P48426 (PI42A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha
EC=2.7.1.149

Alternative name(s):
1-phosphatidylinositol 5-phosphate 4-kinase 2-alpha
Diphosphoinositide kinase 2-alpha
PIP5KIII
Phosphatidylinositol 5-phosphate 4-kinase type II alpha
Short name=PI(5)P 4-kinase type II alpha
Short name=PIP4KII-alpha
PtdIns(4)P-5-kinase B isoform
PtdIns(4)P-5-kinase C isoform
PtdIns(5)P-4-kinase isoform 2-alpha

Gene names

Name:	PIP4K2A
Synonyms:	PIP5K2, PIP5K2A

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	406 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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). 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. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. May negatively regulate insulin-stimulated glucose uptake by lowering the levels of PtdIns5P. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size. Ref.9
Catalytic activity	ATP + 1-phosphatidyl-1D-myo-inositol 5-phosphate = ADP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate. Ref.8
Subunit structure	Homodimer By similarity. Interacts with PIP4K2B. Interaction with PIP4K2B may regulate localization to the nucleus. Ref.13
Subcellular location	Cell membrane By similarity. Nucleus. Cytoplasm. Note: May translocate from the cytosol to the cell membrane upon activation of tyrosine phosphorylation. May translocate from the inner to the outer segments of the rod photoreceptor cells in response to light By similarity. Localization to the nucleus is modulated by the interaction with PIP4K2B. Ref.13
Tissue specificity	Expressed ubiquitously, with high levels in the brain. Present in most tissues, except notably skeletal muscle and small intestine. Ref.1 Ref.3
Sequence similarities	Contains 1 PIPK domain.
Caution	This protein was previously thought to be a phosphatidylinositol 4-phosphate 5-kinase.
Biophysicochemical properties	Kinetic parameters: KM=50 µM for phosphatidylinositol-5- phosphate Ref.13 Vmax=466 pmol/min/µg enzyme

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	megakaryocyte development Inferred from electronic annotation. Source: Compara phosphatidylinositol biosynthetic process Traceable author statement. Source: Reactome small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	1-phosphatidylinositol-4-phosphate 5-kinase activity Non-traceable author statement Ref.3. Source: UniProtKB 1-phosphatidylinositol-5-phosphate 4-kinase activity Inferred from electronic annotation. Source: EC ATP binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.11

Chain

2 – 406

405

Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha

PRO_0000185465

Regions

Domain

33 – 405

373

PIPK

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.11 Ref.15

Modified residue

3

1

Phosphothreonine Ref.11

Modified residue

14

1

Phosphoserine Ref.10 Ref.11 Ref.15

Modified residue

89

1

N6-acetyllysine Ref.12

Modified residue

145

1

N6-acetyllysine Ref.12

Natural variations

Natural variant

7

1

L → I.
Corresponds to variant rs11813789 [ dbSNP | Ensembl ].

VAR_059764

Natural variant

251

1

N → S. Ref.3
Corresponds to variant rs10828317 [ dbSNP | Ensembl ].

VAR_024565

Experimental info

Mutagenesis

131

1

G → L: Abolishes catalytic activity; when associated with F-138. Ref.13

Mutagenesis

138

1

Y → F: Abolishes catalytic activity; when associated with L-131. Ref.13

Sequence conflict

101 – 103

3

LRE → CGK in AAB35041. Ref.3

Sequence conflict

109

1

D → V in AAB35041. Ref.3

Sequence conflict

143

1

I → M in AAB35041. Ref.3

Sequence conflict

177 – 178

2

QF → HL in AAB35041. Ref.3

Sequence conflict

333

1

D → E in AAB35041. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

406

Helix Strand Turn

Details...

