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PIK3CA  -  phosphatidylinositol-4,5-bisphosphate 3...

Homo sapiens

Synonyms: CLOVE, CWS5, MCAP, MCM, MCMTC, ...
 
 
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Disease relevance of PIK3CA

 

Psychiatry related information on PIK3CA

 

High impact information on PIK3CA

  • One region at 3q26 found to be increased in copy number in approximately 40% of ovarian and others cancers contains PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase) [1].
  • A PI3K has already been purified, cloned, and shown to be regulated by receptors that act via tyrosine kinase-dependent regulatory mechanisms [16].
  • Phosphoinositide 3 kinase (PI3K) is a key signaling enzyme implicated in receptor-stimulated mitogenesis, oxidative bursting in neutrophils, membrane ruffling, and glucose uptake [16].
  • We report that an immunologically, pharmacologically, and chromatographically distinct form of PI3K activity present in neutrophils and U937 cells is specifically activated by G protein beta gamma subunits [16].
  • In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets [17].
 

Chemical compound and disease context of PIK3CA

 

Biological context of PIK3CA

 

Anatomical context of PIK3CA

 

Associations of PIK3CA with chemical compounds

  • Treatment with the PI3K inhibitor LY294002 abrogated PIK3CA signaling and preferentially inhibited growth of PIK3CA mutant cells [26].
  • We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases [27].
  • This interaction involves the proline-rich region of Ruk and the SH3 domain of the p85 alpha regulatory subunit of the class I(A) PI 3-kinase [28].
  • Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration [29].
  • Phosphatidylinositol 3-kinase (PI3K) is a heterodimer lipid kinase consisting of an 85-kD subunit bound to a 110-kD catalytic subunit that also possesses intrinsic, Mn(2+)-dependent protein serine kinase activity capable of phosphorylating the 85-kD subunit [30].
 

Physical interactions of PIK3CA

  • CONCLUSIONS: These results suggest that VEGF signaling in ECs is coupled to forkhead transcription factors through a PI3K/Akt-dependent pathway [31].
  • Further, by deleting amino acids 203-217 of p55PIK inter-SH2 domain, we engineered a p55PIK mutant unable to bind to the p110alpha catalytic subunit of PI 3-kinase [32].
 

Enzymatic interactions of PIK3CA

  • We find that p110 alpha phosphorylates p85 alpha Ser608 in vivo with significant stoichiometry [33].
  • The identification of APPL1 as a potential interactor with FSHR and the finding that FOXO1a is phosphorylated in response to FSH provide a possible link between FSH and PI3K/Akt signaling, which may help to delineate a survival mechanism whereby FSH selects the dominant follicle to survive [34].
 

Regulatory relationships of PIK3CA

 

Other interactions of PIK3CA

  • Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53 [23].
  • PIK3CA expression in vivo positively correlated, both at the mRNA and the protein level, with the expression of VEGF as well as with the extent of microvascular development [18].
  • Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation [39].
  • We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR-SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits [39].
  • The PIK3CA gene encodes the p110alpha catalytic subunit of PI3K, and is amplified in some ovarian cancers, whereas the AKT2 gene is amplified in some ovarian, breast, and pancreatic cancers [40].
  • A higher incidence of PIK3CA alterations and the possible synergistic effect of PIK3CA alterations and BRAF mutations suggest their major role in Middle Eastern PTC tumorigenesis and argue for therapeutic targeting of PI3K/AKT and MAPK pathways [41].
 

Analytical, diagnostic and therapeutic context of PIK3CA

References

  1. PIK3CA is implicated as an oncogene in ovarian cancer. Shayesteh, L., Lu, Y., Kuo, W.L., Baldocchi, R., Godfrey, T., Collins, C., Pinkel, D., Powell, B., Mills, G.B., Gray, J.W. Nat. Genet. (1999) [Pubmed]
  2. p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Singh, B., Reddy, P.G., Goberdhan, A., Walsh, C., Dao, S., Ngai, I., Chou, T.C., O-Charoenrat, P., Levine, A.J., Rao, P.H., Stoffel, A. Genes Dev. (2002) [Pubmed]
  3. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Isakoff, S.J., Engelman, J.A., Irie, H.Y., Luo, J., Brachmann, S.M., Pearline, R.V., Cantley, L.C., Brugge, J.S. Cancer Res. (2005) [Pubmed]
  4. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Broderick, D.K., Di, C., Parrett, T.J., Samuels, Y.R., Cummins, J.M., McLendon, R.E., Fults, D.W., Velculescu, V.E., Bigner, D.D., Yan, H. Cancer Res. (2004) [Pubmed]
  5. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Barbareschi, M., Buttitta, F., Felicioni, L., Cotrupi, S., Barassi, F., Del Grammastro, M., Ferro, A., Dalla Palma, P., Galligioni, E., Marchetti, A. Clin. Cancer Res. (2007) [Pubmed]
  6. Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Lin, Y., Jiang, X., Shen, Y., Li, M., Ma, H., Xing, M., Lu, Y. Endocr. Relat. Cancer (2009) [Pubmed]
  7. PIK3CA mutations predict local recurrences in rectal cancer patients. He, Y., Van't Veer, L.J., Mikolajewska-Hanclich, I., van Velthuysen, M.L., Zeestraten, E.C., Nagtegaal, I.D., van de Velde, C.J., Marijnen, C.A. Clin. Cancer Res. (2009) [Pubmed]
  8. Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Gonzalez-Angulo, A.M., Stemke-Hale, K., Palla, S.L., Carey, M., Agarwal, R., Meric-Berstam, F., Traina, T.A., Hudis, C., Hortobagyi, G.N., Gerald, W.L., Mills, G.B., Hennessy, B.T. Clin. Cancer Res. (2009) [Pubmed]
  9. PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer. Dupont Jensen, J., Laenkholm, A.V., Knoop, A., Ewertz, M., Bandaru, R., Liu, W., Hackl, W., Barrett, J.C., Gardner, H. Clin. Cancer Res. (2011) [Pubmed]
  10. Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer. Sewell, A., Brown, B., Biktasova, A., Mills, G.B., Lu, Y., Tyson, D.R., Issaeva, N., Yarbrough, W.G. Clin. Cancer Res. (2014) [Pubmed]
  11. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: Implications for Alzheimer's disease. Mohmmad Abdul, H., Butterfield, D.A. Free Radic. Biol. Med. (2007) [Pubmed]
  12. Activation of protein kinase B/Akt in the periphery contributes to pain behavior induced by capsaicin in rats. Sun, R., Yan, J., Willis, W.D. Neuroscience (2007) [Pubmed]
  13. Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau. Zhang, X., Zhang, Y.W., Liu, S., Bulloj, A., Tong, G.G., Zhang, Z., Liao, F.F., Xu, H. Molecular neurodegeneration [electronic resource]. (2006) [Pubmed]
  14. Control of neurite outgrowth and growth cone motility by phosphatidylinositol-3-kinase. Tornieri, K., Welshhans, K., Geddis, M.S., Rehder, V. Cell Motil. Cytoskeleton (2006) [Pubmed]
  15. Phosphatidylinositol 3-kinase in the G protein-coupled receptor-induced chemokinesis and chemotaxis of MDA-MB-468 breast carcinoma cells: a comparison with leukocytes. Bastian, P., Posch, B., Lang, K., Niggemann, B., Zaenker, K.S., Hatt, H., Entschladen, F. Mol. Cancer Res. (2006) [Pubmed]
  16. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Stephens, L., Smrcka, A., Cooke, F.T., Jackson, T.R., Sternweis, P.C., Hawkins, P.T. Cell (1994) [Pubmed]
  17. PI 3-kinase p110beta: a new target for antithrombotic therapy. Jackson, S.P., Schoenwaelder, S.M., Goncalves, I., Nesbitt, W.S., Yap, C.L., Wright, C.E., Kenche, V., Anderson, K.E., Dopheide, S.M., Yuan, Y., Sturgeon, S.A., Prabaharan, H., Thompson, P.E., Smith, G.D., Shepherd, P.R., Daniele, N., Kulkarni, S., Abbott, B., Saylik, D., Jones, C., Lu, L., Giuliano, S., Hughan, S.C., Angus, J.A., Robertson, A.D., Salem, H.H. Nat. Med. (2005) [Pubmed]
  18. The oncogene phosphatidylinositol 3'-kinase catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Zhang, L., Yang, N., Katsaros, D., Huang, W., Park, J.W., Fracchioli, S., Vezzani, C., Rigault de la Longrais, I.A., Yao, W., Rubin, S.C., Coukos, G. Cancer Res. (2003) [Pubmed]
  19. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Lee, S., Choi, E.J., Jin, C., Kim, D.H. Gynecol. Oncol. (2005) [Pubmed]
  20. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Wu, G., Xing, M., Mambo, E., Huang, X., Liu, J., Guo, Z., Chatterjee, A., Goldenberg, D., Gollin, S.M., Sukumar, S., Trink, B., Sidransky, D. Breast Cancer Res. (2005) [Pubmed]
  21. Mutations in PIK3CA are infrequent in neuroblastoma. Dam, V., Morgan, B.T., Mazanek, P., Hogarty, M.D. BMC Cancer (2006) [Pubmed]
  22. Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway. Lin, H.L., Lui, W.Y., Liu, T.Y., Chi, C.W. Br. J. Cancer (2003) [Pubmed]
  23. Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA. Kim, J.S., Lee, C., Bonifant, C.L., Ressom, H., Waldman, T. Mol. Cell. Biol. (2007) [Pubmed]
  24. Mutation of the PIK3CA gene in anaplastic thyroid cancer. García-Rostán, G., Costa, A.M., Pereira-Castro, I., Salvatore, G., Hernandez, R., Hermsem, M.J., Herrero, A., Fusco, A., Cameselle-Teijeiro, J., Santoro, M. Cancer Res. (2005) [Pubmed]
  25. Molecular cloning, cDNA sequence, and chromosomal localization of the human phosphatidylinositol 3-kinase p110 alpha (PIK3CA) gene. Volinia, S., Hiles, I., Ormondroyd, E., Nizetic, D., Antonacci, R., Rocchi, M., Waterfield, M.D. Genomics (1994) [Pubmed]
  26. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Samuels, Y., Diaz, L.A., Schmidt-Kittler, O., Cummins, J.M., Delong, L., Cheong, I., Rago, C., Huso, D.L., Lengauer, C., Kinzler, K.W., Vogelstein, B., Velculescu, V.E. Cancer Cell (2005) [Pubmed]
  27. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., Cantley, L.C. Mol. Cell (2002) [Pubmed]
  28. Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein. Gout, I., Middleton, G., Adu, J., Ninkina, N.N., Drobot, L.B., Filonenko, V., Matsuka, G., Davies, A.M., Waterfield, M., Buchman, V.L. EMBO J. (2000) [Pubmed]
  29. Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration. Ueda, S., Mizuki, M., Ikeda, H., Tsujimura, T., Matsumura, I., Nakano, K., Daino, H., Honda Zi, Z., Sonoyama, J., Shibayama, H., Sugahara, H., Machii, T., Kanakura, Y. Blood (2002) [Pubmed]
  30. The p85 and p110 subunits of phosphatidylinositol 3-kinase-alpha are substrates, in vitro, for a constitutively associated protein tyrosine kinase in platelets. Geltz, N.R., Augustine, J.A. Blood (1998) [Pubmed]
  31. Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Abid, M.R., Guo, S., Minami, T., Spokes, K.C., Ueki, K., Skurk, C., Walsh, K., Aird, W.C. Arterioscler. Thromb. Vasc. Biol. (2004) [Pubmed]
  32. Interaction of wild type and dominant-negative p55PIK regulatory subunit of phosphatidylinositol 3-kinase with insulin-like growth factor-1 signaling proteins. Mothe, I., Delahaye, L., Filloux, C., Pons, S., White, M.F., Van Obberghen, E. Mol. Endocrinol. (1997) [Pubmed]
  33. Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo. Foukas, L.C., Beeton, C.A., Jensen, J., Phillips, W.A., Shepherd, P.R. Mol. Cell. Biol. (2004) [Pubmed]
  34. Human follicle-stimulating hormone (FSH) receptor interacts with the adaptor protein APPL1 in HEK 293 cells: potential involvement of the PI3K pathway in FSH signaling. Nechamen, C.A., Thomas, R.M., Cohen, B.D., Acevedo, G., Poulikakos, P.I., Testa, J.R., Dias, J.A. Biol. Reprod. (2004) [Pubmed]
  35. Activated G alpha q inhibits p110 alpha phosphatidylinositol 3-kinase and Akt. Ballou, L.M., Lin, H.Y., Fan, G., Jiang, Y.P., Lin, R.Z. J. Biol. Chem. (2003) [Pubmed]
  36. Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity. Imanishi, T., Hano, T., Nishio, I. J. Hypertens. (2005) [Pubmed]
  37. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1alpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. Skinner, H.D., Zheng, J.Z., Fang, J., Agani, F., Jiang, B.H. J. Biol. Chem. (2004) [Pubmed]
  38. Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas. Zhang, J., Hu, S., Schofield, D.E., Sorensen, P.H., Triche, T.J. Cancer Res. (2004) [Pubmed]
  39. Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Mizoguchi, M., Nutt, C.L., Mohapatra, G., Louis, D.N. Brain Pathol. (2004) [Pubmed]
  40. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Levine, D.A., Bogomolniy, F., Yee, C.J., Lash, A., Barakat, R.R., Borgen, P.I., Boyd, J. Clin. Cancer Res. (2005) [Pubmed]
  41. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. Abubaker, J., Jehan, Z., Bavi, P., Sultana, M., Al-Harbi, S., Ibrahim, M., Al-Nuaim, A., Ahmed, M., Amin, T., Al-Fehaily, M., Al-Sanea, O., Al-Dayel, F., Uddin, S., Al-Kuraya, K.S. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  42. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Massion, P.P., Kuo, W.L., Stokoe, D., Olshen, A.B., Treseler, P.A., Chin, K., Chen, C., Polikoff, D., Jain, A.N., Pinkel, D., Albertson, D.G., Jablons, D.M., Gray, J.W. Cancer Res. (2002) [Pubmed]
  43. Mutation of the PIK3CA gene in ovarian and breast cancer. Campbell, I.G., Russell, S.E., Choong, D.Y., Montgomery, K.G., Ciavarella, M.L., Hooi, C.S., Cristiano, B.E., Pearson, R.B., Phillips, W.A. Cancer Res. (2004) [Pubmed]
  44. Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients. Tanaka, Y., Kanai, F., Tada, M., Asaoka, Y., Guleng, B., Jazag, A., Ohta, M., Ikenoue, T., Tateishi, K., Obi, S., Kawabe, T., Yokosuka, O., Omata, M. Oncogene (2006) [Pubmed]
  45. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. Wu, G., Mambo, E., Guo, Z., Hu, S., Huang, X., Gollin, S.M., Trink, B., Ladenson, P.W., Sidransky, D., Xing, M. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  46. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Massion, P.P., Taflan, P.M., Shyr, Y., Rahman, S.M., Yildiz, P., Shakthour, B., Edgerton, M.E., Ninan, M., Andersen, J.J., Gonzalez, A.L. Am. J. Respir. Crit. Care Med. (2004) [Pubmed]
 
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