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P42336

- PK3CA_HUMAN

UniProt

P42336 - PK3CA_HUMAN

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Protein

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

Gene

PIK3CA

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.1 Publication

Catalytic activityi

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.

GO - Molecular functioni

  1. 1-phosphatidylinositol-3-kinase activity Source: UniProtKB
  2. 1-phosphatidylinositol-4-phosphate 3-kinase activity Source: RefGenome
  3. ATP binding Source: UniProtKB-KW
  4. kinase activity Source: Reactome
  5. phosphatidylinositol 3-kinase activity Source: UniProtKB
  6. phosphatidylinositol-4,5-bisphosphate 3-kinase activity Source: Reactome
  7. protein kinase activator activity Source: Ensembl
  8. protein serine/threonine kinase activity Source: UniProtKB-KW

GO - Biological processi

  1. angiogenesis Source: UniProtKB-KW
  2. blood coagulation Source: Reactome
  3. cardiac muscle contraction Source: UniProtKB
  4. endothelial cell migration Source: UniProtKB
  5. epidermal growth factor receptor signaling pathway Source: Reactome
  6. Fc-epsilon receptor signaling pathway Source: Reactome
  7. Fc-gamma receptor signaling pathway involved in phagocytosis Source: Reactome
  8. fibroblast growth factor receptor signaling pathway Source: Reactome
  9. glucose metabolic process Source: Ensembl
  10. hypomethylation of CpG island Source: Ensembl
  11. innate immune response Source: Reactome
  12. insulin receptor signaling pathway Source: Reactome
  13. insulin receptor signaling pathway via phosphatidylinositol 3-kinase Source: UniProtKB
  14. leukocyte migration Source: Reactome
  15. negative regulation of anoikis Source: UniProtKB
  16. negative regulation of fibroblast apoptotic process Source: Ensembl
  17. negative regulation of neuron apoptotic process Source: Ensembl
  18. neurotrophin TRK receptor signaling pathway Source: Reactome
  19. phosphatidylinositol biosynthetic process Source: Reactome
  20. phosphatidylinositol-mediated signaling Source: Reactome
  21. phosphatidylinositol phosphorylation Source: BHF-UCL
  22. phospholipid metabolic process Source: Reactome
  23. platelet activation Source: UniProtKB
  24. positive regulation of peptidyl-serine phosphorylation Source: Ensembl
  25. protein kinase B signaling Source: Ensembl
  26. regulation of genetic imprinting Source: Ensembl
  27. regulation of multicellular organism growth Source: Ensembl
  28. small molecule metabolic process Source: Reactome
  29. T cell costimulation Source: Reactome
  30. T cell receptor signaling pathway Source: Reactome
  31. vasculature development Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Angiogenesis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS04527-MONOMER.
BRENDAi2.7.1.137. 2681.
ReactomeiREACT_111040. Signaling by SCF-KIT.
REACT_115852. Signaling by constitutively active EGFR.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_121025. Synthesis of PIPs at the plasma membrane.
REACT_121141. Signaling by FGFR1 fusion mutants.
REACT_121398. Signaling by FGFR mutants.
REACT_12464. PI3K/AKT activation.
REACT_12555. Downstream TCR signaling.
REACT_12578. GAB1 signalosome.
REACT_12621. Tie2 Signaling.
REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
REACT_147814. DAP12 signaling.
REACT_160158. Role of phospholipids in phagocytosis.
REACT_163769. Role of LAT2/NTAL/LAB on calcium mobilization.
REACT_1695. GPVI-mediated activation cascade.
REACT_17025. Downstream signal transduction.
REACT_18283. G alpha (q) signalling events.
REACT_18407. G alpha (12/13) signalling events.
REACT_19290. G beta:gamma signalling through PI3Kgamma.
REACT_19344. Costimulation by the CD28 family.
REACT_19358. CD28 dependent PI3K/Akt signaling.
REACT_21270. PI-3K cascade.
REACT_228166. VEGFA-VEGFR2 Pathway.
REACT_23787. Regulation of signaling by CBL.
REACT_23832. Nephrin interactions.
REACT_23837. Interleukin-3, 5 and GM-CSF signaling.
REACT_23891. Interleukin receptor SHC signaling.
REACT_75829. PIP3 activates AKT signaling.
REACT_976. PI3K Cascade.
SignaLinkiP42336.

