Nomenclature
Short Name:
PIK3CA
Full Name:
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform alpha; PK3CA; PtdIns-3-kinase p110
Alias:
- Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform alpha
- PK3CA
- PtdIns-3-kinase p110
Classification
Type:
Protein-serine/threonine kinase
Group:
Atypical
Family:
PIKK
SubFamily:
NA
Specific Links
Structure
Mol. Mass (Da):
124284
# Amino Acids:
1068
# mRNA Isoforms:
1
mRNA Isoforms:
124,284 Da (1068 AA; P42336)
4D Structure:
1D Structure:
3D Image (rendered using PV Viewer):
PDB ID
Subfamily Alignment
Domain Distribution:
| Start | End | Domain |
|---|
Post-translation Modifications
For detailed information on phosphorylation of this kinase go to PhosphoNET
Serine phosphorylated:
S306, S312, S332, S507, S509, S874.
Threonine phosphorylated:
T313, T315, T876, T957.
Tyrosine phosphorylated:
Y246, Y294, Y317, Y355, Y361, Y508, Y584, Y698, Y1038.
Ubiquitinated:
K159, K173.
Distribution
Based on gene microarray analysis from the NCBI
Human Tissue Distribution
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
26
1355
28
1004
0.5
25
12
23
2
112
12
102
4
202
135
318
14
721
34
600
1.4
72
56
45
3
142
39
321
27
1415
58
3552
10
537
10
538
1.2
64
115
41
0.7
39
36
40
10
517
140
614
2
87
23
67
1
53
9
21
0.8
44
23
45
1
50
18
44
2
112
252
759
0.9
47
18
63
2
102
97
79
13
696
112
593
1
53
33
60
2
98
35
107
1.1
59
21
75
1.2
64
19
73
2
97
33
111
15
796
88
1176
1.4
72
26
64
1.1
57
19
69
2
99
19
122
1.4
73
42
66
17
903
18
529
100
5217
31
10172
1.2
65
105
149
14
731
83
621
0.7
39
48
23
Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
40.5
57.9
100
41.5
59.8
100
-
-
100
-
-
-
41
58.6
100
-
-
-
98.5
99.2
99
41.3
59.5
99
-
-
-
97.5
98.9
-
96.2
98.5
96
21.3
40
92
91.6
96
-
-
-
-
-
-
-
40.1
59.2
-
26.7
46.7
34
35.3
55.4
-
-
-
-
-
-
-
-
-
-
21.2
40.1
-
22.3
41.8
-
-
-
-
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Regulation
Activation:
NA
Inhibition:
NA
Synthesis:
NA
Degradation:
NA
Known Downstream Substrates
For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET
predictions.
Based on in vitro and/or in vivo phosphorylation data
| Substrate Short Name | UniProt ID (Human) | Phosphosite Location | Phosphosite Sequence | Effect of Phosphorylation |
|---|
Inhibitors
For further details on these inhibitors click on the Compound Name and enter it into DrugKiNET or click on the ID's
Based on in vitro and/or in vivo phosphorylation data
| Compound Name | KD, Ki or IC50 (nM) | PubChem ID | ChEMBL ID | PubMed ID |
|---|
Disease Linkage
General Disease Association:
Cancer, cardiovascular, skin, and neuronal disorders
Specific Diseases (Non-cancerous):
Megalencephaly-capillary malformation-polymicrogyria syndrome, Somatic; Keratosis, Seborrheic, Somatic; Clove syndrome, Somatic; Keratosis; Megalencephaly; Hemimegalencephaly; Cowden syndrome 5; Lipomatosis; Dermatosis Papulosa nigra; Cloves syndrome; Leopard syndrome; Cowden disease; Nephrogenic systemic fibrosis; Urinary tract Obstruction; Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; Pik3ca-related segmental overgrowth; Cowden syndrome 1; Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, Somatic; Hemihyperplasia-multiple lipomatosis syndrome; Macrodactyly of fingers, Unilateral; Macrodactyly of toes, Unilateral; Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
Comments:
Mutations at many sites in PIK3CA are associated with megalencephaly-capillary malformation-polymicrogyria syndrome, with typical features such as primary megalencephaly, prenatal overgrowth, and brain and body asymmetry. Genetic variations are also linked with congenital lipomatous overgrowth, vascular malformations, and epidermal nevi, which is characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. Mutations are also associated with cowden syndrome 5, which is a hamartomatous polyposis syndrome with age-related penetrance. Cowden Syndrome is characterized by hamartomatous lesions.
