Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A)

The protein contains 406 amino acids for an estimated molecular weight of 46225 Da.

 

Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PubMed:9367159, PubMed:23326584). Has both ATP- and GTP-dependent kinase activities (PubMed:26774281). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2 (PubMed:18364242). May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation (By similarity). Required for lysosome-peroxisome membrane contacts and intracellular cholesterol transport through modulating peroxisomal PtdIns(4,5)P2 level (PubMed:29353240). In collaboration with PIP4K2B, has a role in mediating autophagy in times of nutrient stress (By similarity). Required for autophagosome-lysosome fusion and the regulation of cellular lipid metabolism (PubMed:31091439). May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size (By similarity). Negatively regulates insulin signaling through a catalytic-independent mechanism (PubMed:31091439). PIP4Ks interact with PIP5Ks and suppress PIP5K-mediated PtdIns(4,5)P2 synthesis and insulin-dependent conversion to PtdIns(3,4,5)P3 (PubMed:31091439). (updated: Feb. 10, 2021)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.


Interpro domains
Total structural coverage: 96%
Model score: 0
No model available.

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VariantDescription
dbSNP:rs11813789
No effect on kinase activity

The reference OMIM entry for this protein is 603140

Phosphatidylinositol 4-phosphate 5-kinase, type ii, alpha; pip5k2a
Phosphatidylinositol 5-phosphate 4-kinase, alpha; pi5p4ka

DESCRIPTION

Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) occupies an essential position in the phosphoinositide signal transduction cascades as the precursor to second messengers. Its functions include regulation of secretion, cell proliferation, differentiation, and motility. The final step in the synthesis of PtdIns(4,5)P2 is the phosphorylation of PtdIns(4)P (also known as PIP) by type I PIP kinases, or the phosphorylation of PtdIns(5)P by type II PIP kinases (EC 2.7.1.149), such as PIP5K2A (Rameh et al., 1997).

CLONING

Using peptide sequences from purified human erythroid 53-kD type II PIP5K (PIP5K2A), Boronenkov and Anderson (1995) cloned a human placenta cDNA encoding PIP5K2A, which they called PIP5KII. The deduced 405-amino acid protein has a calculated molecular mass of 46,600 Da; the authors stated that the discrepancy between the calculated and experimental masses appears to be due to anomalous mobility of PIP5K2A on SDS-polyacrylamide gels. Although the amino acid sequence of PIP5K2A does not show homology to known kinases, recombinant PIP5K2A exhibited kinase activity. PIP5K2A contains a putative Src (190090) homology 3 (SH3) domain-binding sequence. The C-terminal region of PIP5K2A has 34% and 27% sequence identity with the C-terminal regions of the S. cerevisiae proteins Mss4 and Fab1, respectively. Northern blot analysis detected a ubiquitously expressed 4.1-kb PIP5K2A transcript. By screening a translated DNA database for sequences similar to pig PtdIns(4)P 5-kinase isoform C peptides, followed by screening a peripheral blood cell cDNA library, Divecha et al. (1995) cloned human PIP5K2A. The deduced 406-amino acid protein contains 2 SH3 domains and has a calculated molecular mass of 46 kD. The amino acid sequence differs from that reported by Boronenkov and Anderson (1995) between residues 297 and 311. Northern blot analysis detected a 4.1-kb transcript in all tissues tested except skeletal muscle and small intestine. A faint transcript of 2.3 kb was detected in testis. Bacterially expressed PIP5K2A showed a molecular mass of 46 kD, whereas the purified pig platelet enzyme had an apparent mass of 53 kD, suggesting posttranslational modification of the protein in eukaryotes.

GENE FUNCTION

Rameh et al. (1997) characterized the substrate specificity of the red cell-purified type II PIPK cloned by Boronenkov and Anderson (1995) and the isoform cloned by Divecha et al. (1995) and compared these to a type I mouse PIP kinase. Both human type II enzymes converted PtdIns(5)P to PtdIns(4,5)P2, but they produced virtually no product when PtdIns(4)P was used as substrate. Rameh et al. (1997) suggested that the earlier error in characterizing the type II enzyme activity was due to the presence of contaminating PtdIns(5)P in commercial preparations of PtdIns(4)P. Rameh et al. (1997) concluded that type I enzymes preferentially utilize PtdIns(4)P, whereas type II enzymes preferentially utilize PtdIns(5)P in the production of PtdIns(4,5)P2.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the PIP5K2A gene to chromosome 10 (TMAP STS-H93068). ... More on the omim web site

Subscribe to this protein entry history

Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603140 was added.

Jan. 28, 2016: Protein entry updated
Automatic update: model status changed

Jan. 25, 2016: Protein entry updated
Automatic update: model status changed