Names & Taxonomyi

Protein namesi
Recommended name:
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (EC:2.7.1.153)
Short name:
PI3-kinase subunit alpha
Short name:
PI3K-alpha
Short name:
PI3Kalpha
Short name:
PtdIns-3-kinase subunit alpha
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 namesi
Name:PIK3CA
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 3

Organism-specific databases

HGNCiHGNC:8975. PIK3CA.

Subcellular locationi

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. lamellipodium Source: Ensembl
  3. phosphatidylinositol 3-kinase complex Source: BHF-UCL
  4. phosphatidylinositol 3-kinase complex, class IA Source: UniProtKB
  5. plasma membrane Source: RefGenome
Complete GO annotation...

Pathology & Biotechi

Involvement in diseasei

PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.
Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
Note: The gene represented in this entry may be involved in disease pathogenesis.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti38 – 381R → H in CRC; likely involved in disease pathogenesis; shows an increase in lipid kinase activity; may disrupt the interaction between the PI3K-ABD domain and the N-terminal lobe of PI3K/PI4K kinase domain possibly affecting the conformation of the kinase domain.
VAR_026166
Natural varianti106 – 1061G → V in CRC; likely involved in disease pathogenesis; shows an increase in lipid kinase activity.
VAR_026168
Natural varianti420 – 4201C → R in CLOVE and CRC; shows an increase in lipid kinase activity; may increase the affinity for lipid membranes. 1 Publication
VAR_026171
Natural varianti453 – 4531E → Q in CRC; likely involved in disease pathogenesis; shows an increase in lipid kinase activity; may disrupt the interaction of the C2 PI3K-type domain with the iSH2 region of the p85 regulatory subunit.
VAR_026172
Natural varianti542 – 5421E → K in CLOVE, KERSEB, CRC and BC; also found in glioblastoma multiforme and endometrial carcinoma; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation. 9 Publications
VAR_026173
Natural varianti545 – 5451E → K in MCAP, KERSEB, CRC and BC; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells. 10 Publications
VAR_026178
Natural varianti1023 – 10231R → Q in CRC; unknown pathological significance. 1 Publication
VAR_026187
Natural varianti1043 – 10431M → I in MCAP and CRC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity. 2 Publications
VAR_026190
Natural varianti1047 – 10471H → R in CLOVE, KERSEB, CRC, BC and OC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity; oncogenic in vivo; requires binding to p85 regulatory subunit to induce cellular transformation but not interaction with RAS; may mimic the conformatitonal change triggered by the interaction with RAS; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells; increases lipid kinase activity; may alter the interaction of the PI3K/PI4K kinase domain with the cell membrane. 12 Publications
VAR_026192
Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.1 Publication
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti542 – 5421E → K in CLOVE, KERSEB, CRC and BC; also found in glioblastoma multiforme and endometrial carcinoma; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation. 9 Publications
VAR_026173
Natural varianti542 – 5421E → V in BC; unknown pathological significance. 1 Publication
VAR_026175
Natural varianti545 – 5451E → K in MCAP, KERSEB, CRC and BC; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells. 10 Publications
VAR_026178
Natural varianti546 – 5461Q → E in BC; unknown pathological significance. 1 Publication
VAR_026179
Natural varianti546 – 5461Q → R in BC; unknown pathological significance. 1 Publication
VAR_026182
Natural varianti1047 – 10471H → L in BC; unknown pathological significance. 4 Publications
VAR_026191
Natural varianti1047 – 10471H → R in CLOVE, KERSEB, CRC, BC and OC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity; oncogenic in vivo; requires binding to p85 regulatory subunit to induce cellular transformation but not interaction with RAS; may mimic the conformatitonal change triggered by the interaction with RAS; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells; increases lipid kinase activity; may alter the interaction of the PI3K/PI4K kinase domain with the cell membrane. 12 Publications
VAR_026192
Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti546 – 5461Q → K in OC; unknown pathological significance. 1 Publication
VAR_026180
Natural varianti1047 – 10471H → R in CLOVE, KERSEB, CRC, BC and OC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity; oncogenic in vivo; requires binding to p85 regulatory subunit to induce cellular transformation but not interaction with RAS; may mimic the conformatitonal change triggered by the interaction with RAS; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells; increases lipid kinase activity; may alter the interaction of the PI3K/PI4K kinase domain with the cell membrane. 12 Publications
