Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Phosphatidylinositol 5-Phosphate 4-Kinase

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_418


Historical Background

Phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) is an enzyme activity capable of converting a monophosphorylated lipid substrate into a bisphosphorylated product, a reaction that is fundamental in the maintenance of the cellular phosphoinositide (PI) cycle. PI5P4K catalyzes the addition of a phosphate group to position D-4 of the inositol head-group of PtdIns5P (Figs. 1 and 2). Downstream effects of signaling molecules generated by the PI cycle are diverse and include vesicle trafficking, ion channel activity, cytoskeletal dynamics, cell differentiation, proliferation, and apoptosis (Di Paolo and De Camilli 2006; Balla 2016; Viaud et al. 2016).
Phosphatidylinositol 5-Phosphate 4-Kinase, Fig. 1

Molecular structure of PtdIns (1[stearoyl], 2[arachidonoyl]-diacyl-sn-glycero-3-phospho-[1-d-myo-inositol]). Stearoyl (C18:0) and arachidonyl (C20:6) fatty acid chains on the diacylglycerol moiety are the commonest substitutions found in cellular phosphoinositides. The hydrophilic diacylglycerol “tail” sits within the membrane while positions D-3, D-4, and D-5 of the inositol head-group are available for phosphorylation

Phosphatidylinositol 5-Phosphate 4-Kinase, Fig. 2

Production of PtdInsP2 from PtdInsP. PI5P4K is able to use two of the three possible PtdInsP species as substrates (in vitro), producing PtdIns(4,5)P2 from PtdIns5P and PtdIns(3,4)P2 from PtdIns3P (filled arrows, relative substrate preference indicated by width). Alternative routes of production (from PtdIns4P) by PI3K (PtdIns(3,4)P2) and PI4P5K (PtdIns(4,5)P2) are also shown (dashed arrows, relative contribution indicated by width), although other phosphoinositides are omitted

Pioneering work in the early 1950s led to the elucidation of the roles of multiple kinases and phosphatases required to generate the diverse array of inositol lipid species in the PI cycle and in the numerous regulatory, signaling, and metabolic pathways that they are involved in (reviewed in Anderson et al. 1999). The first activities, isolated from human erythrocytes, to convert PtdIns4P to PtdIns(4,5)P2 were classified as Type I and Type II enzymes (Bazenet et al. 1990). Subsequent studies revealed that these two enzymes had distinct substrate specificities, and that the Type II enzyme was in fact solely utilizing PtdIns5P, a contaminant of the commercial PtdIns4P substrate in the assay (Rameh et al. 1997). Although the preferred substrate of PI5P4K is PtdIns5P it has also been shown to phosphorylate PtdIns3P in vitro (Fig. 2), producing PtdIns(3,4)P2 (Clarke et al. 2007). Both of these substrates are minor components of the typical cellular phosphoinositide content, PtdIns5P and PtdIns3P constituting 2% and 5% of total PtdInsP, respectively, the majority being PtdIns4P (Toker 2002). As a consequence, the contribution of PI5P4K activity to cellular PtdIns(4,5)P2 synthesis is thought to be restricted to specific isolated compartments, or another possible role of the enzyme is to attenuate the putative signaling function of PtdIns5P itself. Three mammalian PI5P4K isoforms have so far been discovered (α, β, and γ) and each has been shown to have a specific distribution and subcellular localization (Clarke et al. 2010).

PI5P4K Molecular Evolution

Homologs to genes encoding PI5P4K proteins have been discovered in over 60 species with completed genomic sequences (Clarke and Irvine 2013). Early divergence of the PI5P4K and phosphatidylinositol 4-phosphate 5-kinase (PI4P5K) enzymes (Fig. 3), which share significant identity over the conserved kinase-core domain (discussed below), presumably occurred by gene duplication, as did the later emergence of PIP5KL1, an inactive scaffolding protein for PIPKs (Chang et al. 2004). Lower eukaryotes, such as the yeast Saccharomyces cerevisiae, do not have an identified PI5P4K activity, and within the plant kingdom, 11 of the Arabidopsis thaliana atPIPK proteins have sequence similarity to both PI5P4K and PI4P5Ks although the examples studied so far use PtdIns4P as substrate (Mueller-Roeber and Pical 2002). A single PI5P4K activity is present in nematodes such as Caenorhabditis elegans (PPK-2), arthropods such as Drosophila melanogaster (dPIP4K), and urochordates such as Ciona intestinalis. The later divergences produce first PI5P4Kγ, then PI5P4Kα and PI5P4Kβ (Fig. 3). PI5P4Kα is present in all vertebrates, with a few organisms missing either PI5P4Kβ or PI5P4Kγ; the exception of the latter isoform from any of the bird genomes completed to date is particularly notable (Clarke and Irvine 2013). Within the human genome each isoform is present as a single-copy gene, with PIP4K2A (coding for PI5P4Kα) located on chromosome 10 (p12.2), PIP4K2B (coding for PI5P4Kβ) on chromosome 17 (q21.2), and PIP4K2C (coding for PI5P4Kγ) on chromosome 12 (q13.2).
Phosphatidylinositol 5-Phosphate 4-Kinase, Fig. 3

