PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase type 1 alpha)

2017-04-01   Barnabas Nyesiga , Anette Gjörloff Wingren 

Biomedical science, Health and society, Malmö University, Malmö, Sweden nyesigabarnabas@gmail.com; anette.gjorloff-wingren@mah.se

Identity

HGNC
LOCATION
1q21.3
LOCUSID
ALIAS
-
FUSION GENES

Abstract

: Review on PIP5K1A, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Description

The cDNAs encoding the phosphatidylinositol 4-phosphate 5-kinases (PIP5K) were isolated from the human brain using peptide sequences from the erythroid 68-kDa type I PIP5KI (Loijens 1996). A human fetal brain cDNA library was screened leading to isolation of full-length type IA, PIP5K1A cDNAs (Loijens 1996). PIP5K1A is located in the chromosomal region 1q21.3 (Xie 2000), the product of which is predominantly responsible for the synthesis of PtdIns-4,5-P2 (PIP2), a substrate used by PI3K to produce PtdIns-3,4,5-P3 (PIP3) (Shaw 2006). PIP5K1A gene was localized to chromosome 1q22-q24 by fluorescence in situ hybridization (FISH) (Xie 2000).

Transcription

The 549-amino acid protein has a conserved kinase homology domain similar to the rest of the PIP5K family members. Northern blot analysis showed a wide distribution of a PIP5K1A 4.2-kb transcript mostly expressed in skeletal muscle. In addition, high levels of PIP5K1A were also seen in heart, placenta, kidney, and pancreas while low levels of expression were observed in brain, liver, and lung (Loijens 1996). Deletion-mutant analysis was used to determine an approximately 380-amino acid minimal core sequence of mouse PIP5K1A that was sufficient for phosphatidylinositol 4-phosphate kinase activity.

Proteins

Atlas Image
Figure 1. Schematic representation of human PIP5K1A isoform with the conserved kinase core domain (adopted from Porciello 2016).

Description

PIP5K1A is a 61-kDa protein migrating at about 68 kDa in SDS-PAGE (Fruman 1998). The protein shows 83% and 35% amino acid identity with PIP5K1B and PIP4K2A (PIP5K2A), respectively, within the conserved kinase homology domain (Loijens 1996). Overall, the PIP5K1A and PIP5K1B proteins are 64% identical and Northern analysis shows the two to have a wide tissue distributions, but greatly differing expression levels. Recombinant, bacterially expressed PIP5KA was observed to have PIP5K activity and to be immunoreactive with erythroid PIP5KI antibodies (Loijens 1996). Furthermore, the authors isolated additional PIP5K1A cDNAs which they suggested represent splicing isoforms. Overexpression of mouse PIP5K1A in COS-7 cells stimulates an increase in short actin fibers and a decrease in actin stress fibers (Ishihara 1998).
PIP5K1A mediate the phosphorylation of phosphatidylinositol 4-phosphate on the D5 position of the inositol ring, thus inducing the production of phosphatidylinositol 4,5-biphosphate (PIP2) (van den Bout 2009). In both humans and mice, all PIP5K isoforms show variation in their sequence by alternative splicing (Ishihara 1998). Three PIP5K1α, four β, and one γ splice variants were identified in humans and eight PIP5K1α, two β, and three γ splice variants are present in mice. (Ishihara 1998).
All PIP5K isoforms α, β, and γ, and splice variants have a highly conserved kinase core domain that consists of 330-380 amino acids (Fig. 1), and a sub-domain called the activation loop, that regulates their activity and subcellular localization (Tuosto 2015). The variables N- and C-termini of PIP5K isoforms are also involved in the regulation of lipid kinase activity and in targeting PIP5Ks to specific cellular compartments (Kwiatkowska 2010). The C-terminal residues (440-562) of PIP5K1A regulate its localization at nuclear speckles (Mellman 2008). The 83 C-terminal amino acids of PIP5K1β are essential for its polarization at the uropod (Lacalle 2007), whereas the N-terminus controls PIP5K1β targeting to the plasma membrane and its dimerization with other PIP5K isoforms (Lacalle 2015). (Ishihara 1998).
The crystal structure of the catalytic domain of zebrafish PIP5K1A has been reported at 3.3Å resolution and the molecule forms a side-to-side dimer (Hu 2015). Mutagenesis study of PIP5K1A indicated two adjacent interfaces for the dimerization and interaction with the DIX domain of the Wnt signalling molecule dishevelled. Much as the interfaces were located distally to the catalytic/substrate-binding site, binding to these interfaces either through dimerization or the interaction with DIX stimulated PIP5K1 catalytic activity. DIX binding additionally enhanced PIP5K1 substrate binding (Hu 2015). (Ishihara 1998).
All the three PIP5K isoforms are expressed by primary T cells (Sun 2011) and they are triggered by phosphatidic acid (PA), which is generated by phospholipase D (PLD), through the hydrolysis of phosphatidylcholine (Jenkins 1994, Moritz 1992). PIP5K1α cooperates with PIP5Kβ and VAV1 in promoting actin polymerization and CD28 signaling functions in human T lymphocytes (Porciello 2016). PIP5K1A localises to the plasma membrane and the Golgi complex, and has also been observed at sites of membrane ruffling induced by the Rho GTPase RAC1 (van den Bout 2009). PIP5K1A in particular is recruited to the plasma membrane in response to several receptors to provide the substrate PIP2 for PLCγ leading to IP3 formation and Ca2+ mobilization (Saito 2003, Wang 2008 and Xie 2009). Both PIP5K1α and PIP5Kγ are known to interact and colocalize with phospholipase D 2 ( PLD2) at the membrane to stimulate cell adhesion (Divecha 2000, Powner 2005). Some studies have also shown pronounced association of PIP5K1A with nuclear speckles (Chakrabarti 2013) where it may regulate pre-mRNA processing and mRNA export (Barlow 2010).