VAR_026192
Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes.1 Publication
Note: The gene represented in this entry may be involved in disease pathogenesis.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti545 – 5451E → A in CWS5 and HCC; also found in a glioblastoma multiforme sample. 3 Publications
VAR_026176
Keratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti542 – 5421E → K in CLOVE, KERSEB, CRC and BC; also found in glioblastoma multiforme and endometrial carcinoma; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation. 9 Publications
VAR_026173
Natural varianti545 – 5451E → G in KERSEB; also found in an endometrial carcinoma sample. 4 Publications
VAR_026177
Natural varianti545 – 5451E → K in MCAP, KERSEB, CRC and BC; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells. 10 Publications
VAR_026178
Natural varianti1047 – 10471H → R in CLOVE, KERSEB, CRC, BC and OC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity; oncogenic in vivo; requires binding to p85 regulatory subunit to induce cellular transformation but not interaction with RAS; may mimic the conformatitonal change triggered by the interaction with RAS; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells; increases lipid kinase activity; may alter the interaction of the PI3K/PI4K kinase domain with the cell membrane. 12 Publications
VAR_026192
Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) [MIM:602501]: A syndrome characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti81 – 811E → K in MCAP. 1 Publication
VAR_069251
Natural varianti88 – 881R → Q in MCAP; also found in a glioblastoma multiforme sample; may disrupt the interaction between the PI3K-ABD domain and the N-terminal lobe of PI3K/PI4K kinase domain possibly affecting the conformation of the kinase domain. 2 Publications
VAR_026167
Natural varianti364 – 3641G → R in MCAP. 1 Publication
VAR_069252
Natural varianti365 – 3651E → K in MCAP. 1 Publication
VAR_069253
Natural varianti378 – 3781C → Y in MCAP. 1 Publication
VAR_069254
Natural varianti453 – 4531Missing in MCAP. 1 Publication
VAR_069255
Natural varianti545 – 5451E → K in MCAP, KERSEB, CRC and BC; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells. 10 Publications
VAR_026178
Natural varianti726 – 7261E → K in MCAP. 1 Publication
VAR_069256
Natural varianti914 – 9141G → R in MCAP. 1 Publication
VAR_069257
Natural varianti1021 – 10211Y → C in MCAP; also found in an endometrial carcinoma sample. 2 Publications
VAR_026184
Natural varianti1025 – 10251T → A in MCAP. 1 Publication
VAR_069258
Natural varianti1035 – 10351A → V in MCAP; also found in an endometrial carcinoma sample. 2 Publications
VAR_026189
Natural varianti1043 – 10431M → I in MCAP and CRC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity. 2 Publications
VAR_026190
Natural varianti1047 – 10471H → Y in MCAP; also found in an endometrial carcinoma sample. 2 Publications
VAR_026193
Natural varianti1049 – 10491G → S in MCAP. 1 Publication
VAR_069259
Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:612918]: A sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti420 – 4201C → R in CLOVE and CRC; shows an increase in lipid kinase activity; may increase the affinity for lipid membranes. 1 Publication
VAR_026171
Natural varianti542 – 5421E → K in CLOVE, KERSEB, CRC and BC; also found in glioblastoma multiforme and endometrial carcinoma; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation. 9 Publications
VAR_026173
Natural varianti1047 – 10471H → R in CLOVE, KERSEB, CRC, BC and OC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity; oncogenic in vivo; requires binding to p85 regulatory subunit to induce cellular transformation but not interaction with RAS; may mimic the conformatitonal change triggered by the interaction with RAS; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells; increases lipid kinase activity; may alter the interaction of the PI3K/PI4K kinase domain with the cell membrane. 12 Publications
VAR_026192
Cowden syndrome 5 (CWS5) [MIM:615108]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti118 – 1181G → D in CWS5. 1 Publication
VAR_069786
Natural varianti135 – 1351E → K in CWS5. 1 Publication
VAR_069787
Natural varianti218 – 2181E → K in CWS5. 1 Publication
VAR_069788
Natural varianti356 – 3561V → I in CWS5. 1 Publication
VAR_069789
Natural varianti382 – 3821R → K in CWS5. 1 Publication
VAR_069790
Natural varianti545 – 5451E → A in CWS5 and HCC; also found in a glioblastoma multiforme sample. 3 Publications
VAR_026176

