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Cited by 29Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchAutism Spectrum Disorder Research

Towards Kinase Inhibitor Therapies for Fragile X Syndrome: Tweaking Twists in the Autism Spectrum Kinase Signaling Network

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D’Incal, Claudio, Broos, Jitse, Torfs, Thierry, Kooy, R. Frank, Vanden Berghe, Wim·2022·Cells
DOI 10.3390/cells11081325PMC PMC9029738
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Abstract

Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in Fmr1 knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies.

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  • High membrane phosphatidylserine activates many membrane-bound kinases, which have been studied as targets of therapy in FXS.

    “High membrane PS activates many membrane-bound kinases, which have been studied as targets of therapy in FXS55.”

    From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [55]

    Section 4.15 (page unavailable) says protein kinase C signals in a lipid-dependent manner, including through phosphatidylserine binding, and discusses PKC inhibitors as potential FXS treatments. Section 4 more broadly reviews kinases involved in FXS. The paper does not establish that high membrane phosphatidylserine activates many membrane-bound kinases, or that this is why those kinases have been studied as therapeutic targets. (LLM, conf=0.88)

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  1. [2]Levenga J. De Vrij F.M.S. Oostra B.A. Willemsen R. Potential therapeutic interventions for fragile X syndrome Trends Mol. Med. 2010 16 516 527 10.1016/j.molmed.2010.08.005 20864408 PMC2981507 · DOI
  2. [3]Tsiouris J.A. Brown W.T. Neuropsychiatric symptoms of fragile X syndrome: Pathophysiology and pharmacotherapy CNS Drugs 2004 18 687 703 10.2165/00023210-200418110-00001 15330685 · DOI
  3. [4]Lovelace J.W. Rais M. Palacios A.R. Shuai X.S. Bishay S. Popa O. Pirbhoy P.S. Binder D.K. Nelson D.L. Ethell I.M. Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome Cereb. Cortex 2020 30 969 988 10.1093/cercor/bhz141 31364704 PMC7132927 · DOI
  4. [5]Musumeci S.A. Hagerman R.J. Ferri R. Bosco P. Bernardina B.D. Tassinari C.A. Sarro G.B. Elia M. Epilepsy and EEG Findings in Males with Fragile X Syndrome Epilepsia 1999 40 1092 1099 10.1111/j.1528-1157.1999.tb00824.x 10448821 · DOI
  5. [6]Santoro M.R. Bray S.M. Warren S.T. Molecular mechanisms of fragile X syndrome: A twenty-year perspective Annu. Rev. Pathol. Mech. Dis. 2012 7 219 245 10.1146/annurev-pathol-011811-132457 22017584 · DOI · Paper page
  6. [7]Lanni S. Goracci M. Borrelli L. Mancano G. Chiurazzi P. Moscato U. Ferrè F. Helmer-Citterich M. Tabolacci E. Neri G. Role of CTCF Protein in Regulating FMR1 Locus Transcription PLoS Genet. 2013 9 e1003601 10.1371/journal.pgen.1003601 23874213 PMC3715420 · DOI
  7. [8]Naumann A. Hochstein N. Weber S. Fanning E. Doerfler W. A Distinct DNA-Methylation Boundary in the 5′- Upstream Sequence of the FMR1 Promoter Binds Nuclear Proteins and Is Lost in Fragile X Syndrome Am. J. Hum. Genet. 2009 85 606 616 10.1016/j.ajhg.2009.09.018 19853235 PMC2775827 · DOI · Paper page
  8. [9]Rooms L. Kooy R.F. Advances in understanding fragile X syndrome and related disorders Curr. Opin. Pediatr. 2011 23 601 606 10.1097/MOP.0b013e32834c7f1a 22001764 · DOI
  9. [10]Darnell J.C. Klann E. The translation of translational control by FMRP: Therapeutic targets for FXS Nat. Neurosci. 2013 16 1530 1536 10.1038/nn.3379 23584741 PMC3999698 · DOI · Paper page
  10. [11]Bagni C. Zukin R.S. A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders Neuron 2019 101 1070 1088 10.1016/j.neuron.2019.02.041 30897358 PMC9628679 · DOI · Paper page
  11. [12]Braat S. Kooy R.F. The GABA A Receptor as a Therapeutic Target for Neurodevelopmental Disorders Neuron 2015 86 1119 1130 10.1016/j.neuron.2015.03.042 26050032 · DOI · Paper page
  12. [13]Dölen G. Bear M.F. Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome J. Physiol. 2008 586 1503 1508 10.1113/jphysiol.2008.150722 18202092 PMC2375688 · DOI
  13. [14]Wu C. Sun D. GABA receptors in brain development, function, and injury Metab. Brain Dis. 2015 30 367 379 10.1007/s11011-014-9560-1 24820774 PMC4231020 · DOI
  14. [16]Janusz A. Miłek J. Perycz M. Pacini L. Bagni C. Kaczmarek L. Dziembowska M. The Fragile X Mental Retardation Protein Regulates Matrix Metalloproteinase 9 mRNA at Synapses J. Neurosci. 2013 33 18234 18241 10.1523/JNEUROSCI.2207-13.2013 24227732 PMC6619756 · DOI · Paper page
  15. [17]Kondratiuk I. Łęski S. Urbańska M. Biecek P. Devijver H. Lechat B. Van Leuven F. Kaczmarek L. Jaworski T. GSK-3β and MMP-9 Cooperate in the Control of Dendritic Spine Morphology Mol. Neurobiol. 2017 54 200 211 10.1007/s12035-015-9625-0 26738851 PMC5219889 · DOI
  16. [19]Willemsen R. Kooy F.R. Fragile X Syndrome-From Genetics to Targeted Treatment Elsevier Rotterdam, The Netherlands 2016
