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P42337 (PK3CA_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

Short name=PI3-kinase subunit alpha
Short name=PI3K-alpha
Short name=PI3Kalpha
Short name=PtdIns-3-kinase subunit alpha
EC=2.7.1.153
Alternative name(s):
Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha
Short name=PtdIns-3-kinase subunit p110-alpha
Short name=p110alpha
Phosphoinositide-3-kinase catalytic alpha polypeptide
Serine/threonine protein kinase PIK3CA
EC=2.7.11.1
Gene names
Name:Pik3ca
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1068 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10

Catalytic activity

ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate.

ATP + a protein = ADP + a phosphoprotein.

Subunit structure

Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) By similarity. Interacts with IRS1 in nuclear extracts By similarity. Interacts with RUFY3 By similarity. Interacts with RASD2 By similarity. Interacts with APPL1 By similarity. Interacts with HRAS and KRAS By similarity. Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 By similarity. Ref.4 Ref.8

Domain

The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain By similarity. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane By similarity. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1 By similarity.

Disruption phenotype

Lethal. Embryonic fibroblasts cells are resistant to oncogenic transformation induced by oncogenic receptor tyrosine kinases (RTKs), are unable to differentiate into adipocytes and deficient in cellular signaling in response to various growth factors. Defective responsiveness to insulin led to reduced somatic growth, hyperinsulinemia, glucose intolerance, hyperphagia and increased adiposity. Ref.6 Ref.7 Ref.8 Ref.9

Sequence similarities

Belongs to the PI3/PI4-kinase family.

Contains 1 C2 PI3K-type domain.

Contains 1 PI3K-ABD domain.

Contains 1 PI3K-RBD domain.

Contains 1 PI3K/PI4K domain.

Contains 1 PIK helical domain.

Ontologies

Keywords
   Biological processAngiogenesis
   DiseaseProto-oncogene
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processangiogenesis

Inferred from electronic annotation. Source: UniProtKB-KW

glucose metabolic process

Inferred from mutant phenotype Ref.6. Source: MGI

hypomethylation of CpG island

Inferred from direct assay PubMed 21047779. Source: BHF-UCL

negative regulation of anoikis

Inferred from electronic annotation. Source: Ensembl

negative regulation of fibroblast apoptotic process

Inferred from direct assay PubMed 15192701. Source: MGI

negative regulation of neuron apoptotic process

Inferred from mutant phenotype PubMed 12904469. Source: MGI

phosphatidylinositol-3-phosphate biosynthetic process

Inferred from direct assay PubMed 14657280. Source: GOC

phosphatidylinositol-mediated signaling

Inferred from electronic annotation. Source: InterPro

positive regulation of peptidyl-serine phosphorylation

Inferred from direct assay PubMed 21047779. Source: BHF-UCL

positive regulation of protein kinase activity

Inferred from direct assay PubMed 21047779. Source: GOC

protein kinase B signaling

Inferred from mutant phenotype Ref.6. Source: MGI

protein phosphorylation

Inferred from direct assay PubMed 15192701. Source: MGI

regulation of genetic imprinting

Inferred from direct assay PubMed 21047779. Source: BHF-UCL

regulation of multicellular organism growth

Inferred from mutant phenotype Ref.6. Source: MGI

   Cellular_component1-phosphatidylinositol-4-phosphate 3-kinase, class IA complex

Inferred from electronic annotation. Source: Ensembl

lamellipodium

Inferred from direct assay PubMed 14657280. Source: MGI

phosphatidylinositol 3-kinase complex

Inferred from physical interaction PubMed 7542745. Source: MGI

plasma membrane

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_function1-phosphatidylinositol-3-kinase activity

Inferred from direct assay PubMed 14657280. Source: MGI

1-phosphatidylinositol-4-phosphate 3-kinase activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

ATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

insulin receptor substrate binding

Inferred from physical interaction PubMed 12486171. Source: MGI

phosphatidylinositol-4,5-bisphosphate 3-kinase activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

protein binding

Inferred from physical interaction PubMed 15102471Ref.8. Source: IntAct

protein kinase activator activity

Inferred from direct assay PubMed 21047779. Source: BHF-UCL

protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

HRASP011122EBI-641748,EBI-350145From a different organism.
Pik3r1P264506EBI-641748,EBI-641764

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 10681068Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
PRO_0000088786