Keywords - Diseasei

Disease mutation, Proto-oncogene

Organism-specific databases

MIMi114480. phenotype.
114500. phenotype.
114550. phenotype.
167000. phenotype.
182000. phenotype.
602501. phenotype.
612918. phenotype.
615108. phenotype.
Orphaneti140944. CLOVE syndrome.
201. Cowden syndrome.
276280. Hemihyperplasia-multiple lipomatosis syndrome.
99802. Hemimegalencephaly.
144. Hereditary nonpolyposis colon cancer.
295239. Macrodactyly of fingers, unilateral.
295243. Macrodactyly of toes, unilateral.
60040. Megalencephaly-capillary malformation-polymicrogyria syndrome.
314662. Segmental progressive overgrowth syndrome with fibroadipose hyperplasia.
PharmGKBiPA33308.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 10681068Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformPRO_0000088785Add
BLAST

Proteomic databases

MaxQBiP42336.
PaxDbiP42336.
PRIDEiP42336.

PTM databases

PhosphoSiteiP42336.

Expressioni

Gene expression databases

BgeeiP42336.
CleanExiHS_PIK3CA.
ExpressionAtlasiP42336. baseline and differential.
GenevestigatoriP42336.

Organism-specific databases

HPAiCAB017804.
HPA009985.

Interactioni

Subunit structurei

Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with IRS1 in nuclear extracts. Interacts with RUFY3 (By similarity). Interacts with RASD2 (By similarity). Interacts with APPL1. 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).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
ERBB3P218603EBI-2116585,EBI-720706
IRS1P3556820EBI-2116585,EBI-517592
PIK3R1P2798613EBI-2116585,EBI-79464

Protein-protein interaction databases

BioGridi111308. 52 interactions.
DIPiDIP-42728N.
IntActiP42336. 26 interactions.
MINTiMINT-1367228.
STRINGi9606.ENSP00000263967.

