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| 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. |
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| Localisation | PIP4K2A is predominantly located in the cytoplasm. However, in some cell types PIP4K2A was found in both nucleus and cytoplasm (Figure 2). |
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| 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) |
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| 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). |
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| 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). |
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| 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). |
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| 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). |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Mutations in phosphoinositide metabolizing enzymes and human disease |
| McCrea HJ, De Camilli P |
| Physiology (Bethesda) 2009 Feb;24:8-16 |
| PMID 19196647 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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