-phosphatidylinositol-5-phosphate 4-kinase activity  1-phosphatidylinositol-5-phosphate 4-kinase activity  megakaryocyte development  phosphatidylinositol phosphorylation  1-phosphatidylinositol-3-phosphate 4-kinase activity  positive regulation of autophagosome assembly  
Pathways : KEGGInositol phosphate metabolism    Phosphatidylinositol signaling system    Regulation of actin cytoskeleton   
REACTOMEP48426 [protein]
REACTOME PathwaysR-HSA-8847453 [pathway]   
NDEx NetworkPIP4K2A
Atlas of Cancer Signalling NetworkPIP4K2A
Wikipedia pathwaysPIP4K2A
Orthology - Evolution
OrthoDB5305
GeneTree (enSembl)ENSG00000150867
Phylogenetic Trees/Animal Genes : TreeFamPIP4K2A
HOVERGENP48426
HOGENOMP48426
Homologs : HomoloGenePIP4K2A
Homology/Alignments : Family Browser (UCSC)PIP4K2A
Gene fusions - Rearrangements
Fusion : MitelmanPIP4K2A/ABLIM1 [10p12.2/10q25.3]  
Fusion : MitelmanRIMKLB/PIP4K2A [12p13.31/10p12.2]  [t(10;12)(p12;p13)]  
Fusion: TCGAPIP4K2A 10p12.2 ABLIM1 10q25.3 KIRC
Fusion: TCGARIMKLB 12p13.31 PIP4K2A 10p12.2 LGG
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPIP4K2A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PIP4K2A
dbVarPIP4K2A
ClinVarPIP4K2A
1000_GenomesPIP4K2A 
Exome Variant ServerPIP4K2A
ExAC (Exome Aggregation Consortium)ENSG00000150867
GNOMAD BrowserENSG00000150867
Genetic variants : HAPMAP5305
Genomic Variants (DGV)PIP4K2A [DGVbeta]
DECIPHERPIP4K2A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPIP4K2A 
Mutations
ICGC Data PortalPIP4K2A 
TCGA Data PortalPIP4K2A 
Broad Tumor PortalPIP4K2A
OASIS PortalPIP4K2A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPIP4K2A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPIP4K2A
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PIP4K2A
DgiDB (Drug Gene Interaction Database)PIP4K2A
DoCM (Curated mutations)PIP4K2A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PIP4K2A (select a term)
intoGenPIP4K2A
NCG5 (London)PIP4K2A
Cancer3DPIP4K2A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603140   
Orphanet14433   
MedgenPIP4K2A
Genetic Testing Registry PIP4K2A
NextProtP48426 [Medical]
TSGene5305
GENETestsPIP4K2A
Target ValidationPIP4K2A
Huge Navigator PIP4K2A [HugePedia]
snp3D : Map Gene to Disease5305
BioCentury BCIQPIP4K2A
ClinGenPIP4K2A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5305
Chemical/Pharm GKB GenePA162399615
Clinical trialPIP4K2A
Miscellaneous
canSAR (ICR)PIP4K2A (select the gene name)
Probes
Litterature
PubMed59 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePIP4K2A
EVEXPIP4K2A
GoPubMedPIP4K2A
iHOPPIP4K2A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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