Structurei

Secondary structure

1
1068
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi5 – 106Combined sources
Beta strandi13 – 153Combined sources
Beta strandi18 – 258Combined sources
Beta strandi31 – 377Combined sources
Helixi42 – 5211Combined sources
Helixi53 – 553Combined sources
Beta strandi56 – 583Combined sources
Helixi59 – 613Combined sources
Helixi65 – 673Combined sources
Beta strandi69 – 746Combined sources
Beta strandi75 – 773Combined sources
Beta strandi79 – 824Combined sources
Helixi89 – 913Combined sources
Beta strandi94 – 1029Combined sources
Helixi108 – 12114Combined sources
Helixi126 – 1305Combined sources
Helixi134 – 1429Combined sources
Helixi144 – 15512Combined sources
Turni156 – 1594Combined sources
Helixi160 – 1667Combined sources
Helixi179 – 1824Combined sources
Beta strandi185 – 19814Combined sources
Turni199 – 2024Combined sources
Beta strandi203 – 21210Combined sources
Helixi217 – 22610Combined sources
Turni230 – 2323Combined sources
Turni236 – 2394Combined sources
Helixi240 – 2456Combined sources
Helixi246 – 2483Combined sources
Beta strandi249 – 2546Combined sources
Turni255 – 2584Combined sources
Helixi267 – 2693Combined sources
Helixi271 – 2799Combined sources
Beta strandi284 – 2896Combined sources
Helixi290 – 2945Combined sources
Helixi306 – 3094Combined sources
Turni320 – 3234Combined sources
Beta strandi324 – 3263Combined sources
Helixi327 – 3293Combined sources
Beta strandi332 – 34211Combined sources
Turni348 – 3503Combined sources
Beta strandi353 – 36210Combined sources
Beta strandi365 – 3684Combined sources
Beta strandi376 – 3794Combined sources
Beta strandi382 – 39211Combined sources
Helixi393 – 3953Combined sources
Beta strandi401 – 41313Combined sources
Beta strandi416 – 43015Combined sources
Beta strandi434 – 4363Combined sources
Beta strandi439 – 4446Combined sources
Beta strandi454 – 4563Combined sources
Beta strandi458 – 4603Combined sources
Beta strandi468 – 4703Combined sources
Beta strandi472 – 4776Combined sources
Beta strandi481 – 4855Combined sources
Helixi489 – 4924Combined sources
Helixi495 – 4984Combined sources
Turni505 – 5084Combined sources
Beta strandi511 – 5133Combined sources
Helixi517 – 5204Combined sources
Helixi526 – 53611Combined sources
Beta strandi539 – 5413Combined sources
Helixi545 – 5539Combined sources
Turni554 – 5574Combined sources
Helixi558 – 5603Combined sources
Helixi562 – 5643Combined sources
Helixi565 – 5717Combined sources
Helixi577 – 58913Combined sources
Helixi595 – 5984Combined sources
Helixi599 – 6024Combined sources
Helixi609 – 62214Combined sources
Helixi625 – 63814Combined sources
Helixi639 – 6413Combined sources
Beta strandi643 – 6464Combined sources
Helixi648 – 65710Combined sources
Helixi661 – 67212Combined sources
Turni673 – 6764Combined sources
Turni678 – 6803Combined sources
Helixi681 – 69414Combined sources
Helixi698 – 72023Combined sources
Turni721 – 7255Combined sources
Helixi728 – 73912Combined sources
Helixi742 – 7487Combined sources
Beta strandi749 – 7535Combined sources
Beta strandi756 – 7616Combined sources
Helixi766 – 7683Combined sources
Beta strandi774 – 7763Combined sources
Beta strandi779 – 7846Combined sources
Helixi790 – 7923Combined sources
Beta strandi795 – 80511Combined sources
Helixi808 – 82518Combined sources
Turni826 – 8283Combined sources
Beta strandi838 – 8425Combined sources
Beta strandi845 – 8495Combined sources
Beta strandi852 – 8565Combined sources
Helixi857 – 8615Combined sources
Turni865 – 8673Combined sources
Helixi871 – 8733Combined sources
Helixi876 – 8849Combined sources
Helixi887 – 8893Combined sources
Helixi890 – 91122Combined sources
Beta strandi920 – 9245Combined sources
Beta strandi929 – 9313Combined sources
Beta strandi937 – 9393Combined sources
Helixi942 – 9454Combined sources
Helixi958 – 9647Combined sources
Turni965 – 9673Combined sources
Beta strandi969 – 9713Combined sources
Beta strandi972 – 9743Combined sources
Helixi975 – 99319Combined sources
Helixi995 – 10039Combined sources
Turni1004 – 10074Combined sources
Beta strandi1013 – 10153Combined sources
Helixi1016 – 102510Combined sources
Turni1026 – 10294Combined sources
Helixi1032 – 104716Combined sources
Beta strandi1053 – 10553Combined sources
Beta strandi1056 – 10583Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2ENQNMR-A331-481[»]
2RD0X-ray3.05A1-1068[»]
3HHMX-ray2.80A1-1068[»]
3HIZX-ray3.30A1-1068[»]
3ZIMX-ray2.85A107-1046[»]
4JPSX-ray2.20A1-1068[»]
4L1BX-ray2.59A1-1068[»]
4L23X-ray2.50A1-1068[»]
4L2YX-ray2.80A1-1068[»]
4OVUX-ray2.96A1-1068[»]
4OVVX-ray3.50A1-1068[»]
4TUUX-ray2.64A105-1048[»]
4TV3X-ray2.85A105-1048[»]
ProteinModelPortaliP42336.
SMRiP42336. Positions 16-105, 107-1046.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP42336.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini16 – 10590PI3K-ABDPROSITE-ProRule annotationAdd
BLAST
Domaini187 – 289103PI3K-RBDPROSITE-ProRule annotationAdd
BLAST
Domaini330 – 487158C2 PI3K-typePROSITE-ProRule annotationAdd
BLAST
Domaini517 – 694178PIK helicalPROSITE-ProRule annotationAdd
BLAST
Domaini797 – 1068272PI3K/PI4KPROSITE-ProRule annotationAdd
BLAST

Domaini

The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. 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 PIK3R1.2 Publications

Sequence similaritiesi

Belongs to the PI3/PI4-kinase family.PROSITE-ProRule annotation
Contains 1 C2 PI3K-type domain.PROSITE-ProRule annotation
Contains 1 PI3K-ABD domain.PROSITE-ProRule annotation
Contains 1 PI3K-RBD domain.PROSITE-ProRule annotation
Contains 1 PI3K/PI4K domain.PROSITE-ProRule annotation
Contains 1 PIK helical domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG5032.
GeneTreeiENSGT00760000119110.
HOVERGENiHBG052721.
InParanoidiP42336.
KOiK00922.
OMAiAFAVRCL.
OrthoDBiEOG70CR65.
PhylomeDBiP42336.
TreeFamiTF102031.