Phylogenetic plot of PI5P4K gene evolution with all currently annotated genes in the Ensembl database (EMBL-EBI). Branch points indicate divergence, black nodes represent speciation, and red nodes represent a potential gene duplication event. Species with single genes with similarity to human PI5P4K are listed by name (gene name in brackets). Separate PIPK gene branches indicate number of total homologs (orthologs of PI5P4Ks and PIP5KL1, orthologs plus paralogs of PI4P5K) in vertebrates (63 species with PI5P4Kα, 58 species with PI5P4Kβ, and 54 species with PI5P4Kγ). Boxed numbers represent percentage similarity of human homologs (or individual D. melanogaster, C. elegans, S. cerevisiae, Ciona and Tetraodontidae genes) to human PI5P4Kα protein sequence (average similarity for Ciona and Tetraodontidae species and PI4P5K isoforms)

PI5P4K Structure

Although the PI5P4K isoforms have a significant level of identity at the amino acid level, they share only 30% identity with the PI4P5Ks and constitute a novel family with no significant identity to any other lipid or protein kinases (Anderson et al. 1999).

Homology between the PIPKs is mostly limited to the large kinase core domain (Fig. 4) as defined in deletion studies by Ishihara et al. and structural similarity alignment by Rao et al. (reviewed in Anderson et al. 1999). Regions of low similarity outside of the kinase core define the functional differences between the PI5P4K and PI4P5Ks. Three-dimensional structure by X-ray crystallography has been elucidated for all isoforms, and these show a high degree of similarity by structural comparison: PI5P4Kα (2.6 Å resolution, PDB i.d. 2YBX, Tresaugues, Protein Data Bank online submission), PI5P4Kβ (3.0 Å resolution, PDB i.d. 1BO1, Rao et al. 1998), and PI5P4Kγ (2.8 Å resolution, PDB i.d. 2GK9, Thorsell, Protein Data Bank online submission). These data show the PI5P4K structure to be two domains arranged across a central cleft, which has catalytic and ATP-binding residues conserved with a protein kinase, PKA. Four conserved catalytic residues are identified, and the mutation of at least one (e.g., the equivalent of the conserved aspartate 273 in PI5P4Kα) results in biochemical inactivity. This active site is open on one side, such that the proposed binding of ATP and a phospholipid head-group would accommodate PtdIns5P or PtdIns3P (Rao et al. 1998).
Phosphatidylinositol 5-Phosphate 4-Kinase, Fig. 4

PI5P4K structure. (a) The PI5P4K domain structure shows that the kinase catalytic core domain (light blue) is interrupted by the “variable insert,” a region with the least sequence similarity between the three isoforms (green). The C-terminal kinase domain contains the “activation loop” (dark blue) and the N-terminal domain contains the “G-loop” motif (yellow). The dimerization region is shown in red. (b, c) Ribbon diagrams of the crystallographic structure of PI5P4Kβ as a homodimer (Rao et al. 1998) with the dimerization region highlighted (green monomer with yellow region, blue monomer with red region). Views are from the membrane contact surface (b), showing the flattened face, and from the cytosolic side (c), showing the stabilization of the dimerization interface by α-helices

The N-terminal domain has seven β-sheets and four α-helices, and the crystal structure shows that the protein homodimerizes along the interface of two adjacent β1 strands (Fig. 4) to form a broad, flat face that is able to contact cell membranes by means of electrostatic interaction with lipid head-groups (Rao et al. 1998). Recent data has also shown the potential of the PI5P4K isoforms to heterodimerize, suggesting a possible means of inter-isoform regulation based on protein expression levels in different tissues (Bultsma et al. 2010; Wang et al. 2010; Clarke and Irvine 2013). This domain also contains a putative ATP-stabilizing G-loop motif (Rao et al. 1998).