  17. [21]Hagerman R. Lauterborn J. Au J. Berry-Kravis E. Fragile X syndrome and targeted treatment trials Results Probl. Cell Differ. 2012 54 297 335 10.1007/978-3-642-21649-7_17 22009360 PMC4114775 · DOI
  18. [22]Hamilton T.A. Protein Kinases Encyclopedia of Immunology Elsevier Amsterdam, The Netherlands 1998 2028 2033
  19. [23]Ardito F. Giuliani M. Perrone D. Troiano G. Lo Muzio L. The crucial role of protein phosphorylation in cell signalingand its use as targeted therapy (Review) Int. J. Mol. Med. 2017 40 271 280 10.3892/ijmm.2017.3036 28656226 PMC5500920 · DOI
  20. [24]Stultz C.M. Levin A.D. Edelman E.R. Phosphorylation-induced conformational changes in a mitogen-activated protein kinase substrate: Implications for tyrosine hydroxylase activation J. Biol. Chem. 2002 277 47653 47661 10.1074/jbc.M208755200 12361946 · DOI
  21. [25]Rabiller M. Getlik M. Klüter S. Richters A. Tückmantel S. Simard J.R. Rauh D. Review Proteus in the World of Proteins: Conformational Changes in Protein Kinases Arch. Pharm. Chem. Life Sci. 2010 343 193 206 10.1002/ardp.201000028 20336692 · DOI
  22. [26]Lin J. Xie Z. Zhu H. Qian J. Understanding protein phosphorylation on a systems level Brief. Funct. Genom. 2010 9 32 42 10.1093/bfgp/elp045 20056723 PMC3096446 · DOI
  23. [27]Cohen P. Protein kinases-the major drug targets of the twenty-first century? Nat. Rev. Drug Discov. 2002 1 309 315 10.1038/nrd773 12120282 · DOI
  24. [28]Zafarullah M. Tassone F. Molecular biomarkers in fragile x syndrome Brain Sci. 2019 9 96 10.3390/brainsci9050096 PMC6562871 31035599 · DOI
  25. [29]Sharma A. Hoeffer C.A. Takayasu Y. Miyawaki T. McBride S.M. Klann E. Zukin R.S. Dysregulation of mTOR Signaling in Fragile X Syndrome J. Neurosci. 2010 30 694 702 10.1523/JNEUROSCI.3696-09.2010 20071534 PMC3665010 · DOI · Paper page
  26. [30]Shchemelinin L.I. Šefc E.N. Protein Kinases, Their Function and Implication in Cancer and Other Diseases Folia Biol. 2006 52 81 101 17089919
  27. [31]Tabolacci E. Palumbo F. Nobile V. Neri G. Transcriptional Reactivation of the FMR1 Gene. A Possible Approach to the Treatment of the Fragile X Syndrome † Genes 2016 7 49 10.3390/genes7080049 PMC4999837 27548224 · DOI
  28. [33]Deelen W. Bakker C. Halley D.J.J. Oostra B.A. Conservation of CGG region in FMR1 gene in mammals Am. J. Med. Genet. 1994 51 513 516 10.1002/ajmg.1320510445 7943032 · DOI
  29. [35]Zalfa F. Bagni C. FMRP Dysfunction and Mental Retardation 73 Molecular Insights into Mental Retardation: Multiple Functions for the Fragile X Mental Retardation Protein? Curr. Issues Mol. Biol. 2004 6 73 88 15119819
  30. [37]Sullivan A.K. Crawford D.C. Scott E.H. Leslie M.L. Sherman S.L. Paternally transmitted FMR1 alleles are less stable than maternally transmitted alleles in the common and intermediate size range Am. J. Hum. Genet. 2002 70 1532 1544 10.1086/340846 11992259 PMC379140 · DOI
  31. [38]Moutou C. Vincent M.-C. Biancalana V. Mandel J.-L. Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic Hum. Mol. Genet. 1997 6 971 979 10.1093/hmg/6.7.971 9215664 · DOI
  32. [39]Schneider A. Winarni T.I. Cabal-Herrera A.M. Bacalman S. Gane L. Hagerman P. Tassone F. Hagerman R. Elevated FMR1-mRNA and lowered FMRP–A double-hit mechanism for psychiatric features in men with FMR1 premutations Transl. Psychiatry 2020 10 205 10.1038/s41398-020-00863-w 32576818 PMC7311546 · DOI
  33. [40]Hecht M. Tabib A. Kahan T. Orlanski S. Gropp M. Tabach Y. Yanuka O. Benvenisty N. Keshet I. Cedar H. Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome Int. J. Dev. Biol. 2017 61 285 292 10.1387/ijdb.170022hc 28621425 · DOI
  34. [41]Dean D.D. Muthuswamy S. Agarwal S. Fragile X syndrome: Current insight Egypt. J. Med. Hum. Genet. 2016 17 303 309 10.1016/j.ejmhg.2016.01.005 · DOI
  35. [42]Maurin T. Melko M. Abekhoukh S. Khalfallah O. Davidovic L. Jarjat M. D’Antoni S. Catania M.V. Moine H. Bechara E. The FMRP/GRK4 mRNA interaction uncovers a new mode of binding of the Fragile X mental retardation protein in cerebellum Nucleic Acids Res. 2015 43 8540 8550 10.1093/nar/gkv801 26250109 PMC4787806 · DOI
  36. [43]Myrick L.K. Hashimoto H. Cheng X. Warren S.T. Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain Hum. Mol. Genet. 2015 24 1733 1740 10.1093/hmg/ddu586 25416280 PMC4381759 · DOI
  37. [45]Zhang F. Kang Y. Wang M. Li Y. Xu T. Yang W. Song H. Wu H. Shu Q. Jin P. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets Hum. Mol. Genet. 2018 27 3936 3950 10.1093/hmg/ddy292 30107516 PMC6216232 · DOI
  38. [46]Edens B.M. Vissers C. Su J. Arumugam S. Xu Z. Shi H. Miller N. Rojas Ringeling F. Ming G.L. He C. FMRP Modulates Neural Differentiation through m 6 A-Dependent mRNA Nuclear Export Cell Rep. 2019 28 845 854.e5 10.1016/j.celrep.2019.06.072 31340148 PMC6687293 · DOI · Paper page
  39. [47]Siomi H. Ishizuka A. Siomi M.C. RNA Interference: A New Mechanism by which FMRP Acts in the Normal Brain? What Can Drosophila Teach Us? Ment. Retard. Dev. Disabil. Res. Rev. 2004 10 68 74 10.1002/mrdd.20011 14994291 · DOI
  40. [48]Bassell G.J. Gross C. Reducing glutamate signaling pays off in fragile X Nat. Med. 2008 14 249 250 10.1038/nm0308-249 18323845 · DOI