Function

Treatment of primary cultured astrocytes with gangliosides significantly enhanced PIP5K1α mRNA and protein expression levels (Sang 2010). MicroRNA-based PIP5K1α knockdown strongly reduced ganglioside-induced transcription of proinflammatory cytokines. In addition, PIP5K1α knockdown suppressed phosphorylation and nuclear translocation of NF-kB (Sang 2010).
PIPK-mediated mechanisms regulate microtubule dynamics in neuronal development (Noda 2012). Using immunoprecipitation with an antibody specific to KIF2A, PIPKα was identified as a candidate membrane protein that regulates the activity of KIF2A. Yeast two-hybrid and biochemical assays showed direct binding between KIF2A and PIPKα. Furthermore, the microtubule (MT)- depolymerizing activity of KIF2A was enhanced in the presence of PIPKα in vitro and in vivo.

Implicated in

Entity name
Prostate cancer
Note
Some studies have shown that overexpression of PIP5K1α in non-malignant PNT1A cells induces the invasive capacity of these cells. An increased expression of major factors that drive cancer cell proliferation and invasion such as VEGF, phosphorylated PTK2 (FAK), TWIST1, and MMP9, was observed in these cells due to PIP5K1α overexpression. PIP5K1α overexpression in these cells led to an increased AKT activity and an increased survival, as well as invasive malignant phenotype. The siRNA-mediated knockdown of PIP5K1α in these cells resulted into a reduced AKT activity and an inhibition in tumor growth. PIP5K1α, PIP2 and PIP3 are important lipids for membrane structure and actin polymerization, thus increased levels of these lipids may lead to malignant transformation and progression of cancer cells into a more invasive phenotype (Semenas 2014).

Bibliography

Pubmed IDLast YearTitleAuthors
198463102010Nuclear phosphoinositides: a signaling enigma wrapped in a compartmental conundrum.Barlow CA et al
239941362013Nuclear pool of phosphatidylinositol 4 phosphate 5 kinase 1α is modified by polySUMO-2 during apoptosis.Chakrabarti R et al
110328112000Interaction of the type Ialpha PIPkinase with phospholipase D: a role for the local generation of phosphatidylinositol 4, 5-bisphosphate in the regulation of PLD2 activity.Divecha N et al
97594951998Phosphoinositide kinases.Fruman DA et al
263657822015Resolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled.Hu J et al
95358511998Type I phosphatidylinositol-4-phosphate 5-kinases. Cloning of the third isoform and deletion/substitution analysis of members of this novel lipid kinase family.Ishihara H et al
81576861994Type I phosphatidylinositol 4-phosphate 5-kinase isoforms are specifically stimulated by phosphatidic acid.Jenkins GH et al
205596792010One lipid, multiple functions: how various pools of PI(4,5)P(2) are created in the plasma membrane.Kwiatkowska K et al
257130542015Type I phosphatidylinositol 4-phosphate 5-kinase homo- and heterodimerization determines its membrane localization and activity.Lacalle RA et al
207204562010Phosphatidylinositol 4-phosphate 5-kinase alpha is induced in ganglioside-stimulated brain astrocytes and contributes to inflammatory responses.Lee SY et al
89551361996Type I phosphatidylinositol-4-phosphate 5-kinases are distinct members of this novel lipid kinase family.Loijens JC et al
182881972008A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs.Mellman DL et al
13137921992Phosphatidic acid is a specific activator of phosphatidylinositol-4-phosphate kinase.Moritz A et al
223076382012Phosphatidylinositol 4-phosphate 5-kinase alpha (PIPKα) regulates neuronal microtubule depolymerase kinesin, KIF2A and suppresses elongation of axon branches.Noda Y et al
272427932016Phosphatidylinositol 4-Phosphate 5-Kinases in the Regulation of T Cell Activation.Porciello N et al
159764552005Phospholipase D2 stimulates integrin-mediated adhesion via phosphatidylinositol 4-phosphate 5-kinase Igamma b.Powner DJ et al
146148542003BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity.Saito K et al
250712042014The role of PI3K/AKT-related PIP5K1α and the discovery of its selective inhibitor for treatment of advanced prostate cancer.Semenas J et al
167240532006Ras, PI(3)K and mTOR signalling controls tumour cell growth.Shaw RJ et al
220965412011Phosphatidylinositol (4,5) bisphosphate controls T cell activation by regulating T cell rigidity and organization.Sun Y et al
262651812015The multifaceted role of PIP2 in leukocyte biology.Tuosto L et al
187723782008Loss of PIP5KIbeta demonstrates that PIP5KI isoform-specific PIP2 synthesis is required for IP3 formation.Wang Y et al
108285842000Assignment of type I phosphatidylinositol-4-phosphate 5-kinase (PIP5K1A) to human chromosome bands 1q22--> q24 by in situ hybridization.Xie Y et al
198899692009PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions.van den Bout I et al