The C-terminal domain consists of five β-sheets and four α-helices and contains the “activation loop” and “variable insert” (Fig. 4). The activation loop region (amino acids 373–391) confers substrate specificity as demonstrated by domain swapping between PI5P4K and PI4P5K enzymes (Kunz et al. 2000). The variable insert region interrupts the catalytic kinase core and represents the region of least similarity between the PI5P4K isoforms. In PI5P4Kβ the α7 helix in this insert serves as a specific nuclear localization motif (Ciruela et al. 2000), and other inter-isoform differences could be accounted for in this region.

Mammalian PI5P4K Isoforms


The PI5P4Kα isoform was the first to be cloned independently by two groups in 1995, from human circulating-leukocyte and bone marrow cDNA libraries (Boronenkov and Anderson 1995; Divecha et al. 1995). It is the most catalytically active of the three isoforms (Table 1). Northern blotting suggests that the enzyme has a ubiquitous but low expression in tissues compared to the other isoforms, with slightly elevated levels in brain and hematocytes (reviewed in Clarke et al. 2010), which is confirmed in subsequent quantitative PCR experiments (Fig. 5). Overexpression studies in DT40 and HeLa cells suggest that PI5P4Kα is predominantly cytosolic (Clarke et al. 2007; Richardson et al. 2007) and has been observed to translocate to the cytoskeleton upon integrin-mediated signaling, potentially via interaction with a PI4P5K activity (Hinchliffe et al. 2002). Translocation of a PI5P4K enzyme was also seen in agonist-induced platelet α-granule secretion, and this activity was regulated by PKC activation and attenuated by calpain cleavage (Rozenvayn and Flaumenhaft 2003; O’Connell et al. 2005). Recent studies, using genomically tagged PI5P4Kα and high-resolution mass spectrometry, were able to assess endogenous protein in DT40 cells and show that significant amounts of this enzyme are also found in the nucleus. This distribution is thought to occur via association with the PI5P4Kβ isoform (Bultsma et al. 2010; Wang et al. 2010) as discussed above. The PI5P4Kα isoform activity is regulated by phosphorylation on different serine and threonine residues. Cell stimulation results in both removal of inhibitory phosphorylation, such as at threonine 376 by protein kinase D, and further activating phosphorylation (Hinchliffe and Irvine 2006). Protein kinase CK2 also specifically phosphorylates serine 304, although this has not been shown to affect enzyme activity (Hinchliffe et al. 1999). Upregulation of PI5P4Kα activity has also been observed on tyrosine phosphorylation in bovine photoreceptor rod outer segments, although this is thought to be an indirect response (Huang et al. 2001).
Phosphatidylinositol 5-Phosphate 4-Kinase, Table 1

Comparison of activities of the PI5P4K isoforms (Clarke and Irvine 2013). Specific activity is defined as nmoles of ATP incorporated into lipid per minute per mg of protein under the same assay conditions. Turnover number (kcat) is defined as the number of ATP (hence PtdIns5P to PtdIns(4,5)P2) reactions per second

PIP4K isoform

Specific activity

KM for ATP (μM)

kcat (s−1)


3.7 × 10−2 (±0.12)


1.1 × 10−2


1.6 × 10−5 (±0.08)


9.6 × 10−5


3.7 × 10−7 (±0.12)


5.7 × 10−6

Phosphatidylinositol 5-Phosphate 4-Kinase, Fig. 5

Expression of PI5P4K mRNA in mouse tissues. Expression of PIP4K2A, PIP4K2B, and PIP4K2C was determined by quantitative PCR using the comparative threshold cycle (CT) method (As described in Clarke et al. 2008)