  41. [49]Clifton N.E. Thomas K.L. Wilkinson L.S. Hall J. Trent S. FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability Complex Psychiatry 2020 6 5 10.1159/000506858 34883502 PMC7673588 · DOI · Paper page
  42. [50]Ceman S. O’Donnell W.T. Reed M. Patton S. Pohl J. Warren S.T. Phosphorylation influences the translation state of FMRP-associated polyribosomes Hum. Mol. Genet. 2003 12 3295 3305 10.1093/hmg/ddg350 14570712 · DOI · Paper page
  43. [51]De Rubeis S. Bagni C. Regulation of molecular pathways in the Fragile X Syndrome: Insights into Autism Spectrum Disorders J. Neurodev. Disord. 2011 3 257 269 10.1007/s11689-011-9087-2 21842222 PMC3167042 · DOI · Paper page
  44. [52]Gareau C. Martel D. Coudert L. Mellaoui S. Mazroui R. Characterization of Fragile X Mental Retardation Protein granules formation and dynamics in Drosophila Biol. Open 2013 2 68 10.1242/bio.20123012 23336078 PMC3545270 · DOI
  45. [54]Bartley C.M. O’keefe R.A. Lique Bordey A. FMRP S499 Is Phosphorylated Independent of mTORC1-S6K1 Activity PLoS ONE 2014 9 e96956 10.1371/journal.pone.0096956 24806451 PMC4013076 · DOI
  46. [55]Cheever A. Ceman S. Phosphorylation of FMRP inhibits association with Dicer RNA 2009 15 362 366 10.1261/rna.1500809 19155329 PMC2657015 · DOI · Paper page
  47. [56]Tsang B. Arsenault J. Vernon R.M. Lin H. Sonenberg N. Wang L.Y. Bah A. Forman-Kay J.D. Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation Proc. Natl. Acad. Sci. USA 2019 116 4218 4227 10.1073/pnas.1814385116 30765518 PMC6410804 · DOI
  48. [57]Lisman J.E. A mechanism for memory storage insensitive to molecular turnover: A bistable autophosphorylating kinase Proc. Natl. Acad. Sci. USA 1985 82 3055 3057 10.1073/pnas.82.9.3055 2986148 PMC397705 · DOI · Paper page
  49. [58]Ubersax J.A. Ferrell J.E. Jr. Mechanisms of specificity in protein phosphorylation Nat. Rev. Mol. Cell Biol. 2007 8 530 541 10.1038/nrm2203 17585314 · DOI · Paper page
  50. [59]Matt L. Kim K. Chowdhury D. Hell J.W. Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity Front. Mol. Neurosci. 2019 8 10.3389/fnmol.2019.00008 30766476 PMC6365469 · DOI
  51. [60]Hoffman L. Jensen C.C. Yoshigi M. Beckerle M. Mechanical signals activate p38 MAPK pathway-dependent reinforcement of actin via mechanosensitive HspB1 Mol. Biol. Cell 2017 28 2661 2675 10.1091/mbc.e17-02-0087 28768826 PMC5620374 · DOI
  52. [61]Berry-Kravis E. Hessl D. Abbeduto L. Reiss A.L. Beckel-Mitchener A. Urv T.K. Measures O. Groups W. Aman M. Clapp K. Outcome Measures for Clinical Trials in Fragile X Syndrome J. Dev. Behav. Pediatr. 2013 34 508 522 10.1097/DBP.0b013e31829d1f20 24042082 PMC3784007 · DOI
  53. [62]Kandel E.S. Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB Exp. Cell Res. 1999 253 210 229 10.1006/excr.1999.4690 10579924 · DOI
  54. [63]Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. Hemmings B.A. Mechanism of activation of protein kinase B by insulin and IGF-1 EMBO J. 1996 15 6541 10.1002/j.1460-2075.1996.tb01045.x 8978681 PMC452479 · DOI
  55. [64]Fayard E. Tintignac L.A. Baudry A. Hemmings B.A. Protein kinase B/Akt at a glance J. Cell Sci. 2005 118 5675 5678 10.1242/jcs.02724 16339964 · DOI
  56. [65]Alessi D.R. James S.R. Downes C. Holmes A.B. Gaffney P.R. Reese C.B. Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha Curr. Biol. 1997 7 261 269 10.1016/S0960-9822(06)00122-9 9094314 · DOI
  57. [66]Manning B.D. Cantley L.C. AKT/PKB signaling: Navigating downstream Cell 2007 129 1261 1274 10.1016/j.cell.2007.06.009 17604717 PMC2756685 · DOI · Paper page
  58. [67]Rajala R.V. Phosphoinositide 3-kinase signaling in the vertebrate retina J. Lipid Res. 2010 51 4 22 10.1194/jlr.R000232 19638643 PMC2789784 · DOI
  59. [68]Hresko R.C. Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes J. Biol. Chem. 2005 280 40406 40416 10.1074/jbc.M508361200 16221682 · DOI
  60. [69]Alessi D. Kozlowski M.T. Weng Q.-P. Morrice N. Avruch J. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro Curr. Biol. 1998 8 69 81 10.1016/S0960-9822(98)70037-5 9427642 · DOI
  61. [70]Parcellier A. Tintignac L.A. Zhuravleva E. Hemmings B.A. PKB and the mitochondria: AKTing on apoptosis Cell. Signal. 2008 20 21 30 10.1016/j.cellsig.2007.07.010 17716864 · DOI
  62. [71]New D.C. Wu K. Kwok A.W.S. Wong Y.H. G protein-coupled receptor-induced Akt activity in cellular proliferation and apoptosis FEBS J. 2007 274 6025 6036 10.1111/j.1742-4658.2007.06116.x 17949438 · DOI
  63. [72]Hu H. Qin Y. Bochorishvili G. Zhu Y. van Aelst L. Zhu J.J. Ras Signaling Mechanisms Underlying Impaired GluR1-Dependent Plasticity Associated with Fragile X Syndrome J. Neurosci. 2008 28 7847 7862 10.1523/JNEUROSCI.1496-08.2008 18667617 PMC2553221 · DOI
  64. [73]Liu Z.-H. Huang T. Smith C.B. Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome Neurobiol. Dis. 2012 45 1145 1152 10.1016/j.nbd.2011.12.037 22227453 PMC4988124 · DOI
  65. [74]Lim C.-S. Hoang E.T. Viar K.E. Stornetta R.L. Scott M.M. Zhu J.J. Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model Genes Dev. 2014 28 273 10.1101/gad.232470.113 24493647 PMC3923969 · DOI