Family and domain databases

Gene3Di1.10.1070.11. 1 hit.
1.25.40.70. 1 hit.
2.60.40.150. 1 hit.
InterProiIPR016024. 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]
PANTHERiPTHR10048. PTHR10048. 1 hit.
PfamiPF00454. 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]
SMARTiSM00239. 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]
SUPFAMiSSF48371. SSF48371. 1 hit.
SSF49562. SSF49562. 1 hit.
SSF54236. SSF54236. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00915. 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]

Sequencei

Sequence statusi: Complete.

P42336-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF
60 70 80 90 100
KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK
110 120 130 140 150
VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA
160 170 180 190 200
VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP
210 220 230 240 250
NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY
260 270 280 290 300
ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD
310 320 330 340 350
CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD
360 370 380 390 400
IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA
410 420 430 440 450
RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH
460 470 480 490 500
GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV
510 520 530 540 550
SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF
560 570 580 590 600
LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME
610 620 630 640 650
LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV
660 670 680 690 700
RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK
710 720 730 740 750
HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG
760 770 780 790 800
FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII
810 820 830 840 850
FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV
860 870 880 890 900
VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS
910 920 930 940 950
CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE
960 970 980 990 1000
RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN
1010 1020 1030 1040 1050
LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG
1060
WTTKMDWIFH TIKQHALN
Length:1,068
Mass (Da):124,284
Last modified:February 20, 2007 - v2
Checksum:i041487231A9A1207
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti170 – 1701N → H in CAA82333. (PubMed:7713498)Curated
Sequence conflicti187 – 1871K → R in CAA82333. (PubMed:7713498)Curated
Sequence conflicti286 – 2872ML → KM in CAA82333. (PubMed:7713498)Curated
Sequence conflicti346 – 3461V → L in CAA82333. (PubMed:7713498)Curated
Sequence conflicti723 – 7231K → R in CAA82333. (PubMed:7713498)Curated
Sequence conflicti751 – 7511F → L in CAA82333. (PubMed:7713498)Curated
Sequence conflicti767 – 7671E → K in CAA82333. (PubMed:7713498)Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti38 – 381R → H in CRC; likely involved in disease pathogenesis; shows an increase in lipid kinase activity; may disrupt the interaction between the PI3K-ABD domain and the N-terminal lobe of PI3K/PI4K kinase domain possibly affecting the conformation of the kinase domain.
VAR_026166
Natural varianti43 – 431I → V.1 Publication
Corresponds to variant rs1051399 [ dbSNP | Ensembl ].
VAR_042942
Natural varianti81 – 811E → K in MCAP. 1 Publication
VAR_069251
Natural varianti88 – 881R → Q in MCAP; also found in a glioblastoma multiforme sample; may disrupt the interaction between the PI3K-ABD domain and the N-terminal lobe of PI3K/PI4K kinase domain possibly affecting the conformation of the kinase domain. 2 Publications
VAR_026167
Natural varianti106 – 1061G → V in CRC; likely involved in disease pathogenesis; shows an increase in lipid kinase activity.
VAR_026168
Natural varianti118 – 1181G → D in CWS5. 1 Publication
VAR_069786
Natural varianti135 – 1351E → K in CWS5. 1 Publication
VAR_069787
Natural varianti218 – 2181E → K in CWS5. 1 Publication
VAR_069788
Natural varianti332 – 3321S → R.1 Publication
Corresponds to variant rs1051407 [ dbSNP | Ensembl ].
VAR_042943
Natural varianti343 – 3431Y → C Found in a cancer sample; unknown pathological significance. 1 Publication
VAR_026169
Natural varianti356 – 3561V → I in CWS5. 1 Publication
VAR_069789
Natural varianti364 – 3641G → R in MCAP. 1 Publication
