PI4K2A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4HND, 4HNE, 4PLA, 4YC4, 5EUT, 5I0N
Identifiers
Aliases	PI4K2A, PI4KII, PIK42A, phosphatidylinositol 4-kinase type 2 alpha
External IDs	OMIM: 609763 MGI: 1934031 HomoloGene: 101681 GeneCards: PI4K2A
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q24.2 Start 97,640,686 bp[1] End 97,676,434 bp[1]
Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19 C3|19 35.74 cM Start 42,078,909 bp[2] End 42,110,526 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left adrenal gland stromal cell of endometrium retinal pigment epithelium prefrontal cortex amniotic fluid islet of Langerhans pons gastric mucosa hypothalamus anterior pituitary Top expressed in pontine nuclei left lobe of liver facial motor nucleus dorsal tegmental nucleus medulla oblongata subiculum medial vestibular nucleus inferior colliculus medial geniculate nucleus medial dorsal nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding kinase activity protein binding AP-3 adaptor complex binding ATP binding magnesium ion binding 1-phosphatidylinositol 4-kinase activity protein-containing complex binding Cellular component cytosol Golgi apparatus cell projection membrane BLOC-1 complex synapse integral component of plasma membrane lysosomal membrane cell junction dendrite mitochondrion neuron projection intrinsic component of membrane membrane raft cytoplasmic vesicle presynaptic membrane endosome trans-Golgi network plasma membrane growing cell tip neuronal cell body host cell presynaptic membrane synaptic vesicle membrane early endosome membrane protein-containing complex perikaryon intracellular membrane-bounded organelle exocytic vesicle Biological process phosphorylation phosphatidylinositol biosynthetic process phosphatidylinositol phosphate biosynthetic process Golgi organization endosome organization basophil degranulation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 55361 84095 Ensembl ENSG00000155252 ENSMUSG00000025178 UniProt Q9BTU6 Q2TBE6 RefSeq (mRNA) NM_018425 NM_145501 RefSeq (protein) NP_060895 NP_663476 Location (UCSC) Chr 10: 97.64 – 97.68 Mb Chr 19: 42.08 – 42.11 Mb PubMed search [3] [4]
Wikidata
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Phosphatidylinositol 4-kinase 2-alpha is an enzyme that in humans is encoded by the PI4K2A gene.^[5][6][7]

Classification

This gene encodes a phosphatidylinositol 4-kinase which catalyzes phosphorylation of phosphatidylinositol at the D-4 position, yielding phosphatidylinositol 4-phosphate (PI4P). Besides the fact, that PI4P serves as a precursor for other important phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate, PI4P is an essential molecule in the cellular signaling and trafficking especially in the Golgi apparatus and the trans Golgi network.

Phosphatidylinositol 4-kinases are evolutionary conserved among eukaryotes and include four human isoforms

• phosphatidylinositol 4-kinase alpha (PI4KA)
• phosphatidylinositol 4-kinase beta (PI4KB)
• phosphatidylinositol 4-kinase 2-alpha (PI4K2A)
• phosphatidylinositol 4-kinase 2-beta (PI4K2B)

Function

Phosphatidylinositol 4-kinase 2-alpha (PI4K2A) is the most abundant phosphatidylinositol 4-kinase in human cells and is responsible for the synthesis of approximately 50% of the total PI4P within the cell. PI4K2A is associated mainly with the membranes of the trans Golgi network and early and late endosomes;^[8] its membrane association is achieved by a heavy palmitoylation within a specific cysteine-rich motif.^[9] Besides the synthesis of phosphatidylinositol 4,5-bisphosphate, PI4K2A is involved in various cell processes including membrane trafficking, regulation of endosomal sorting promoting target protein recruitment to endosomes or trans Golgi network, or signal transduction. Particularly, it regulates e.g. targeting of clathrin adaptor complexes to the Golgi apparatus,^[10] EGFR signaling,^[11] or the Wnt signaling pathway.^[12]

PI4K2A is important in lysosomal quality control. It is the first essential enzyme of the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.^[13] Upon lysosomal membrane damage, PI4K2A is strongly recruited to lysosomes, leading to robust lysosomal PI4P production. Such lysosomal PI4K2A/PI4P signaling drives rapid lysosomal repair through extensive membrane contacts between the endoplasmic reticulum (ER) and damaged lysosomes as well as multiple ER-to-lysosomal lipid transfer processes.

Pi4k2a gene trap mouse show pre-mature aging and neurodegeneration, with increased lipofuscin accumulation.^[14] PI4K2A-deleted patients have complex and severe developmental problems along with neurodegeneration.^[15]

Clinical significance

Dysfunction of PI4K2A may contribute to tumour growth,^[16] spastic paraplegia,^[14] Gaucher's disease,^[17] or Alzheimer's disease.^[18]

Structure

Cartoon representation of the kinase domain of the phosphatidylinositol 4-kinase 2-alpha. N-lobe is colored in gold, C-lobe in aquamarine, ATP in the active site between the lobes in the stick representation. PDB code: 4PLA.^[19]

PI4K2A is composed of a proline-rich N-terminal region and a kinase domain located C-terminally. The proline-rich N-terminal region contains physiologically important binding sites for a ubiquitin ligase Itch ^[20] and clathrin adaptor complex 3,^[21] but is likely disordered and dispensable for the kinase activity.^[22] The kinase domain can be divided into N-terminal and C-terminal lobes with the ATP binding groove and putative phosphatidylinositol binding pocket in between. The C-lobe of the kinase domain contains an additional lateral hydrophobic pocket with no distinct function assigned yet.^[19][23]

References

Further reading