  66. [76]Pellerin D. Çaku A. Fradet M. Bouvier P. Dubé J. Corbin F. Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: Potential of platelet’s signaling cascades as new outcome measures in clinical trials Biomarkers 2016 21 497 508 10.3109/1354750X.2016.1160289 27058300 · DOI
  67. [78]Ding Q. Zhang F. Feng Y. Wang H. Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome Int. J. Mol. Sci. 2020 21 9327 10.3390/ijms21239327 PMC7731004 33297570 · DOI
  68. [79]Herzig S. Shaw R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis HHS Public Access Nat. Rev. Mol. Cell Biol. 2018 19 121 135 10.1038/nrm.2017.95 28974774 PMC5780224 · DOI
  69. [81]BXiao B. Sanders M.J. Carmena D. Bright N.J. Haire L.F. Underwood E. Patel B.R. Heath R.B. Walker P.A. Hallen S. Structural basis of AMPK regulation by small molecule activators Nat. Commun. 2013 4 3017 10.1038/NCOMMS4017 24352254 PMC3905731 · DOI
  70. [82]Monyak R.E. Emerson D. Schoenfeld B.P. Zheng X. Chambers D.B. Rosenfelt C. Langer S. Hinchey P. Choi C.H. McDonald T.V. Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model Mol. Psychiatry 2016 22 1140 1148 10.1038/mp.2016.51 27090306 PMC5071102 · DOI · Paper page
  71. [83]Gantois I. Khoutorsky A. Popic J. Aguilar-Valles A. Freemantle E. Cao R. Sharma V. Pooters T. Nagpal A. Skalecka A. Metformin ameliorates core deficits in a mouse model of fragile X syndrome Nat. Med. 2017 23 674 677 10.1038/nm.4335 28504725 · DOI
  72. [84]Yan J. Porch M.W. Court-Vazquez B. Bennett M.V.L. Zukin R.S. Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice Proc. Natl. Acad. Sci. USA 2018 115 E9707 E9716 10.1073/pnas.1808247115 30242133 PMC6187122 · DOI
  73. [85]Coultrap S.J. Bayer K.U. CaMKII regulation in information processing and storage Trends Neurosci. 2012 35 607 10.1016/j.tins.2012.05.003 22717267 PMC3461103 · DOI
  74. [86]Lucchesi W. Mizuno K. Giese K.P. Novel insights into CaMKII function and regulation during memory formation Brain Res. Bull. 2011 85 2 8 10.1016/j.brainresbull.2010.10.009 21070840 · DOI
  75. [87]Wu X. McMurray C.T. Calmodulin kinase II attenuation of gene transcription by preventing cAMP response element-binding protein (CREB) dimerization and binding of the CREB-binding protein J. Biol. Chem. 2001 276 1735 1741 10.1074/jbc.M006727200 11013247 · DOI
  76. [88]Srinivasan M. Edman C.F. Schulman H. Alternative splicing introduces a nuclear localization signal that targets multifunctional CaM kinase to the nucleus J. Cell Biol. 1994 126 839 10.1083/jcb.126.4.839 7519621 PMC2120112 · DOI
  77. [89]Gaertner T.R. Kolodziej S.J. Wang D. Kobayashi R. Koomen J.M. Stoops J.K. Waxham M.N. Comparative Analyses of the Three-dimensional Structures and Enzymatic Properties of α, β, γ, and δ Isoforms of Ca2+-Calmodulin-dependent Protein Kinase II * J. Biol. Chem. 2004 279 12484 12494 10.1074/jbc.M313597200 14722083 · DOI
  78. [90]Schulman H. Heist K. Srinivasan M. Decoding Ca2+ signals to the nucleus by multifunctional CaM kinase Prog. Brain Res. 1995 105 95 104 10.1016/S0079-6123(08)63287-2 7568901 · DOI
  79. [91]Bassell G.J. Warren S.T. Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function Neuron 2008 60 201 214 10.1016/j.neuron.2008.10.004 18957214 PMC3691995 · DOI · Paper page
  80. [92]Guo W. Ceolin L. Collins K.A. Perroy J. Huber K.M. Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model Cell Rep. 2015 13 2297 2311 10.1016/j.celrep.2015.11.013 26670047 PMC4685008 · DOI
  81. [94]Malumbres M. Cyclin-dependent kinases Genome Biol. 2014 15 122 10.1186/gb4184 25180339 PMC4097832 · DOI
  82. [95]Colas P. Cyclin-dependent kinases and rare developmental disorders Orphanet J. Rare Dis. 2020 15 203 10.1186/s13023-020-01472-y 32762766 PMC7410148 · DOI
  83. [96]Luo Y. Shan G. Guo W. Smrt R.D. Johnson E.B. Li X. Pfeiffer R. Szulwach K.E. Duan R. Barkho B.Z. Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells PLoS Genet. 2010 6 e1000898 10.1371/journal.pgen.1000898 20386739 PMC2851565 · DOI
  84. [97]Sakane F. Imai S.-I. Kai M. Yasuda S. Kanoh H. Diacylglycerol kinases: Why so many of them? Biochim. Biophys. Acta 2007 1771 793 806 10.1016/j.bbalip.2007.04.006 17512245 · DOI
  85. [98]Rhee S.G. Regulation of phosphoinositide-specific phospholipase C Annu. Rev. Biochem. 2001 70 281 312 10.1146/annurev.biochem.70.1.281 11395409 PMC4781088 · DOI · Paper page
  86. [99]Topham M.K. Epand R.M. Mammalian Diacylglycerol Kinases: Molecular Interactions and Biological Functions of Selected Isoforms Biochim. Biophys. Acta 2009 1790 416 10.1016/j.bbagen.2009.01.010 19364481 PMC2744455 · DOI
  87. [100]Tu-Sekine B. Raben D.M. Regulation and roles of neuronal diacylglycerol kinases: A lipid perspective Crit. Rev. Biochem. Mol. Biol. 2011 46 353 364 10.3109/10409238.2011.577761 21539478 · DOI
  88. [101]Ishisaka M. Hara H. The roles of diacylglycerol kinases in the central nervous system: Review of genetic studies in mice J. Pharmacol. Sci. 2014 124 336 343 10.1254/jphs.13R07CR 24599142 · DOI