Other Information

Locus ID:

NCBI: 8394
MIM: 603275
HGNC: 8994
Ensembl: ENSG00000143398

Variants:

dbSNP: 8394
ClinVar: 8394
TCGA: ENSG00000143398
COSMIC: PIP5K1A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000143398ENST00000349792Q99755
ENSG00000143398ENST00000368888Q99755
ENSG00000143398ENST00000368890Q99755
ENSG00000143398ENST00000409426A6PW57
ENSG00000143398ENST00000418435A6PW58
ENSG00000143398ENST00000424999A6PW56
ENSG00000143398ENST00000441902Q99755
ENSG00000143398ENST00000447555A2A5X0
ENSG00000143398ENST00000454769E9PSF8

Expression (GTEx)

0
10
20
30
40
50
60
70
80

Pathways

PathwaySourceExternal ID
Inositol phosphate metabolismKEGGko00562
Phosphatidylinositol signaling systemKEGGko04070
Regulation of actin cytoskeletonKEGGko04810
Inositol phosphate metabolismKEGGhsa00562
Phosphatidylinositol signaling systemKEGGhsa04070
Regulation of actin cytoskeletonKEGGhsa04810
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Metabolic pathwaysKEGGhsa01100
Inositol phosphate metabolism, PI=> PIP2 => Ins(1,4,5)P3 => Ins(1,3,4,5)P4KEGGhsa_M00130
Inositol phosphate metabolism, PI=> PIP2 => Ins(1,4,5)P3 => Ins(1,3,4,5)P4KEGGM00130
Choline metabolism in cancerKEGGhsa05231
Choline metabolism in cancerKEGGko05231
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
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
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
126820532003Membrane ruffling requires coordination between type Ialpha phosphatidylinositol phosphate kinase and Rac signaling.44
278708282016Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases.28
204267902010Phosphatidylinositol 4,5-bisphosphate and PIP5-kinase Ialpha are required for invadopodia formation in human breast cancer cells.27
191583932009Phosphatidylinositol-4-phosphate 5-kinase 1alpha mediates extracellular calcium-induced keratinocyte differentiation.26
158702702005The LIM protein Ajuba regulates phosphatidylinositol 4,5-bisphosphate levels in migrating cells through an interaction with and activation of PIPKI alpha.22
189811072008PI4P5-kinase Ialpha is required for efficient HIV-1 entry and infection of T cells.20
185349832008Beta-arrestin scaffolding of phosphatidylinositol 4-phosphate 5-kinase Ialpha promotes agonist-stimulated sequestration of the beta2-adrenergic receptor.17
180733472008PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway.16
169795642006A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis.15
206606312010Type I PIPK-alpha regulates directed cell migration by modulating Rac1 plasma membrane targeting and activation.15

Citation

Barnabas Nyesiga ; Anette Gjörloff Wingren

PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase type 1 alpha)

Atlas Genet Cytogenet Oncol Haematol. 2017-04-01

Online version: http://atlasgeneticsoncology.org/gene/47397/pip5k1a-(phosphatidylinositol-4-phosphate-5-kinase-type-1-alpha)