Yeast two-hybrid screening of a murine cerebellar cDNA library, using a cytoplasmic domain of the human p55 TNF-α receptor as bait, resulted in the cloning of the PI5P4Kβ isoform (Castellino et al. 1997). Although this isoform has 77% amino acid similarity to PI5P4Kα, it has 100-fold less in vitro activity (Table 1). PI5P4Kβ mRNA was detected in all tissues tested and was found to be specifically enriched in skeletal muscle and brain (Fig. 5 and Castellino et al. 1997). At a subcellular level, although PI5P4Kβ has been shown to associate with the TNF-α, EGF, and ErbB2 (HER2) receptors (Castellino et al. 1997; Castellino and Chao 1999), and undoubtedly has a cytoplasmic role, it is also the only isoform to specifically localize to the cell nucleus. The targeting of PI5P4Kβ to the nucleus is affected by a nuclear localization sequence unique to this isoform (Ciruela et al. 2000), and genomic tagging indicates that the majority of endogenous PI5P4Kβ is transported across the nuclear membrane in DT40 cells (Richardson et al. 2007). Activation of PI5P4Kβ has been shown to be mediated by TNF-α in specific cytokine-responsive cells (Castellino et al. 1997). Within the nucleus, PI5P4Kβ activity is inhibited by p38 mitogen-activated protein kinase (MAPK) phosphorylation of serine 326 after ultraviolet irradiation, leading to increases in nuclear PtdIns5P, which is sensed by the cell stress–responsive nuclear adapter protein ING2 (Jones et al. 2006); note that this residue is also present in PI5P4Kα, so it is possible that nuclear PI5P4Kα (see above) is similarly regulated. PI5P4Kβ that is co-localized to nuclear speckles (pre-mRNA processing sites) with the Cul3-SPOP ubiquitin ligase complex is itself targeted for degradation by ubiquitylation (Bunce et al. 2008). Intriguingly, PtdIns5P activation of p38 MAPK stimulates the activity of the Cul3-SPOP complex, suggesting that a feed-forward mechanism of regulation exists, which could in part be explained by the interaction between PI5P4Kβ and PI5P4Kα in the nucleus (Bultsma et al. 2010). There is also evidence that PI5P4Kβ is able to regulate insulin-induced signaling in cells by an indirect mechanism. Carricaburu et al. showed that PI5P4Kβ-regulated PtdIns5P levels were responsible for activation of a PtdIns(3,4,5)P3-specific 5-phosphatase, which removed this PI 3-kinase (PI3K) signaling product, resulting in reduced Akt/PKB protein kinase phosphorylation (Carricaburu et al. 2003).


The PIP4Kγ isoform is the most recent to be discovered and was isolated from a rat brain cDNA library by Itoh et al. in 1998. PI5P4Kγ shares approximately 63% similarity with PI5P4Kα and PI5P4Kβ at the protein level, but has a 2,000-fold lower in vitro catalytic turnover of PtdIns5P than the PI5P4Kα isoform (Table 1), and no detectable activity against any other phosphoinositide substrates. Highest levels of PI5P4Kγ expression are observed in the kidney and brain (Fig. 5), with significant levels also in the heart, ovary, and testis (Itoh et al. 1998; Clarke et al. 2008, 2009). Within the kidney, the expression is limited to the distal nephron and restricted to the epithelial cells of the thick ascending limb of the loop of Henle and to intercalated cells of the collecting duct (Clarke et al. 2008). Expression of PI5P4Kγ is also seen at early developmental stages in the zebra fish embryo, localized to the pronephric duct and brain. In the mouse brain PI5P4Kγ has a restricted expression, found only in specific neuronal subpopulations, such as cerebellar Purkinje cells, hippocampal pyramidal cells, and mitral cells in the olfactory bulb, and is excluded from granule cells (Clarke et al. 2009). At a subcellular level, endogenous PI5P4Kγ is partially associated with the cis-Golgi matrix and predominantly with an unidentified vesicular compartment, which in kidney epithelial cells is concentrated at the apical secretory membrane (Clarke et al. 2008). PI5P4Kγ undergoes protein phosphorylation on serine residues in vivo, and at least two phosphorylated forms are differentially expressed in mouse brain regions (Itoh et al. 1998; Clarke et al. 2009). In a β-pancreatic cell line, the mTORC1 complex is responsible for phosphorylation of PI5P4Kγ at two specific sites and contributes to the feedback regulation of mTORC1 activation during starvation (Mackey et al. 2014), potentially by a localization mechanism rather than in vivo activation of the enzyme. Phosphorylation may also be regulated by mitogenic cell stimulation with EGF or PDGF and to a lesser extent with lysophosphatidic acid or bradykinin (Itoh et al. 1998). Enzyme expression may also be regulated in thyrocytes by thyroid-stimulating hormone (Park et al. 2001).