  89. [102]Tabet R. Moutin E. Becker J.A.J. Heintz D. Fouillen L. Flatter E. Krężel W. Alunni V. Koebel P. Dembélé D. Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons Proc. Natl. Acad. Sci. USA 2016 113 E3619 E3628 10.1073/pnas.1522631113 27233938 PMC4932937 · DOI
  90. [103]Habbas K. Cakil O. Zambo B. Tabet R. Riet F. Dembele D. Mandel J.-L. Hocquemiller M. Laufer R. Piguet F. AAV-delivery of diacylglycerol kinase kappa achieves long-term rescue of Fmr1-KO mouse model deficits of fragile X syndrome bioRxiv 2021 10.1101/2021.04.14.439810 PMC9081908 35373916 · DOI
  91. [104]Geoffroy A. Habbas K. Zambo B. Schramm L. Duchon A. Flatter E. Fouillen L. Zumsteg J. Heintz D. Mandel J.-L. Pioglitazone improves deficits of Fmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling bioRxiv 2020 10.1101/2020.09.22.301762 · DOI
  92. [105]Boulton T.G. Nye S.H. Robbins D.J. Ip N.Y. Radzlejewska E. Morgenbesser S.D. DePinho R. Panayotatos N. Cobb M. Yancopoulos G.D. ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF Cell 1991 65 663 675 10.1016/0092-8674(91)90098-J 2032290 · DOI
  93. [106]Boulton T.G. Yancopoulos G.D. Gregory J.S. Slaughter C. Moomaw C. Hsu J. Cobb M.H. An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control Science 1990 249 64 67 10.1126/science.2164259 2164259 · DOI
  94. [107]Cargnello M. Roux P.P. Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases Microbiol. Mol. Biol. Rev. 2011 75 50 10.1128/MMBR.00031-10 21372320 PMC3063353 · DOI · Paper page
  95. [108]Lavoie H. Gagnon J. Therrien M. ERK signalling: A master regulator of cell behaviour, life and fate Nat. Rev. Mol. Cell Biol. 2020 21 607 632 10.1038/s41580-020-0255-7 32576977 · DOI · Paper page
  96. [109]Roux P.P. Blenis J. ERK and p38 MAPK-Activated Protein Kinases: A Family of Protein Kinases with Diverse Biological Functions Microbiol. Mol. Biol. Rev. 2004 68 320 344 10.1128/MMBR.68.2.320-344.2004 15187187 PMC419926 · DOI
  97. [110]Vithayathil J. Pucilowska J. Landreth G.E. ERK/MAPK signaling and autism spectrum disorders Prog. Brain Res. 2018 241 63 112 10.1016/BS.PBR.2018.09.008 30447757 · DOI
  98. [111]Taylor S.S. Kornev A.P. Protein kinases: Evolution of dynamic regulatory proteins Trends Biochem. Sci. 2011 36 65 77 10.1016/j.tibs.2010.09.006 20971646 PMC3084033 · DOI
  99. [112]Zhang J. Zhang F. Ebert D. Cobb M. Goldsmith E.J. Activity of the MAP kinase ERK2 is controlled by a flexible surface loop Structure 1995 3 299 307 10.1016/S0969-2126(01)00160-5 7540485 · DOI
  100. [113]Harding A. Tian T. Westbury E. Frische E. Hancock J.F. Subcellular localization determines MAP kinase signal output Curr. Biol. 2005 15 869 873 10.1016/j.cub.2005.04.020 15886107 · DOI
  101. [114]Casar B. Pinto A. Crespo P. Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes Mol. Cell 2008 31 708 721 10.1016/j.molcel.2008.07.024 18775330 · DOI
  102. [115]Hou L. Antion M.D. Hu D. Spencer C.M. Paylor R. Klann E. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression Neuron 2006 51 441 454 10.1016/j.neuron.2006.07.005 16908410 · DOI · Paper page
  103. [116]Price T.J. Rashid M.H. Millecamps M. Sanoja R. Entrena J.M. Cervero F. Decreased Nociceptive Sensitization in Mice Lacking the Fragile X Mental Retardation Protein: Role of mGluR1/5 and mTOR J. Neurosci. 2007 27 13958 10.1523/JNEUROSCI.4383-07.2007 18094233 PMC2206543 · DOI
  104. [117]Kim S.H. Markham J.A. Weiler I.J. Greenough W.T. Aberrant early-phase ERK inactivation impedes neuronal function in fragile X syndrome Proc. Natl. Acad. Sci. USA 2008 105 4429 4434 10.1073/pnas.0800257105 18332424 PMC2393788 · DOI · Paper page
  105. [118]Gross C. Nakamoto M. Yao X. Chan C.B. Yim S.Y. Ye K. Warren S.T. Bassell G.J. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome J. Neurosci. 2010 30 10624 10638 10.1523/JNEUROSCI.0402-10.2010 20702695 PMC2924772 · DOI · Paper page
  106. [120]Bhattacharya A. Kaphzan H. Alvarez-Dieppa A.C. Murphy J.P. Pierre P. Klann E. Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice Neuron 2012 76 325 337 10.1016/j.neuron.2012.07.022 23083736 PMC3479445 · DOI · Paper page
  107. [121]Hoeffer C.A. Sanchez E. Hagerman R.J. Mu Y. Nguyen D.V. Wong H. Whelan A.M. Zukin R.S. Klann E. Tassone F. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome Genes Brain Behav. 2012 11 332 341 10.1111/j.1601-183X.2012.00768.x 22268788 PMC3319643 · DOI · Paper page
  108. [123]Srikanth K.D. Meirson T. Sams D.S. Gil-Henn H. Srikanth K.D. Meirson T. Sams D.S. Gil-Henn H. FAK family kinases in brain health and disease J. Mol. Clin. Med. 2018 1 177 190 10.31083/J.JMCM.2018.03.007 · DOI
  109. [124]Schaller M.D. Cellular functions of FAK kinases: Insight into molecular mechanisms and novel functions J. Cell Sci. 2010 123 1007 1013 10.1242/jcs.045112 20332118 · DOI
  110. [125]Armendáriz B.G. Masdeu M.D.M. Soriano E. Ureña J.M. Burgaya F. The diverse roles and multiple forms of focal adhesion kinase in brain Eur. J. Neurosci. 2014 40 3573 3590 10.1111/ejn.12737 25263991 · DOI
