Activating Compound | Comment | Organism | Structure |
---|---|---|---|
additional information | physiological activation of PI3Kalpha is triggered by binding of phosphorylated tyrosine kinase receptors RTK or their accessory proteins, such as the insulin receptor substrate 1, IRS-1, that bridge the interaction between RTK and PI3Kalpha | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
E542K/E545K | the mutation disrupts the interaction between residues E545 (helical domain) and K379 (nSH2 domain) | Homo sapiens |
additional information | determination of p110alpha subunit oncogenic mutations disrupt the interactions at the p110alpha-p85alpha interface, overview. Even distant mutations (R38C/R88Q and N345K) effectively weaken the interaction between the nSH2 and helical domain, thus increasing the population of molecules that are not inhibited by the the nSH2 domain. The oncogenic mutations increase the conformational heterogeneity of the p85alpha subunit and lead to PI3Kalpha activation by releasing the p85? nSH2 inhibitory effect | Homo sapiens |
N345K | the mutation significantly change the distance distribution for helical domain residues K379, I381 and K382 | Homo sapiens |
R38C/R88C | the mutation significantly change the distance distribution for helical domain residues K379, I381 and K382 | Homo sapiens |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
additional information | in its resting state, PI3Kapha is autoinhibited by the interaction of a loop of the helical domain of p110alpha with a groove in the nSH2 domain of p85alpha. Despite this inhibition, the enzyme has a significant basal activity | Homo sapiens |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Mg2+ | required | Homo sapiens |
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 | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P42336 | gene PI3KCA ; gene PI3KCA | - |
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 | - |
? |
Synonyms | Comment | Organism |
---|---|---|
phosphatidylinositol 3-kinase alpha | - |
Homo sapiens |
PI3Kalpha | - |
Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
ATP | - |
Homo sapiens |
General Information | Comment | Organism |
---|---|---|
malfunction | the PI3Kalpha signaling pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110alpha PI3Kalpha subunit, is mutated. Oncogenic mutations that are far from the catalytic site and increase the enzymatic affinity, destabilize the p110alpha/p85alpha dimer. By affecting the dynamics of the protein, these mutations favor the conformations that reduce the autoinhibitory effect of the p85alpha nSH2 domain. Molecular dynamics simulations suggest that all the tumor-associated mutations effectively weaken the interactions between the p110alpha and the p85alpha subunits by disrupting key stabilizing interactions | Homo sapiens |
physiological function | the PI3Kalpha signaling pathway plays an important role in cell growth, proliferation and survival. This pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110alpha PI3Kalpha subunit, is mutated. Physiological activation of PI3Kalpha is triggered by binding of phosphorylated tyrosine kinase receptors RTK or their accessory proteins, such as the insulin receptor substrate 1, IRS-1, that bridge the interaction between RTK and PI3Kalpha | Homo sapiens |