VAR_069252
Natural varianti365 – 3651E → K in MCAP. 1 Publication
VAR_069253
Natural varianti378 – 3781C → Y in MCAP. 1 Publication
VAR_069254
Natural varianti382 – 3821R → K in CWS5. 1 Publication
VAR_069790
Natural varianti391 – 3911I → M.1 Publication
Corresponds to variant rs3729680 [ dbSNP | Ensembl ].
VAR_026170
Natural varianti420 – 4201C → R in CLOVE and CRC; shows an increase in lipid kinase activity; may increase the affinity for lipid membranes. 1 Publication
VAR_026171
Natural varianti453 – 4531E → Q in CRC; likely involved in disease pathogenesis; shows an increase in lipid kinase activity; may disrupt the interaction of the C2 PI3K-type domain with the iSH2 region of the p85 regulatory subunit.
VAR_026172
Natural varianti453 – 4531Missing in MCAP. 1 Publication
VAR_069255
Natural varianti542 – 5421E → K in CLOVE, KERSEB, CRC and BC; also found in glioblastoma multiforme and endometrial carcinoma; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation. 9 Publications
VAR_026173
Natural varianti542 – 5421E → Q Found in an endometrial carcinoma sample; unknown pathological significance. 1 Publication
VAR_026174
Natural varianti542 – 5421E → V in BC; unknown pathological significance. 1 Publication
VAR_026175
Natural varianti545 – 5451E → A in CWS5 and HCC; also found in a glioblastoma multiforme sample. 3 Publications
VAR_026176
Natural varianti545 – 5451E → G in KERSEB; also found in an endometrial carcinoma sample. 4 Publications
VAR_026177
Natural varianti545 – 5451E → K in MCAP, KERSEB, CRC and BC; shows an increase in lipid kinase activity; oncogenic in vivo; occurs in the interface between the PI3K helical domain and the nSH2 (N-terminal SH2) region of the p85 regulatory subunit and may reduce the inhibitory effect of p85; requires interaction with RAS to induce cellular transformation; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells. 10 Publications
VAR_026178
Natural varianti546 – 5461Q → E in BC; unknown pathological significance. 1 Publication
VAR_026179
Natural varianti546 – 5461Q → K in OC; unknown pathological significance. 1 Publication
VAR_026180
Natural varianti546 – 5461Q → P Found in an anaplastic astrocytoma sample; unknown pathological significance. 1 Publication
VAR_026181
Natural varianti546 – 5461Q → R in BC; unknown pathological significance. 1 Publication
VAR_026182
Natural varianti726 – 7261E → K in MCAP. 1 Publication
VAR_069256
Natural varianti914 – 9141G → R in MCAP. 1 Publication
VAR_069257
Natural varianti1007 – 10071G → R Found in an endometrial carcinoma sample; unknown pathological significance. 1 Publication
VAR_026183
Natural varianti1021 – 10211Y → C in MCAP; also found in an endometrial carcinoma sample. 2 Publications
VAR_026184
Natural varianti1021 – 10211Y → H Found in an endometrial carcinoma sample; unknown pathological significance. 1 Publication
VAR_026185
Natural varianti1021 – 10211Y → N Found in a glioblastoma multiforme sample; unknown pathological significance. 1 Publication
VAR_026186
Natural varianti1023 – 10231R → Q in CRC; unknown pathological significance. 1 Publication
VAR_026187
Natural varianti1025 – 10251T → A in MCAP. 1 Publication
VAR_069258
Natural varianti1025 – 10251T → N Found in a glioblastoma multiforme sample; unknown pathological significance. 1 Publication
VAR_026188
Natural varianti1035 – 10351A → V in MCAP; also found in an endometrial carcinoma sample. 2 Publications
VAR_026189
Natural varianti1043 – 10431M → I in MCAP and CRC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity. 2 Publications
VAR_026190
Natural varianti1047 – 10471H → L in BC; unknown pathological significance. 4 Publications
VAR_026191
Natural varianti1047 – 10471H → R in CLOVE, KERSEB, CRC, BC and OC; also found in an endometrial carcinoma sample; shows an increase in lipid kinase activity; oncogenic in vivo; requires binding to p85 regulatory subunit to induce cellular transformation but not interaction with RAS; may mimic the conformatitonal change triggered by the interaction with RAS; enhances invadopodia-mediated extracellular matrix degradation and invasion in breast cancer cells; increases lipid kinase activity; may alter the interaction of the PI3K/PI4K kinase domain with the cell membrane. 12 Publications