  111. [126]Park S.-Y. Avraham H. Avraham S. RAFTK/Pyk2 activation is mediated by trans-acting autophosphorylation in a Src-independent manner J. Biol. Chem. 2004 279 33315 33322 10.1074/jbc.M313527200 15166227 · DOI
  112. [128]Parker P.J. Caudwell F.B. Cohen P. Glycogen Synthase from Rabbit Skeletal Muscle; Effect of Insulin on the State of phosphorylation of the Seven Phosphoserine Residues in vivo Eur. J. Biochem. 1983 130 227 234 10.1111/j.1432-1033.1983.tb07140.x 6402364 · DOI
  113. [129]Cohen P. Frame S. The renaissance of GSK3 Nat. Rev. Mol. Cell Biol. 2001 2 769 776 10.1038/35096075 11584304 · DOI
  114. [130]Li X. Jope R.S. Is Glycogen Synthase Kinase-3 a Central Modulator in Mood Regulation&quest Neuropsychopharmacology 2010 35 2143 2154 10.1038/npp.2010.105 20668436 PMC3055312 · DOI · Paper page
  115. [131]Salcedo-Tello P. Ortiz-Matamoros A. Arias C. GSK3 Function in the Brain during Development, Neuronal Plasticity, and Neurodegeneration Int. J. Alzheimers. Dis. 2011 2011 189728 10.4061/2011/189728 21660241 PMC3109514 · DOI
  116. [132]Min W.W. Yuskaitis C.J. Yan Q. Sikorski C. Chen S. Jope R.S. Bauchwitz R.P. Elevated glycogen synthase kinase-3 activity in Fragile X mice: Key metabolic regulator with evidence for treatment potential Neuropharmacology 2009 56 463 472 10.1016/j.neuropharm.2008.09.017 18952114 PMC2707186 · DOI · Paper page
  117. [133]Mines M.A. Yuskaitis C.J. King M.K. Beurel E. Jope R.S. GSK3 Influences Social Preference and Anxiety-Related Behaviors during Social Interaction in a Mouse Model of Fragile X Syndrome and Autism PLoS ONE 2010 5 e9706 10.1371/journal.pone.0009706 20300527 PMC2838793 · DOI
  118. [134]Yuskaitis C.J. Mines M.A. King M.K. Sweatt J.D. Miller C.A. Jope R.S. Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome Biochem. Pharmacol. 2010 79 632 646 10.1016/j.bcp.2009.09.023 19799873 PMC2810609 · DOI
  119. [136]Westmark P.R. Garrone B. Ombrato R. Milanese C. Di Giorgio F.P. Westmark C.J. Testing Fmr1KO Phenotypes in Response to GSK3 Inhibitors: SB216763 versus AFC03127 Front. Mol. Neurosci. 2021 14 224 10.3389/fnmol.2021.751307 34690696 PMC8529056 · DOI
  120. [137]McCamphill P.K. Stoppel L.J. Senter R.K. Lewis M.C. Heynen A.J. Stoppel D.C. Sridhar V. Collins K.A. Shi X. Pan J.Q. Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome Sci. Transl. Med. 2020 12 eaam8572 10.1126/scitranslmed.aam8572 32434848 PMC8095719 · DOI
  121. [138]Pröschel C. Blouin M.J. Gutowski N.J. Ludwig R. Noble M. Limk1 is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro Oncogene 1995 11 1271 1281 7478547
  122. [139]Edwards D.C. Gill G.N. Structural features of LIM kinase that control effects on the actin cytoskeleton J. Biol. Chem. 1999 274 11352 11361 10.1074/jbc.274.16.11352 10196227 · DOI
  123. [140]Bernard O. Lim kinases, regulators of actin dynamics Int. J. Biochem. Cell Biol. 2007 39 1071 1076 10.1016/j.biocel.2006.11.011 17188549 · DOI
  124. [141]Nagata K. Ohashi K. Yang N. Mizuno K. The N-terminal LIM domain negatively regulates the kinase activity of LIM-kinase 1 Biochem. J. 1999 343 99 105 10.1042/bj3430099 10493917 PMC1220529 · DOI
  125. [142]Spiering D. Hodgson L. Dynamics of the Rho-family small GTPases in actin regulation and motility Cell Adh. Migr. 2011 5 170 180 10.4161/cam.5.2.14403 21178402 PMC3084983 · DOI
  126. [143]Sit S.-T. Manser E. Rho GTPases and their role in organizing the actin cytoskeleton J. Cell Sci. 2011 124 679 683 10.1242/jcs.064964 21321325 · DOI
  127. [144]Dan C. Kelly A. Bernard O. Minden A. Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin J. Biol. Chem. 2001 276 32115 32121 10.1074/jbc.M100871200 11413130 · DOI
  128. [145]Maekawa M. Ishizaki T. Boku S. Watanabe N. Fujita A. Iwamatsu A. Obinata T. Ohashi K. Mizuno K. Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase Science 1999 285 895 898 10.1126/science.285.5429.895 10436159 · DOI
  129. [146]Nadella K.S. Saji M. Jacob N.K. Pavel E. Ringel M.D. Kirschner L.S. Regulation of actin function by protein kinase A-mediated phosphorylation of Limk1 EMBO Rep. 2009 10 599 605 10.1038/embor.2009.58 19424295 PMC2711837 · DOI
  130. [147]Soosairajah J. Maiti S. Wiggan O. Sarmiere P. Moussi N. Sarcevic B. Sampath R. Bamburg J.R. Bernard O. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin EMBO J. 2005 24 473 486 10.1038/sj.emboj.7600543 15660133 PMC548651 · DOI
  131. [148]Arber S. Barbayannis F.A. Hanser H. Schneider C. Stanyon C. Bernard O. Caroni P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase Nature 1998 393 805 809 10.1038/31729 9655397 · DOI
  132. [149]Sacchetti P. Carpentier R. Ségard P. Olivé-Cren C. Lefebvre P. Multiple signaling pathways regulate the transcriptional activity of the orphan nuclear receptor NURR1 Nucleic Acids Res. 2006 34 5515 5527 10.1093/nar/gkl712 17020917 PMC1636490 · DOI
  133. [150]Yang E.J. Yoon J.H. Min D.S. Chung K.C. LIM Kinase 1 Activates cAMP-responsive Element-binding Protein during the Neuronal Differentiation of Immortalized Hippocampal Progenitor Cells J. Biol. Chem. 2004 279 8903 8910 10.1074/jbc.M311913200 14684741 · DOI
