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

2015-09-01   Keli Lima , Joao Agostinho Machado-Neto 

Identity

HGNC
LOCATION
10p12.2
LOCUSID
ALIAS
PI5P4KA,PIP5K2A,PIP5KII-alpha,PIP5KIIA,PIPK
FUSION GENES

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.

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.

Proteins

Atlas Image

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.
Atlas Image

Localisation

PIP4K2A is predominantly located in the cytoplasm. However, in some cell types PIP4K2A was found in both nucleus and cytoplasm (Figure 2).
Atlas Image

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

Entity name
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 name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
205839972010PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha.Bultsma Y et al
235420142013Role of phosphatidylinositol 5-phosphate 4-kinase α in zebrafish development.Elouarrat D et al
242096222013Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.Emerling BM et al
257283922015PIP4K and the role of nuclear phosphoinositides in tumour suppression.Fiume R et al
235302222013Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) regulates TOR signaling and cell growth during Drosophila development.Gupta A et al
232413092013PtdIns5P is an oxidative stress-induced second messenger that regulates PKB activation.Jones DR et al
246819482015A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.Jude JG et al
262278522015Differential profile of PIP4K2A expression in hematological malignancies.Lima K et al
25384721989Characterization and purification of membrane-associated phosphatidylinositol-4-phosphate kinase from human red blood cells.Ling LE et al
191966472009Mutations in phosphoinositide metabolizing enzymes and human disease.McCrea HJ et al
247887272014PIPKIIα 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 et al
220384562012Gene expression signatures and ex vivo drug sensitivity profiles in children with acute lymphoblastic leukemia.Szczepanek J et al
205691992010Genomic tagging reveals a random association of endogenous PtdIns5P 4-kinases IIalpha and IIbeta and a partial nuclear localization of the IIalpha isoform.Wang M et al
232123252012Expression profiles of phosphatidylinositol phosphate kinase genes during normal human in vitro erythropoiesis.Zaccariotto TR et al

Other Information

Locus ID:

NCBI: 5305
MIM: 603140
HGNC: 8997
Ensembl: ENSG00000150867

Variants:

dbSNP: 5305
ClinVar: 5305
TCGA: ENSG00000150867
COSMIC: PIP4K2A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000150867ENST00000323883H7BXS3
ENSG00000150867ENST00000376573P48426
ENSG00000150867ENST00000545335P48426
ENSG00000150867ENST00000604912S4R320

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Inositol phosphate metabolismKEGGko00562
Phosphatidylinositol signaling systemKEGGko04070
Regulation of actin cytoskeletonKEGGko04810
Inositol phosphate metabolismKEGGhsa00562
Phosphatidylinositol signaling systemKEGGhsa04070
Regulation of actin cytoskeletonKEGGhsa04810
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
PI MetabolismREACTOMER-HSA-1483255
Synthesis of PIPs at the plasma membraneREACTOMER-HSA-1660499
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through AcetylationREACTOMER-HSA-6804758
PI5P Regulates TP53 AcetylationREACTOMER-HSA-6811555
Synthesis of PIPs in the nucleusREACTOMER-HSA-8847453

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
239960882013Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype.63
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
242096222013Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.59
210416082011Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up.48
205839972010PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha.24
246819482015A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.24
199379772010Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample.19
199379772010Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample.19
174106402007The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia.17

Citation

Keli Lima ; Joao Agostinho Machado-Neto

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

Atlas Genet Cytogenet Oncol Haematol. 2015-09-01

Online version: http://atlasgeneticsoncology.org/gene/43943/pip4k2a