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Literature summary for 2.7.1.153 extracted from
- The role of class IA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits in glioblastoma (2017), Front. Oncol., 7, 312 .
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| additional information | receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) selectively activates PIK3CB/p110beta (but not PIK3CA/p110alpha or PIK3CD/p110delta), leading to production of phosphatidylinositol-3,4,5-triphosphate (PIP3) and subsequent phosphorylation of AKT | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | knockdown of PIK3CA/p110alpha in a panel of glioblastoma cell lines | Homo sapiens |
| N345K | a naturally occuring oncogenic p110alpha mutant | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| BEZ235 | - |
Homo sapiens | |
| BKM120 | - |
Homo sapiens | |
| BYL719 | a p110alpha-specific inhibitor, BYL719 fails to display selective growth inhibition in p110alphahigh cells | Homo sapiens | |
| GDC-0491 | - |
Homo sapiens | |
| GSK2636771 | a p110beta-specific inhibitor | Homo sapiens | |
| HS173 | a p110alpha-specific inhibitor | Homo sapiens | |
| idelalisib | CAL-101, a p110delta inhibitor | Homo sapiens |  |
| MLN1117 | a p110alpha-specific inhibitor | Homo sapiens | |
| additional information | p110alpha-specific inhibitors (PIK75, BYL719, MLN1117, and HS173) are significantly toxic to astrocytes. The p110beta inhibitor TGX-221 and GSK2636771 mitigate the proliferation of p110betahigh U87MG and SF295 cells while having no effect on p110betalow A172 and LN229 cells | Homo sapiens | |
| PIK75 | p110alpha inhibitor PIK75 shows a strong cytotoxicity to all glioblastoma cell lines tested | Homo sapiens | |
| TGX-221 | a p110beta-specific inhibitor | Homo sapiens | |
| XL147 | - |
Homo sapiens | |
| XL765 | - |
Homo sapiens |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | required | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate | Homo sapiens | - |
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P42336 AND P42338 AND P48736 AND O00329 | subunits PIK3CA/p110alpha, PIK3CB/p110beta, PIK3CG/p110gamma, and PIK3CD/p110delta | - |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| astrocyte | - |
Homo sapiens | - |
| brain | - |
Homo sapiens | - |
| glioblastoma cell | - |
Homo sapiens | - |
| U-87MG cell | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate | - |
Homo sapiens | ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| More | the class IA PI3K gene family consists of three highly homologous catalytic subunits PIK3CA, PIK3CB, and PIK3CD (PI3K catalytic subunit alpha, beta, and delta) that encode p110alpha, p110beta, and p110delta, respectively. These subunits form a complex with any of five regulatory subunits p85alpha, p55alpha (a splicing variant of p85alpha), p50alpha (a splicing variant of p85alpha), p85beta, and p55gamma, encoded by PIK3R1, PIK3R2, and PIK3R3 (PI3K regulatory subunit 1, 2, and 3), respectively. Class IB PI3K is composed of one catalytic subunit p110gamma encoded by PIK3CG (PI3K catalytic subunit gamma) and two regulatory subunits: p101 encoded by PIK3R5 (PI3K regulatory subunit 5) and p87 (also known as p84 or p87PIKAP) encoded by PIK3R6 (PI3K regulatory subunit 6). PI3K catalytic subunits (PIK3CA/p110alpha, PIK3CB/p110beta, PIK3CD/p110delta, and PIK3CG/p110gamma) are not functionally redundant | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| class IA phosphatidylinositol-4,5-bisphosphate 3-kinase | - |
Homo sapiens |
| PI3K | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Homo sapiens | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | class I PI3K genes control the activity of PI3K/AKT signaling and are often genetically altered in glioblastoma. Class II PI3K genes are implicated in regulating angiogenesis and cilium function. Class III PI3K genes are primarily involved in the regulation of autophagy. Compared to other class IA PI3K isoforms, PIK3CB is the only PI3K catalytic subunit that showed a strong association with recurrence rate, risk, and prognosis | Homo sapiens |
| malfunction | PIK3CA subunit mutations have no correlation with recurrence rate of glioblastoma. Knockdown of PIK3CA/p110alpha in a panel of glioblastoma cell lines shows that loss of PIK3CA/p110alpha fails to both inactivate AKT and block the survival of A172, U87MG, SF295, and U251 glioblastoma cells. Compared to PIK3CA, oncogenic PIK3CB mutations are rare in glioblastoma. Knockdown or inhibitors of PIK3CD/p110delta fails to inhibit AKT and cell viability | Homo sapiens |
| metabolism | PIK3CB/p110beta-dictated survival pathway in glioblastoma, overview | Homo sapiens |
| additional information | the class IA PI3K gene family consists of three highly homologous catalytic subunits PIK3CA, PIK3CB, and PIK3CD (PI3K catalytic subunit alpha, beta, and delta) that encode p110alpha, p110beta, and p110delta, respectively. These subunits form a complex with any of five regulatory subunits p85alpha, p55alpha (a splicing variant of p85alpha), p50alpha (a splicing variant of p85alpha), p85beta, and p55gamma, encoded by PIK3R1, PIK3R2, and PIK3R3 (PI3K regulatory subunit 1, 2, and 3), respectively. Class IB PI3K is composed of one catalytic subunit p110gamma encoded by PIK3CG (PI3K catalytic subunit gamma)and two regulatory subunits: p101 encoded by PIK3R5 (PI3K regulatory subunit 5) and p87 (also known as p84 or p87PIKAP) encoded by PIK3R6 (PI3K regulatory subunit 6). The amino acid K342 in wild-type p110beta exhibits structural changes (i.e. disrupted interactions between p110beta and its regulatory partner p85), which endows p110beta with an unusually high transformation potential similar to the oncogenic p110alpha mutant p110alpha-N345K | Homo sapiens |
| physiological function | phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) plays a critical role in the pathogenesis of cancer including glioblastoma, the most common and aggressive form of brain cancer. Analysis of the role of class IA PI3K catalytic subunits in glioblastoma, overview. siRNAs or shRNAs of PIK3CB, but not shRNAs of PIK3CA, inhibits the growth of U-87MG cells. Subunit PIK3CD/p110beta plays a dispensable role in the disease progression of glioblastoma. Receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) selectively activates PIK3CB/p110beta (but not PIK3CA/p110alpha or PIK3CD/p110delta), leading to production of phosphatidylinositol-3,4,5-triphosphate (PIP3) and subsequent phosphorylation of AKT. Divergent roles of class I PI3K genes in normal and malignant tissues, overview | Homo sapiens |
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