Regions

Domain16 – 10590PI3K-ABD
Domain187 – 289103PI3K-RBD
Domain330 – 487158C2 PI3K-type
Domain517 – 694178PIK helical
Domain797 – 1068272PI3K/PI4K

Experimental info

Mutagenesis2081T → D: Abolishes binding to HRAS and KRAS; does not affect kinase activity; displays defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites and is highly resistant to endogenous Ras oncogene-induced tumorigenesis; when associated with A-227. Ref.8
Mutagenesis2271K → A: Abolishes binding to HRAS and KRAS; does not affect kinase activity; displays defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites and is highly resistant to endogenous Ras oncogene-induced tumorigenesis; when associated with D-208. Ref.8
Mutagenesis9331D → A: Loss of kinase activity; displays early embryonic lethality at E10-11 and severe defects in angiogenic sprouting and vascular remodeling. Heterozygous mice yield adult mice with markedly impaired insulin signaling and reduced activation of effector pathways such as Akt/PKB. Ref.6
Sequence conflict3991A → L in AAA18334. Ref.1

Secondary structure

........................................................................................................................................................................... 1068
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P42337 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: D593283B416ABFD0

FASTA1,068124,412
        10         20         30         40         50         60 
MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLVTIKHELF REARKYPLHQ 

        70         80         90        100        110        120 
LLQDETSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFV 

       130        140        150        160        170        180 
IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH 

       190        200        210        220        230        240 
IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK 

       250        260        270        280        290        300 
LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPID 

       310        320        330        340        350        360 
SFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI 

       370        380        390        400        410        420 
YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC 

       430        440        450        460        470        480 
PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF 

       490        500        510        520        530        540 
SSVVKFPDMS VIEEHANWSV SREAGFSYSH TGLSNRLARD NELRENDKEQ LRALCTRDPL 

       550        560        570        580        590        600 
SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME 

       610        620        630        640        650        660 
LLDCNYPDPM VRSFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN 

       670        680        690        700        710        720 
QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK 

       730        740        750        760        770        780 
QEKKDETQKV QMKFLVEQMR QPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW 

       790        800        810        820        830        840 
LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS 

       850        860        870        880        890        900 
IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS 

       910        920        930        940        950        960 
CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF 

       970        980        990       1000       1010       1020 
LIVISKGAQE YTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA 

      1030       1040       1050       1060 
YIRKTLALDK TEQEALEYFT KQMNDAHHGG WTTKMDWIFH TIKQHALN 

« Hide

References

« Hide 'large scale' references
[1]"The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity."
Klippel A., Escobedo J.A., Hirano M., Williams L.T.
Mol. Cell. Biol. 14:2675-2685(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: BALB/c.
[2]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"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].
Strain: C57BL/6.
Tissue: Eye.
[4]"Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase."
Drakas R., Tu X., Baserga R.
Proc. Natl. Acad. Sci. U.S.A. 101:9272-9276(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IRS1.
[5]"A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling."
Knight Z.A., Gonzalez B., Feldman M.E., Zunder E.R., Goldenberg D.D., Williams O., Loewith R., Stokoe D., Balla A., Toth B., Balla T., Weiss W.A., Williams R.L., Shokat K.M.
Cell 125:733-747(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation."
Foukas L.C., Claret M., Pearce W., Okkenhaug K., Meek S., Peskett E., Sancho S., Smith A.J.H., Withers D.J., Vanhaesebroeck B.
Nature 441:366-370(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE, MUTAGENESIS OF ASP-933.
[7]"The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation."
Zhao J.J., Cheng H., Jia S., Wang L., Gjoerup O.V., Mikami A., Roberts T.M.
Proc. Natl. Acad. Sci. U.S.A. 103:16296-16300(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[8]"Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice."
Gupta S., Ramjaun A.R., Haiko P., Wang Y., Warne P.H., Nicke B., Nye E., Stamp G., Alitalo K., Downward J.
Cell 129:957-968(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE, INTERACTION WITH HRAS AND KRAS, MUTAGENESIS OF THR-208 AND LYS-227.
[9]"Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration."
Graupera M., Guillermet-Guibert J., Foukas L.C., Phng L.-K., Cain R.J., Salpekar A., Pearce W., Meek S., Millan J., Cutillas P.R., Smith A.J.H., Ridley A.J., Ruhrberg C., Gerhardt H., Vanhaesebroeck B.
Nature 453:662-666(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[10]"VEGF-mediated PI3K class IA and PKC signaling in cardiomyogenesis and vasculogenesis of mouse embryonic stem cells."
Bekhite M.M., Finkensieper A., Binas S., Mueller J., Wetzker R., Figulla H.-R., Sauer H., Wartenberg M.
J. Cell Sci. 124:1819-1830(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION ON CARDIOMYOGENESIS, FUNCTION ON VASCULOGENESIS.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U03279 mRNA. Translation: AAA18334.1.
CH466530 Genomic DNA. Translation: EDL34990.1.
BC089038 mRNA. Translation: AAH89038.1.
BC130228 mRNA. Translation: AAI30229.1.
CCDSCCDS38409.1.
RefSeqNP_032865.2. NM_008839.2.
XP_006535472.1. XM_006535409.1.
XP_006535473.1. XM_006535410.1.
UniGeneMm.260521.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4A55X-ray3.50A1-1068[»]
ProteinModelPortalP42337.
SMRP42337. Positions 16-105, 107-1046.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid202160. 5 interactions.
DIPDIP-32095N.
IntActP42337. 10 interactions.
MINTMINT-219865.
STRING10090.ENSMUSP00000103878.