  134. [151]Kashima R. Roy S. Ascano M. Martinez-Cerdeno V. Ariza-Torres J. Kim S. Louie J. Lu Y. Leyton P. Bloch K.D. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome Sci. Signal. 2016 9 ra58 10.1126/scisignal.aaf6060 27273096 PMC5274719 · DOI
  135. [153]Waskiewicz A.J. Flynn A. Proud C.G. Cooper J.A. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 EMBO J. 1997 16 1909 1920 10.1093/emboj/16.8.1909 9155017 PMC1169794 · DOI
  136. [154]Wang X. Flynn A. Waskiewicz A.J. Webb B. Vries R.G. Baines I.A. Cooper J.A. Proud C. The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways J. Biol. Chem. 1998 273 9373 9377 10.1074/jbc.273.16.9373 9545260 · DOI
  137. [155]Parra J.L. Buxadé M. Proud C. Features of the catalytic domains and C termini of the MAPK signal-integrating kinases Mnk1 and Mnk2 determine their differing activities and regulatory properties J. Biol. Chem. 2005 280 37623 37633 10.1074/jbc.M508356200 16162500 · DOI
  138. [156]Joshi S. Mnk kinase pathway: Cellular functions and biological outcomes World J. Biol. Chem. 2014 5 321 10.4331/wjbc.v5.i3.321 25225600 PMC4160526 · DOI
  139. [157]Diab S. Kumarasiri M. Yu M. Teo T. Proud C. Milne R. Wang S. Chemistry & Biology Review MAP Kinase-Interacting Kinases-Emerging Targets against Cancer Chem. Biol. 2014 21 441 452 10.1016/j.chembiol.2014.01.011 24613018 · DOI
  140. [158]Shveygert M. Kaiser C. Bradrick S.S. Gromeier M. Regulation of Eukaryotic Initiation Factor 4E (eIF4E) Phosphorylation by Mitogen-Activated Protein Kinase Occurs through Modulation of Mnk1-eIF4G Interaction Mol. Cell. Biol. 2010 30 5160 10.1128/MCB.00448-10 20823271 PMC2953056 · DOI
  141. [159]Li Y. Yue P. Deng X. Ueda T. Fukunaga R. Khuri F.R. Sun S.-Y. Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E Neoplasia 2010 12 848 855 10.1593/neo.10704 20927323 PMC2950334 · DOI
  142. [161]Shukla T. de la Peña J.B. Perish J.M. PLoSki J.E. Stumpf C.R. Webster K.R. Thorn C.A. Campbell Z.T. A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice Neurotherapeutics 2021 18 624 639 10.1007/s13311-020-00932-4 33006091 PMC8116363 · DOI
  143. [162]Asnaghi L. Bruno P. Priulla M. Nicolin A. mTOR: A protein kinase switching between life and death Pharmacol. Res. 2004 50 545 549 10.1016/j.phrs.2004.03.007 15501691 · DOI
  144. [163]Yang H. Rudge D.G. Koos J. Vaidialingam B. Yang H. Pavletich N.P. mTOR kinase structure, mechanism and regulation Nature 2013 497 217 223 10.1038/nature12122 23636326 PMC4512754 · DOI · Paper page
  145. [164]Hay N. Sonenberg N. Upstream and downstream of mTOR Genes Dev. 2004 18 1926 1945 10.1101/gad.1212704 15314020 · DOI · Paper page
  146. [165]Laplante M. Sabatini D.M. mTOR signaling in growth control and disease Cell 2012 149 274 293 10.1016/j.cell.2012.03.017 22500797 PMC3331679 · DOI · Paper page
  147. [166]Bockaert J. Marin P. mTOR in Brain Physiology and Pathologies Physiol. Rev. 2015 95 1157 1187 10.1152/physrev.00038.2014 26269525 · DOI
  148. [167]Sato A. mTOR, a Potential Target to Treat Autism Spectrum Disorder CNS Neurol. Disord. Drug Targets 2016 15 533 10.2174/1871527315666160413120638 27071790 PMC5070418 · DOI
  149. [168]Busquets-Garcia A. Gomis-González M. Guegan T. Agustín-Pavón C. Pastor A. Mato S. Samartin A.L.P. Matute C. de la Torre R. Dierssen M. Targeting the endocannabinoid system in the treatment of fragile X syndrome Nat. Med. 2013 19 603 607 10.1038/nm.3127 23542787 · DOI · Paper page
  150. [169]Saré R.M. Song A. Loutaev I. Cook A. Maita I. Lemons A. Sheeler C. Smith C.B. Negative Effects of Chronic Rapamycin Treatment on Behavior in a Mouse Model of Fragile X Syndrome Front. Mol. Neurosci. 2018 10 452 10.3389/fnmol.2017.00452 29375310 PMC5770365 · DOI
  151. [170]Nobes C.D. Hall A. Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement J. Cell Biol. 1999 144 1235 1244 10.1083/jcb.144.6.1235 10087266 PMC2150589 · DOI
  152. [171]Daniels R.H. Bokoch G.M. p21-activated protein kinase: A crucial component of morphological signaling? Trends Biochem. Sci. 1999 24 350 355 10.1016/S0968-0004(99)01442-5 10470034 · DOI
  153. [172]Zhang K. Wang Y. Fan T. Zeng C. Sun Z.S. The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders Protein Cell 2022 13 6 25 10.1007/s13238-020-00812-9 33306168 PMC8776968 · DOI
  154. [173]Knaus U.G. Bokoch G.M. The p21Rac/Cdc42-activated kinases (PAKs) Int. J. Biochem. Cell Biol. 1998 30 857 862 10.1016/S1357-2725(98)00059-4 9744077 · DOI
  155. [174]Jaffer Z.M. Chernoff J. p21-activated kinases: Three more join the Pak Int. J. Biochem. Cell Biol. 2002 34 713 717 10.1016/S1357-2725(01)00158-3 11950587 · DOI
  156. [175]Rane C.K. Minden A. P21 activated kinases: Structure, regulation, and functions Small GTPases 2014 5 e28003 10.4161/sgtp.28003 24658305 PMC4160339 · DOI
  157. [176]Lei M. Lu W. Meng W. Parrini M.-C. Eck M.J. Mayer B.J. Harrison S.C. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch Cell 2000 102 387 397 10.1016/S0092-8674(00)00043-X 10975528 · DOI