Helix

36 – 52

17

Helix

63 – 67

5

Beta strand

69 – 80

12

Turn

81 – 83

3

Beta strand

86 – 94

9

Helix

95 – 104

10

Helix

109 – 117

9

Beta strand

134 – 136

3

Beta strand

140 – 147

8

Helix

149 – 168

20

Turn

169 – 171

3

Beta strand

178 – 186

9

Beta strand

189 – 197

9

Beta strand

202 – 204

3

Beta strand

207 – 212

6

Beta strand

215 – 217

3

Helix

223 – 226

4

Beta strand

228 – 230

3

Helix

235 – 240

6

Helix

249 – 268

20

Beta strand

271 – 273

3

Beta strand

275 – 282

8

Helix

283 – 291

9

Turn

334 – 336

3

Beta strand

340 – 342

3

Beta strand

351 – 358

8

Beta strand

362 – 364

3

Helix

390 – 404

15

Sequences

	Sequence		Length	Mass (Da)
	P48426 [UniParc]. Last modified August 14, 2001. Version 2. Checksum: 5BAF0A27CC9EF376	FASTA	406	46,225
	10 20 30 40 50 60 MATPGNLGSS VLASKTKTKK KHFVAQKVKL FRASDPLLSV LMWGVNHSIN ELSHVQIPVM 70 80 90 100 110 120 LMPDDFKAYS KIKVDNHLFN KENMPSHFKF KEYCPMVFRN LRERFGIDDQ DFQNSLTRSA 130 140 150 160 170 180 PLPNDSQARS GARFHTSYDK RYIIKTITSE DVAEMHNILK KYHQYIVECH GITLLPQFLG 190 200 210 220 230 240 MYRLNVDGVE IYVIVTRNVF SHRLSVYRKY DLKGSTVARE ASDKEKAKEL PTLKDNDFIN 250 260 270 280 290 300 EGQKIYIDDN NKKVFLEKLK KDVEFLAQLK LMDYSLLVGI HDVERAEQEE VECEENDGEE 310 320 330 340 350 360 EGESDGTHPV GTPPDSPGNT LNSSPPLAPG EFDPNIDVYG IKCHENSPRK EVYFMAIIDI 370 380 390 400 LTHYDAKKKA AHAAKTVKHG AGAEISTVNP EQYSKRFLDF IGHILT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel family of lipid kinases." Boronenkov I.V., Anderson R.A. J. Biol. Chem. 270:2881-2884(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 30-42; 74-88; 93-112; 141-145; 254-259; 281-297 AND 383-406, TISSUE SPECIFICITY. Tissue: Placenta.
[2]	Boronenkov I.V. Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 298-310 AND 381-382.
[3]	"The cloning and sequence of the C isoform of PtdIns4P 5-kinase." Divecha N., Truong O., Hsuan J.J., Hinchliffe K.A., Irvine R.F. Biochem. J. 309:715-719(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, VARIANT SER-251. Tissue: Leukocyte.
[4]	NHLBI resequencing and genotyping service (RS&G) Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Hippocampus.
[8]	"A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate." Rameh L.E., Tolias K.F., Duckworth B.C., Cantley L.C. Nature 390:192-196(1997) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY.
[9]	"Regulation of extranuclear PtdIns5P production by phosphatidylinositol phosphate 4-kinase 2alpha." Wilcox A., Hinchliffe K.A. FEBS Lett. 582:1391-1394(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-3 AND SER-14, MASS SPECTROMETRY, CLEAVAGE OF INITIATOR METHIONINE.
[12]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-89 AND LYS-145, MASS SPECTROMETRY.
[13]	"PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha." Bultsma Y., Keune W.-J., Divecha N. Biochem. J. 430:223-235(2010) [PubMed] [Europe PMC] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION WITH PIP4K2B, SUBCELLULAR LOCATION, MUTAGENESIS OF GLY-131 AND TYR-138, IDENTIFICATION BY MASS SPECTROMETRY.
[14]	"Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases." Clarke J.H., Wang M., Irvine R.F. Adv. Enzyme Regul. 50:12-18(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[15]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[16]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U14957 mRNA. Translation: AAA64835.2.
S78798 mRNA. Translation: AAB35041.1.
AL513128, AL157707, AL390318 Genomic DNA. Translation: CAH72211.1.
EF445009 Genomic DNA. Translation: ACA06044.1.
EF445009 Genomic DNA. Translation: ACA06045.1.
AL157707, AL390318, AL513128 Genomic DNA. Translation: CAI39585.1.
AL390318, AL157707, AL513128 Genomic DNA. Translation: CAH70526.1.
CH471072 Genomic DNA. Translation: EAW86140.1.
CH471072 Genomic DNA. Translation: EAW86141.1.
BC018034 mRNA. Translation: AAH18034.1.

IPI

IPI00009688.

PIR

A55967.
S57217.

RefSeq

NP_005019.2. NM_005028.4.

UniGene

Hs.57079.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2YBX	X-ray	2.56	A/B	35-405	[»]

ProteinModelPortal

P48426.

ModBase

Search...

Protein-protein interaction databases

IntAct

P48426. 3 interactions.

STRING

9606.ENSP00000365757.

PTM databases

PhosphoSite

P48426.

Polymorphism databases

DMDM

18266879.

2D gel databases

OGP

P48426.

Proteomic databases

PaxDb

P48426.

PeptideAtlas

P48426.

PRIDE

P48426.

Protocols and materials databases

DNASU

5305.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000376573; ENSP00000365757; ENSG00000150867.

GeneID

5305.

KEGG

hsa:5305.

UCSC

uc001irl.4. human.

Organism-specific databases

CTD

5305.

GeneCards

GC10M022823.

HGNC

HGNC:8997. PIP4K2A.

MIM

603140. gene.

neXtProt

NX_P48426.

PharmGKB

PA162399615.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5253.

HOGENOM

HOG000007832.

HOVERGEN

HBG000072.

InParanoid

P48426.

KO

K00920.

OMA

THPIGTP.

OrthoDB

EOG4SQWX1.

PhylomeDB

P48426.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P48426.

Bgee

P48426.

CleanEx

HS_PIP4K2A.

Genevestigator

P48426.

GermOnline

ENSG00000150867. Homo sapiens.

Family and domain databases

InterPro

IPR023610. PInositol-4-P-5-kinase.
IPR002498. PInositol-4-P-5-kinase_core.
IPR016034. PInositol-4P-5-kinase_core_sub.
[Graphical view]

PANTHER

PTHR23086. PTHR23086. 1 hit.

Pfam

PF01504. PIP5K. 1 hit.
[Graphical view]

SMART

SM00330. PIPKc. 1 hit.
[Graphical view]

PROSITE

PS51455. PIPK. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL1795194.

ChiTaRS

PIP4K2A. human.

GenomeRNAi

5305.

NextBio

20506.

SOURCE

Search...

Entry information

Entry name

PI42A_HUMAN

Accession

Primary (citable) accession number: P48426
Secondary accession number(s): B0YJ66 , D3DRV1, P53807, Q5VUX3

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	August 14, 2001
Last modified:	May 1, 2013
This is version 112 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.