PI5P4Ks and Disease

Aberrant regulation of cellular phosphoinositides has been implicated in a number of diseases including cancer and diabetes. Interference with PtdIns(3,4,5)P3 regulation of Akt signaling via enzymes such as PI3K and the phosphatases PTEN and SHIP1 are linked to many forms of cancer (McCrea and De Camilli 2009). PtdIns(4,5)P2 can also regulate ion channels, the dysfunction of which can lead to epilepsy and rare forms of congenital channelopathies (Halstead et al. 2005). In these cases any involvement of the PI5P4Ks would be indirect, via the downstream production of lipid substrates and second messengers themselves. However, some direct effects of the PI5P4Ks in disease have been reported.

PI5P4Kβ, as discussed above, has been implicated in the regulation of Akt/PKB activation during insulin signaling by reducing PtdIns5P levels that inhibit the enzymatic removal of PtdIns(3,4,5)P3 (Carricaburu et al. 2003). In agreement, PI5P4Kβ-/- knockout mice are viable but hypersensitive to insulin, suggesting that the presence of the PI5P4Kβ substrate, PtdIns5P, is directly required for maintenance of PtdIns(3,4,5)P3 levels for enhanced Akt/PKB phosphorylation. Removal of PtdIns5P by PI5P4Kβ reduces the effectiveness of insulin signaling, which may have consequences in type 2 diabetes (Lamia et al. 2004).

Early reports suggest that PIPK activity was upregulated in malignant tumors (Singhal et al. 1994). Recent studies have shown that as well as PI5P4Kβ interacting with the HER2b receptor (see above), the PIP4K2B gene is located close to the HER2 locus on chromosome 17. Gene amplification of HER2 occurs in 25% of breast cancer cases, and increased levels of PI5P4Kβ have also been detected in these tumors (Luoh et al. 2004). Recently depletion of PI5P4Kβ in HER2-positive breast cancer cell lines (p53 deficient) was shown to markedly reduce tumorigenesis (Emerling et al. 2013). PIP4K2B has also been linked to neuroblastoma development, as this gene is one of three to be disrupted by a translocation breakpoint characteristic of this tumor type (Schleiermacher et al. 2005).

Treatment of bipolar disorder with lithium is thought to be involved with phosphoinositide metabolism. Subsequent linkage studies have implicated PI5P4Kα as a candidate gene for susceptibility to schizophrenia, either through a common single nucleotide polymorphism or transcriptional repression (Stopkova et al. 2003).

Recent observations that inhibition of PI5P4Ks, particularly PI5P4Kγ, can positively regulate autophagy in cells (Vicinanza et al. 2015, Droubi et al. 2016), concomitant with reports identifying isoform-specific inhibitors (Voss et al. 2014, Clarke et al. 2015), suggest that these enzymes may also have a potential role in combatting neurodegenerative disease.


PI5P4K enzymes phosphorylate their preferred phospholipid substrate, PtdIns5P, to produce PtdIns(4,5)P2. The relative scarcity of PtdIns5P in cells suggests that the PI5P4Ks function to remove a lipid signal provided by this phosphoinositide, or to produce a small pool of PtdIns(4,5)P2 that is required in an isolated cellular compartment. PI5P4K exists as three distinct isoforms (α, β, and γ) with PI5P4Kα being significantly more active than PI5P4Kβ or PI5P4Kγ. Each isoform has a different tissue distribution and subcellular localization, and this is mediated in part by differences in highly variable regions within the more conserved common catalytic core domain. The isoforms form dimers by interaction between β1-sheets, and the formation of heterodimers suggests a mechanism by which isoforms are targeted to different cellular locations in a tissue and possibly cell-type-dependent manner. PI5P4Ks may have direct links to diabetes and neurological disorders, and PI5P4Kβ has recently been shown to be upregulated in human cancers, suggesting that these enzymes may be valid targets for disease treatments. The recent discovery of a number of inhibitors for PI5P4Ks also suggests that these targets are potentially druggable.

See Also


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Alzheimer’s Research UK Cambridge Drug Discovery Institute, Cambridge Biomedical CampusUniversity of CambridgeCambridgeUK
  2. 2.Department of PharmacologyUniversity of CambridgeCambridgeUK