Specific Cancer Types:
Breast cancer; Thyroid cancer (TC); Colorectal cancer (CRC); Tuberous sclerosis (TSC); Lung cancer (LC); Ovarian cancer; Hepatocellular carcinomas (HCC); Ethmoid sinus adenocarcinomas; Primary malignant lymphomas; Colorectal cancer (CRC), hereditary nonpolyposis, type 1; Hepatocellular carcinomas (HCC), somatic; Gastric cancer, somatic; Ovarian cancer, somatic; Breast cancer, somatic; Colorectal cancer, somatic; Epidermal nevus (EN), somatic; Non-small cell lung cancer (NSCLC), somatic
Comments:
PIK3CA appears to be an oncoprotein (OP). It undergoes one of the highest rates of mutations in human cancers, and these mutations are narrowly restricted around amino acid residues 452-455 and 1047. PIK3CA mutations are linked with pancreatic, gastric and colorectal cancer. PIK3CA mutations are a predictor of chemotherapy clinical efficacy in breast cancer.
Gene Expression in Cancers:
TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +140, p<0.0001); Cervical cancer (%CFC= -47, p<0.0001); Oral squamous cell carcinomas (OSCC) (%CFC= +117, p<0.016); Skin squamous cell carcinomas (%CFC= +55, p<0.011); and T-cell prolymphocytic leukemia (%CFC= -49, p<0.063); and Uterine leiomyomas (%CFC= -46, p<0.055). The COSMIC website notes an up-regulated expression score for PIK3CA in diverse human cancers of 1048, which is 2.3-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 56 for this protein kinase in human cancers was 0.9-fold of the average score of 60 for the human protein kinases.
Mutagenesis Experiments:
Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.
Mutation Rate in All Cancers:
Percent mutation rates per 100 amino acids length in human cancers: 0.94 % in 79684 diverse cancer specimens. This rate is 12.5-fold higher than the average rate of 0.075 % calculated for human protein kinases in general.
Mutation Rate in Specific Cancers:
Highest percent mutation rates per 100 amino acids length in human cancers: 2.94 % in 11422 breast cancers tested; 1.99 % in 3248 endometrium cancers tested; 1.49 % in 1863 urinary tract cancers tested; 1.41 % in 624 cervix cancers tested; 1.28 % in 12679 large intestine cancers tested; 0.93 % in 2130 stomach cancers tested; 0.87 % in 3307 ovary cancers tested; 0.68 % in 3025 upper aerodigestive tract cancers tested; 0.65 % in 609 biliary tract cancers tested; 0.65 % in 2875 skin cancers tested; 0.56 % in 3592 central nervous system cancers tested; 0.53 % in 1652 soft tissue cancers tested; 0.53 % in 1318 oesophagus cancers tested; 0.36 % in 9265 lung cancers tested; 0.34 % in 55 peritoneum cancers tested; 0.31 % in 2717 thyroid cancers tested; 0.31 % in 2295 liver cancers tested; 0.27 % in 422 pituitary cancers tested; 0.19 % in 1530 kidney cancers tested; 0.19 % in 1246 prostate cancers tested; 0.16 % in 2275 pancreas cancers tested; 0.14 % in 199 Meninges cancers tested; 0.12 % in 3779 haematopoietic and lymphoid cancers tested; 0.1 % in 735 bone cancers tested; 0.08 % in 777 autonomic ganglia cancers tested.
Frequency of Mutated Sites:
Most frequent mutations with the number of reports indicated in brackets: H1047R (2561); H1047L (247); E455K (1705); E452K (1077); E452A (132); Q546K (130); .
Comments:
Over 20 deletion mutations (10 at E109del), 20 insertions mutations (15 at N1068fs*4), and 25 complex mutations (13 at S553fs*7) are noted on the COSMIC website.