Chemistry

BindingDBP42337.
ChEMBLCHEMBL2499.

PTM databases

PhosphoSiteP42337.

Proteomic databases

MaxQBP42337.
PaxDbP42337.
PRIDEP42337.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000029201; ENSMUSP00000029201; ENSMUSG00000027665.
ENSMUST00000108243; ENSMUSP00000103878; ENSMUSG00000027665.
GeneID18706.
KEGGmmu:18706.
UCSCuc008owd.2. mouse.

Organism-specific databases

CTD5290.
MGIMGI:1206581. Pik3ca.

Phylogenomic databases

eggNOGCOG5032.
GeneTreeENSGT00620000087742.
HOGENOMHOG000252911.
HOVERGENHBG052721.
InParanoidQ0VGQ5.
KOK00922.
OMAAFAVRCL.
OrthoDBEOG70CR65.
TreeFamTF102031.

Enzyme and pathway databases

BRENDA2.7.1.137. 3474.

Gene expression databases

ArrayExpressP42337.
BgeeP42337.
GenevestigatorP42337.

Family and domain databases

Gene3D1.10.1070.11. 1 hit.
1.25.40.70. 1 hit.
2.60.40.150. 1 hit.
InterProIPR016024. ARM-type_fold.
IPR000008. C2_dom.
IPR011009. Kinase-like_dom.
IPR000403. PI3/4_kinase_cat_dom.
IPR018936. PI3/4_kinase_CS.
IPR003113. PI3K_adapt-bd_dom.
IPR002420. PI3K_C2_dom.
IPR000341. PI3K_Ras-bd_dom.
IPR015433. PI_Kinase.
IPR001263. PInositide-3_kin_accessory_dom.
IPR029071. Ubiquitin-rel_dom.
[Graphical view]
PANTHERPTHR10048. PTHR10048. 1 hit.
PfamPF00454. PI3_PI4_kinase. 1 hit.
PF00792. PI3K_C2. 1 hit.
PF02192. PI3K_p85B. 1 hit.
PF00794. PI3K_rbd. 1 hit.
PF00613. PI3Ka. 1 hit.
[Graphical view]
SMARTSM00239. C2. 1 hit.
SM00142. PI3K_C2. 1 hit.
SM00143. PI3K_p85B. 1 hit.
SM00144. PI3K_rbd. 1 hit.
SM00145. PI3Ka. 1 hit.
SM00146. PI3Kc. 1 hit.
[Graphical view]
SUPFAMSSF48371. SSF48371. 1 hit.
SSF49562. SSF49562. 1 hit.
SSF54236. SSF54236. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS00915. PI3_4_KINASE_1. 1 hit.
PS00916. PI3_4_KINASE_2. 1 hit.
PS50290. PI3_4_KINASE_3. 1 hit.
PS51544. PI3K_ABD. 1 hit.
PS51547. PI3K_C2. 1 hit.
PS51546. PI3K_RBD. 1 hit.
PS51545. PIK_HELICAL. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSPIK3CA. mouse.
NextBio294769.
PROP42337.
SOURCESearch...

Entry information

Entry namePK3CA_MOUSE
AccessionPrimary (citable) accession number: P42337
Secondary accession number(s): Q0VGQ5
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 130 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot