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Cited by 63PI3K/AKT/mTOR signaling in cancerGenetics and Neurodevelopmental DisordersProtein Kinase Regulation and GTPase Signaling

Neuron-specific regulation of class I PI3K catalytic subunits and their dysfunction in brain disorders

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Gross, Christina, Bassell, Gary J.·2014·Frontiers in Molecular Neuroscience
DOI 10.3389/fnmol.2014.00012PMC PMC3923137
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Abstract

The phosphoinositide 3-kinase (PI3K) complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3K to phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β, p110γ, and p110δ, have recently drawn attention in the neuroscience field due to their specific dysregulation in diverse brain disorders. While in non-neuronal cells these catalytic subunits may have partially redundant functions, there is increasing evidence that in neurons their roles are more specialized, and confined to distinct receptor-dependent pathways. This review will summarize the emerging role of class I PI3K catalytic subunits in neurotransmitter-regulated neuronal signaling, and their dysfunction in a variety of neurological diseases, including fragile X syndrome, schizophrenia, and epilepsy. We will discuss recent literature describing the use of PI3K subunit-selective inhibitors to rescue brain disease-associated phenotypes in in vitro and animal models. These studies give rise to the exciting prospect that these drugs, originally designed for cancer treatment, may be repurposed as therapeutic drugs for brain disorders in the future.

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  • The mTor pathway alteration in Fmr1-knockout neurons is not due to altered expression of mTor but rather to overactivation of PI3K because of overexpression of the catalytic PI3K subunit p110β.

    “This alteration is not due to an altered expression of mTor (Sharma et al., 2010), but rather to the overactivation of PI3K, because of the overexpression of the catalytic PI3K subunit p110β (Gross et al., 2010; Gross and Bassell, 2012).”

    From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Gross and Bassell, 2012

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References 96 · Cited by 63

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  1. Acebes A. Devaud J. M. Arnes M. Ferrus A. (2012). Central adaptation to odorants depends on PI3K levels in local interneurons of the antennal lobe. J. Neurosci. 32 417– 422 10.1523/JNEUROSCI.2921-11.2012 22238078 PMC6621088 · DOI
  2. Acebes A. Martin-Pena A. Chevalier V. Ferrus A. (2011). Synapse loss in olfactory local interneurons modifies perception. J. Neurosci. 31 2734– 2745 10.1523/JNEUROSCI.5046-10.2011 21414896 PMC6623785 · DOI
  3. Akinleye A. Avvaru P. Furqan M. Song Y. Liu D. (2013). Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J. Hematol. Oncol. 6 88 10.1186/1756-8722-6-88 PMC3843585 24261963 · DOI
  4. Angulo I. Vadas O. Garcon F. Banham-Hall E. Plagnol V. Leahy T. R. (2013). Phosphoinositide 3-Kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 342 866– 871 10.1126/science.1243292 24136356 PMC3930011 · DOI
  5. Bi L. Okabe I. Bernard D. J. Nussbaum R. L. (2002). Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase. Mamm. Genome 13 169– 172 10.1007/s00335-001-2123-x 11919689 · DOI
  6. Bosco D. Fava A. Plastino M. Montalcini T. Pujia A. (2011). Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis. J. Cell. Mol. Med. 15 1807– 1821 10.1111/j.1582-4934.2011.01318.x 21435176 PMC3918038 · DOI · Paper page
  7. Brennan-Minnella A. M. Shen Y. El-Benna J. Swanson R. A. (2013). Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death. Cell Death Dis. 4 e580 10.1038/cddis.2013.111 PMC3641334 23559014 · DOI
  8. Camps M. Ruckle T. Ji H. Ardissone V. Rintelen F. Shaw J. (2005). Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med. 11 936– 943 10.1038/nm1284 16127437 · DOI
  9. Chan C.-B. Liu X. Ensslin M. A. Dillehay D. L. Ormandy C. J. Sohn P. (2010). PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development. EMBO J. 29 956– 968 10.1038/emboj.2009.406 20075866 PMC2837170 · DOI
  10. Christie K. J. Webber C. A. Martinez J. A. Singh B. Zochodne D. W. (2010). PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J. Neurosci. 30 9306– 9315 10.1523/jneurosci.6271-09.2010 20610765 PMC6632469 · DOI
  11. Cuesto G. Enriquez-Barreto L. Carames C. Cantarero M. Gasull X. Sandi C. (2011). Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons. J. Neurosci. 31 2721– 2733 10.1523/JNEUROSCI.4477-10.2011 21414895 PMC6623769 · DOI
  12. Cusco I. Medrano A. Gener B. Vilardell M. Gallastegui F. Villa O. (2009). Autism-specific copy number variants further implicate the phosphatidylinositol signaling pathway and the glutamatergic synapse in the etiology of the disorder. Hum. Mol. Genet. 18 1795– 1804 10.1093/hmg/ddp092 19246517 PMC2671988 · DOI
  13. Dbouk H. A. Pang H. Fiser A. Backer J. M. (2010). A biochemical mechanism for the oncogenic potential of the p110beta catalytic subunit of phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 107 19897– 19902 10.1073/pnas.1008739107 21030680 PMC2993364 · DOI
  14. de la Monte S. M. (2013). Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art. Expert Opin. Drug Deliv. 10 1699– 1709 10.1517/17425247.2013.856877 24215447 PMC4551402 · DOI
  15. Domin J. Waterfield M. D. (1997). Using structure to define the function of phosphoinositide 3-kinase family members. FEBS Lett. 410 91– 95 10.1016/S0014-5793(97)00617-0 9247130 · DOI
  16. Eickholt B. J. Ahmed A. I. Davies M. Papakonstanti E. A. Pearce W. Starkey M. L. (2007). Control of axonal growth and regeneration of sensory neurons by the p110δ PI 3-kinase. PLoS ONE 2: e869 10.1371/journal.pone.0000869 PMC1959241 17846664 · DOI
  17. Fayard E. Xue G. Parcellier A. Bozulic L. Hemmings B. A. (2010). Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr. Top. Microbiol. Immunol. 346 31– 56 10.1007/82_2010_58 20517722 · DOI
  18. Foukas L. C. Berenjeno I. M. Gray A. Khwaja A. Vanhaesebroeck B. (2010). Activity of any class IA PI3K isoform can sustain cell proliferation and survival. Proc. Natl. Acad. Sci. U.S.A. 107 11381– 11386 10.1073/pnas.0906461107 20534549 PMC2895061 · DOI
  19. Freiherr J. Hallschmid M. Frey W. H. II Brunner Y. F. Chapman C. D. Holscher C. (2013). Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 27 505– 514 10.1007/s40263-013-0076-8 23719722 PMC3709085 · DOI
  20. Fritsch R. de krijger I. Fritsch K. George R. Reason B. Kumar MS. (2013). RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 153 1050– 1063 10.1016/j.cell.2013.04.031 23706742 PMC3690480 · DOI
  21. Gao X. Lowry P. R. Zhou X. Depry C. Wei Z. Wong G. W. (2011). PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains. Proc. Natl. Acad. Sci. U.S.A. 108 14509– 14514 10.1073/pnas.1019386108 21873248 PMC3167518 · DOI
  22. Gross C. Bassell G. J. (2012). Excess protein synthesis in FXS patient lymphoblastoid cells can be rescued with a p110beta-selective inhibitor. Mol. Med. 18 336– 345 10.2119/molmed.2011.00363 22207187 PMC3356413 · DOI
  23. Gross C. Nakamoto M. Yao X. Chan C. B. Yim S. Y. Ye K. (2010). Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J. Neurosci. 30 10624– 10638 10.1523/JNEUROSCI.0402-10.2010 20702695 PMC2924772 · DOI · Paper page
  24. Guillermet-Guibert J. Bjorklof K. Salpekar A. Gonella C. Ramadani F. Bilancio A. (2008). The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc. Natl. Acad. Sci. U.S.A. 105 8292– 8297 10.1073/pnas.0707761105 18544649 PMC2448830 · DOI
  25. Gutierrez A. Sanda T. Grebliunaite R. Carracedo A. Salmena L. Ahn Y. (2009). High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114 647– 650 10.1182/blood-2009-02-206722 19458356 PMC2713461 · DOI
  26. Hoeffer C. A. Klann E. (2010). mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33 67– 75 10.1016/j.tins.2009.11.003 19963289 PMC2821969 · DOI · Paper page
  27. Huang C.-C. Lee C.-C. Hsu K.-S. (2004). An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus. J. Neurochem. 89 217– 231 10.1111/j.1471-4159.2003.02307.x 15030406 · DOI
  28. Huang C.-C. You J.-L. Lee C.-C. Hsu K.-S. (2003). Insulin induces a novel form of postsynaptic mossy fiber long-term depression in the hippocampus. Mol. Cell. Neurosci. 24 831– 841 10.1016/S1044-7431(03)00238-0 14664829 · DOI
  29. Inoki K. Li Y. Zhu T. Wu J. Guan K.-L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4 648– 657 10.1038/ncb839 12172553 · DOI · Paper page
  30. International Molecular Genetic Study of Autism Consortium. (2001). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum. Mol. Genet. 10 973– 982 10.1093/hmg/10.9.973 11392322 · DOI
  31. Jaworski J. Spangler S. Seeburg D. P. Hoogenraad C. C. Sheng M. (2005). Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25 11300– 11312 10.1523/JNEUROSCI.2270-05.2005 16339025 PMC6725892 · DOI
  32. Jia S. Liu Z. Zhang S. Liu P. Zhang L. Lee S. H. (2008). Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454 776– 779 10.1038/nature07091 18594509 PMC2750091 · DOI
  33. Jou S.-T. Carpino N. Takahashi Y. Piekorz R. Chao J.-R. Carpino N. (2002). Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22 8580– 8591 10.1128/mcb.22.24.8580-8591.2002 12446777 PMC139888 · DOI
  34. Kalkman H. O. (2006). The role of the phosphatidylinositide 3-kinase–protein kinase B pathway in schizophrenia. Pharmacol. Ther. 110 117– 134 10.1016/j.pharmthera.2005.10.014 16434104 · DOI
  35. Kang S. Denley A. Vanhaesebroeck B. Vogt P. K. (2006). Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 103 1289– 1294 10.1073/pnas.0510772103 16432180 PMC1360601 · DOI
  36. Karam C. S. Ballon J. S. Bivens N. M. Freyberg Z. Girgis R. R. Lizardi-Ortiz J. E. (2010). Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol. Sci. 31 381– 390 10.1016/j.tips.2010.05.004 20579747 PMC3635536 · DOI
  37. Kim J. I. Lee H. R. Sim S. E. Baek J. Yu N. K. Choi J. H. (2011). PI3Kgamma is required for NMDA receptor-dependent long-term depression and behavioral flexibility. Nat. Neurosci. 14 1447– 1454 10.1038/nn.2937 22019731 · DOI
  38. Kim T. H. Petrou S. Reid C. A. (2013). Low glycaemic index diet reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy. Epilepsy Res. 10.1016/j.eplepsyres.2013.10.014 24246146 · DOI
  39. Knight Z. A. Gonzalez B. Feldman M. E. Zunder E. R. Goldenberg D. D. Williams O. (2006). A pharmacological map of the PI3-K family defines a role for p110 ± in insulin signaling. Cell 125 733– 747 10.1016/j.cell.2006.03.035 16647110 PMC2946820 · DOI · Paper page
  40. Koren S. Bentires-Alj M. (2013). Mouse models of PIK3CA mutations: one mutation initiates heterogeneous mammary tumors. FEBS J. 280 2758– 2765 10.1111/febs.12175 23384338 · DOI
  41. Kratz C. P. Emerling B. M. Bonifas J. Wang W. Green E. D. Beau M. M. L. (2002). Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor. Blood 99 372– 374 10.1182/blood.V99.1.372 11756194 · DOI
  42. Krueger D. A. Wilfong A. A. Holland-Bouley K. Anderson A. E. Agricola K. Tudor C. (2013). Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann. Neurol. 74 679– 687 10.1002/ana.23960 23798472 · DOI
  43. Kurosu H. Katada T. (2001). Association of phosphatidylinositol 3-kinase composed of p110beta-catalytic and p85-regulatory subunits with the small GTPase Rab5. J. Biochem. 130 73– 78 10.1093/oxfordjournals.jbchem.a002964 11432782 · DOI
  44. Kurosu H. Maehama T. Okada T. Yamamoto T. Hoshino S. Fukui Y. (1997). Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide. J. Biol. Chem. 272 24252– 24256 10.1074/jbc.272.39.24252 9305878 · DOI
  45. Law A. J. Kleinman J. E. Weinberger D. R. Weickert C. S. (2007). Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum. Mol. Genet. 16 129– 141 10.1093/hmg/ddl449 17164265 · DOI
  46. Law A. J. Lipska B. K. Weickert C. S. Hyde T. M. Straub R. E. Hashimoto R. (2006). Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc. Natl. Acad. Sci. U.S.A. 103 6747– 6752 10.1073/pnas.0602002103 16618933 PMC1458952 · DOI
  47. Law A. J. Wang Y. Sei Y. O’Donnell P. Piantadosi P. Papaleo F. (2012). Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110delta inhibition as a potential therapeutic strategy. Proc. Natl. Acad. Sci. U.S.A. 109 12165– 12170 10.1073/pnas.1206118109 22689948 PMC3409795 · DOI · Paper page
  48. Lee C.-C. Huang C.-C. Hsu K.-S. (2011). Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology 61 867– 879 10.1016/j.neuropharm.2011.06.003 21683721 · DOI
  49. Lee J. H. Huynh M. Silhavy J. L. Kim S. Dixon-Salazar T. Heiberg A. (2012). De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44 941– 945 10.1038/ng.2329 22729223 PMC4417942 · DOI · Paper page
  50. Lemmon M. A. (2007). Pleckstrin homology (PH) domains and phosphoinositides. Biochem. Soc. Symp. 81– 93 10.1042/BSS0740081 17233582 PMC3777418 · DOI · Paper page
  51. Liu K. Lu Y. Lee J. K. Samara R. Willenberg R. Sears-Kraxberger I. (2010). PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13 1075– 1081 10.1038/nn.2603 20694004 PMC2928871 · DOI
  52. Man H.-Y. Wang Q. Lu W.-Y. Ju W. Ahmadian G. Liu L. (2003). Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 38 611– 624 10.1016/S0896-6273(03)00228-9 12765612 · DOI
  53. Mitome-Mishima Y. Miyamoto N. Tanaka R. Oishi H. Arai H. Hattori N. (2013). Differences in phosphodiesterase 3A and 3B expression after ischemic insult. Neurosci. Res. 75 340– 348 10.1016/j.neures.2013.02.006 23471014 · DOI
  54. Neddens J. Fish K. N. Tricoire L. Vullhorst D. Shamir A. Chung W. (2011). Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. Biol. Psychiatry 70 636– 645 10.1016/j.biopsych.2011.04.016 21664604 PMC5040357 · DOI
  55. Norton N. Moskvina V. Morris D. W. Bray N. J. Zammit S. Williams N. M. (2006). Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 141B 96– 101 10.1002/ajmg.b.30236 16249994 · DOI
  56. Okkenhaug K. (2013). Signaling by the phosphoinositide 3-kinase family in immune cells. Annu. Rev. Immunol. 31 675– 704 10.1146/annurev-immunol-032712-095946 23330955 PMC4516760 · DOI · Paper page
  57. Okkenhaug K. Bilancio A. Farjot G. Priddle H. Sancho S. Peskett E. (2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297 1031– 1034 10.1126/science.1073560 12130661 · DOI
  58. Opazo P. Watabe A. M. Grant S. G O’Dell T. J. (2003). Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms. J. Neurosci. 23 3679– 3688 12736339 PMC6742185
  59. Ostapchenko V. G. Beraldo F. H. Guimarães A. L. S. Mishra S. Guzman M. Fan J. (2013). Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer’s disease. J. Neurochem. 127 415– 425 10.1111/jnc.12296 23651058 · DOI
  60. Oudit G. Y. Kassiri Z. (2007). Role of PI3 kinase gamma in excitation-contraction coupling and heart disease. Cardiovasc. Hematol. Disord. Drug Targets 7 295– 304 10.2174/187152907782793545 18220729 · DOI
  61. Patrucco E. Notte A. Barberis L. Selvetella G. Maffei A. Brancaccio M. (2004). PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118 375– 387 10.1016/j.cell.2004.07.017 15294162 · DOI
  62. Polak R. Buitenhuis M. (2012). The PI3K/PKB signaling module as key regulator of hematopoiesis: implications for therapeutic strategies in leukemia. Blood 119 911– 923 10.1182/blood-2011-07-366203 22065598 · DOI
  63. Reinhardt R. R. Bondy C. A. (1996). Differential cellular pattern of gene expression for two distinct cGMP-inhibited cyclic nucleotide phosphodiesterases in developing and mature rat brain. Neuroscience 72 567– 578 10.1016/0306-4522(95)00520-X 8737425 · DOI
  64. Rico B. (2012). Finding a druggable target for schizophrenia. Proc. Natl. Acad. Sci. U.S.A. 109 11902– 11903 10.1073/pnas.1209389109 22778429 PMC3409780 · DOI
  65. Rodrigues G. A. Falasca M. Zhang Z. Ong S. H. Schlessinger J. (2000). A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. Mol. Cell. Biol. 20 1448– 1459 10.1128/MCB.20.4.1448-1459.2000 10648629 PMC85307 · DOI
  66. Rong R. Ahn J. Y. Huang H. Nagata E. Kalman D. Kapp J. A. (2003). PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nat. Neurosci. 6 1153– 1161 10.1038/nn1134 14528310 · DOI
  67. Samuels Y. Wang Z. Bardelli A. Silliman N. Ptak J. Szabo S. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304 554 10.1126/science.1096502 15016963 · DOI
  68. Sanna P. P. Cammalleri M. Berton F. Simpson C. Lutjens R. Bloom F. E. (2002). Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J. Neurosci. 22 3359– 3365 11978812 PMC6758361
  69. Sasaki T. Irie-Sasaki J. Jones R. G. Oliveira-Dos-Santos A. J. Stanford W. L. Bolon B. (2000). Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287 1040– 1046 10.1126/science.287.5455.1040 10669416 · DOI
  70. Serajee F. J. Nabi R. Zhong H Mahbubul Huq A. H. M. (2003). Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism. J. Med. Genet. 40 e119 10.1136/jmg.40.11.e119 PMC1735327 14627686 · DOI
  71. Sharma A. Hoeffer C. A. Takayasu Y. Miyawaki T. Mcbride S. M. Klann E. (2010). Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30 694– 702 10.1523/jneurosci.3696-09.2010 20071534 PMC3665010 · DOI · Paper page
  72. Shepherd P. R. Denny W. A. (2012). Beta-testing of PI3-kinase inhibitors: is beta better? Cancer Discov. 2 393– 394 10.1158/2159-8290.cd-12-0122 22588874 · DOI
  73. Shioi T. Kang P. M. Douglas P. S. Hampe J. Yballe C. M. Lawitts J. (2000). The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19 2537– 2548 10.1093/emboj/19.11.2537 10835352 PMC212739 · DOI
  74. Silberberg G. Darvasi A. Pinkas-Kramarski R. Navon R. (2006). The involvement of ErbB4 with schizophrenia: association and expression studies. Am. J. Med. Genet. Part B Neuropsychiat. Genet. 141B 142– 148 10.1002/ajmg.b.30275 16402353 · DOI
  75. Sopasakis V. R. Liu P. Suzuki R. Kondo T. Winnay J. Tran T. T. (2010). Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab. 11 220– 230 10.1016/j.cmet.2010.02.002 20197055 PMC3144706 · DOI
  76. Stefansson H. Petursson H. Sigurdsson E. Steinthorsdottir V. Bjornsdottir S. Sigmundsson T. (2002). Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71 877– 892 10.1086/342734 12145742 PMC378543 · DOI
  77. Sui L. Wang J. Li B. M. (2008). Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn. Mem. 15 762– 776 10.1101/lm.1067808 18832563 · DOI
  78. Tsai P. T. Hull C. Chu Y. Greene-Colozzi E. Sadowski A. R. Leech J. M. (2012). Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488 647– 651 10.1038/nature11310 22763451 PMC3615424 · DOI · Paper page
  79. Vanhaesebroeck B. Guillermet-Guibert J. Graupera M. Bilanges B. (2010). The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 11 329– 341 10.1038/nrm2882 20379207 · DOI · Paper page
  80. Veikkolainen V. Vaparanta K. Halkilahti K. Iljin K. Sundvall M. Elenius K. (2011). Function of ERBB4 is determined by alternative splicing. Cell Cycle 10 2647– 2657 10.4161/cc.10.16.17194 21811097 · DOI
  81. Vullhorst D. Neddens J. Karavanova I. Tricoire L. Petralia R. S. McBain C. J. (2009). Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J. Neurosci. 29 12255– 12264 10.1523/JNEUROSCI.2454-09.2009 19793984 PMC2774835 · DOI
  82. Waite K. Eickholt B. J. (2010). The neurodevelopmental implications of PI3K signaling. Curr. Top. Microbiol. Immunol. 346 245– 265 10.1007/822010_82 20582530 · DOI
  83. Wang H. Doering L. C. (2013). Reversing autism by targeting downstream mTOR signaling. Front. Cell. Neurosci. 7: 28 10.3389/fncel.2013.00028 PMC3607786 23533374 · DOI
  84. Williams S. C. P. (2012). Drugs targeting mGluR5 receptor offer “fragile” hope for autism. Nat. Med. 18 840– 840 10.1038/nm0612-840 22673981 · DOI
  85. Yin D. M. Sun X. D. Bean J. C. Lin T. W. Sathyamurthy A. Xiong W. C. (2013). Regulation of spine formation by ErbB4 in PV-positive interneurons. J. Neurosci. 33 19295– 19303 10.1523/JNEUROSCI.2090-13.2013 24305825 PMC3850044 · DOI
  86. Zhao J. J. Liu Z. Wang L. Shin E. Loda M. F. Roberts T. M. (2005). The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 102 18443– 18448 10.1073/pnas.0508988102 16339315 PMC1317954 · DOI
  87. Zhao L. Vogt P. K. (2008). Class I PI3K in oncogenic cellular transformation. Oncogene 27 5486– 5496 10.1038/onc.2008.244 18794883 PMC2757120 · DOI
  88. Zhao W.-Q. Alkon D. L. (2001). Role of insulin and insulin receptor in learning and memory. Mol. Cell. Endocrinol. 177 125– 134 10.1016/S0303-7207(01)00455-5 11377828 · DOI
  89. Zheng W. Wang H. Zeng Z. Lin J. Little P. J. Srivastava L. K. (2012). The possible role of the Akt signaling pathway in schizophrenia. Brain Res. 1470 145– 158 10.1016/j.brainres.2012.06.032 22771711 · DOI
  90. Zhou J. Parada L. F. (2012). PTEN signaling in autism spectrum disorders. Curr. Opin. Neurobiol. 22 873– 879 10.1016/j.conb.2012.05.004 22664040 · DOI · Paper page

Authors
Gross, C., & Bassell, G. J.
Affiliations
Emory University (US)
Corresponding author
  • Gross, Christina
  • Bassell, Gary J.
ORCID
Venue
Frontiers in Molecular Neuroscience
Publisher
Frontiers Media SA
Published
2014
Volume
7
Pages
12-12
ISSN
1662-5099 (ISSN-L)
DOI
10.3389/fnmol.2014.00012
PMC
PMC3923137
OpenAlex
W2160368943
Cited by
63
References
96
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 5 · 2015: 6 · 2014: 1
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Brain and Behavior Research Foundation
  • Simons Foundation
  • National Alliance for Research on Schizophrenia and Depression
  • Simons Foundation Autism Research Initiative
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
class I PI3K, p110α, p110β, p110γ, p110δ, neuronal signaling, neurotransmitter signaling, fragile X syndrome, schizophrenia, epilepsy, PI3K inhibitors, drug repurposing, neurological disorders

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