  158. [178]Allen K.M. Gleeson J.G. Bagrodia S. Partington M.W. Macmillan J.C. Cerione R.A. Mulley J.C. Walsh C.A. PAK3 mutation in nonsyndromic X-linked mental retardation Nat. Genet. 1998 20 25 30 10.1038/1675 9731525 · DOI
  159. [179]Hayashi M.L. Shankaranarayana Rao B.S. Seo J.-S. Choi H.-S. Dolan B.M. Choi S.-Y. Sumantra C. Tonegawa S. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice Proc. Natl. Acad. Sci. USA 2007 104 11489 11494 10.1073/pnas.0705003104 17592139 PMC1899186 · DOI · Paper page
  160. [181]Waite K. Eickholt B.J. The neurodevelopmental implications of PI3K signaling Curr. Top. Microbiol. Immunol. 2010 346 245 265 10.1007/82_2010_82 20582530 · DOI
  161. [182]Donahue T.R. Tran L.M. Hill R. Li Y. Kovochich A. Calvopina J.H. Patel S.G. Wu N. Hindoyan A. Farrell J.J. Integrative survival-based molecular profiling of human pancreatic cancer Clin. Cancer Res. 2012 18 1352 1363 10.1158/1078-0432.CCR-11-1539 22261810 PMC3816537 · DOI
  162. [183]Yang J. Nie J. Ma X. Wei Y. Peng Y. Wei X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials Mol. Cancer 2019 18 26 10.1186/s12943-019-0954-x 30782187 PMC6379961 · DOI
  163. [184]Yuan T.L. Cantley L.C. PI3K pathway alterations in cancer: Variations on a theme Oncogene 2008 27 5497 5510 10.1038/onc.2008.245 18794884 PMC3398461 · DOI · Paper page
  164. [185]Shin B.C. Suzuki M. Inukai K. Anai M. Asano T. Takata K. Multiple isoforms of the regulatory subunit for phosphatidylinositol 3-kinase (PI3-kinase) are expressed in neurons in the rat brain Biochem. Biophys. Res. Commun. 1998 246 313 319 10.1006/bbrc.1998.8606 9610355 · DOI
  165. [186]Engelman J.A. Luo J. Cantley L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism Nat. Rev. Genet. 2006 7 606 619 10.1038/nrg1879 16847462 · DOI · Paper page
  166. [187]Rodgers E.E. Theibert A.B. Functions of PI 3-kinase in development of the nervous system Int. J. Dev. Neurosci. 2002 20 187 197 10.1016/S0736-5748(02)00047-3 12175854 · DOI
  167. [189]Carracedo A. Pandolfi P.P. The PTEN–PI3K pathway: Of feedbacks and cross-talks Oncogene 2008 27 5527 5541 10.1038/onc.2008.247 18794886 · DOI
  168. [190]Gross C. Bassell G.J. Excess Protein Synthesis in FXS Patient Lymphoblastoid Cells Can Be Rescued with a p110β-Selective Inhibitor Mol. Med. 2012 18 336 10.2119/molmed.2011.00363 22207187 PMC3356413 · DOI
  169. [191]Ding Q. Sethna F. Wu X.T. Miao Z. Chen P. Zhang Y. Xiao H. Feng W. Feng Y. Li X. Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model Commun. Biol. 2020 3 127 10.1038/s42003-020-0833-4 32179850 PMC7075969 · DOI
  170. [192]Raj N. McEachin Z.T. Harousseau W. Zhou Y. Zhang F. Merritt-Garza M.E. Taliaferro J.M. Kalinowska M. Marro S.G. Hales C.M. Cell-type-specific profiling of human cellular models of fragile X syndrome reveal PI3K-dependent defects in translation and neurogenesis Cell Rep. 2021 35 108991 10.1016/j.celrep.2021.108991 33852833 PMC8133829 · DOI · Paper page
  171. [193]Søberg K. Moen L.V. Skålhegg B.S. Laerdahl J.K. Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms PLoS ONE 2017 12 e0181091 10.1371/journal.pone.0181091 28742821 PMC5526564 · DOI
  172. [194]Ji L. Chauhan V. Flory M.J. Chauhan A. Brain Region–Specific Decrease in the Activity and Expression of Protein Kinase A in the Frontal Cortex of Regressive Autism PLoS ONE 2011 6 e23751 10.1371/journal.pone.0023751 21909354 PMC3166116 · DOI
  173. [195]Sjoberg T.J. Kornev A.P. Taylor S.S. Dissecting the cAMP-inducible allosteric switch in protein kinase A RIα Protein Sci. 2010 19 1213 1221 10.1002/pro.400 20512974 PMC2895245 · DOI
  174. [196]Karege F. Schwald M. Papadimitriou P. Lachausse C. Cissé M. The cAMP-dependent protein kinase A and brain-derived neurotrophic factor expression in lymphoblast cells of bipolar affective disorder J. Affect. Disord. 2004 79 187 192 10.1016/S0165-0327(02)00463-9 15023493 · DOI
  175. [197]Tardito D. Tura G.B. Bocchio L. Bignotti S. Pioli R. Racagni G. Perez J. Abnormal Levels of cAMP-dependent Protein Kinase Regulatory Subunits in Platelets from Schizophrenic Patients Neuropsychopharmacology 2000 23 216 219 10.1016/S0893-133X(99)00161-X 10882848 · DOI
  176. [198]Berry-Kravis E. Huttenlocher P.R. Cyclic AMP metabolism in fragile X syndrome Ann. Neurol. 1992 31 22 26 10.1002/ana.410310105 1371909 · DOI · Paper page
  177. [199]Choi C.H. Schoenfeld B.P. Weisz E.D. Bell A.J. Chambers D.B. Hinchey J. Choi R.J. Hinchey P. Kollaros M. Gertner M.J. PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome J. Neurosci. 2015 35 396 408 10.1523/JNEUROSCI.1356-12.2015 25568131 PMC4287155 · DOI
  178. [200]Androschuk A. He R.X. Weber S. Rosenfelt C. Bolduc F.V. Stress Odorant Sensory Response Dysfunction in Drosophila Fragile X Syndrome Mutants Front. Mol. Neurosci. 2018 11 242 10.3389/fnmol.2018.00242 30135642 PMC6092503 · DOI
  179. [202]Kelley D.J. Davidson R.J. Elliott J.L. Lahvis G.P. Yin J.C.P. Bhattacharyya A. The cyclic AMP cascade is altered in the fragile X nervous system PLoS ONE 2007 2 e931 10.1371/journal.pone.0000931 17895972 PMC1976557 · DOI
  180. [203]Koga K. Liu M.-G. Qiu S. Song Q. O’den G. Chen T. Zhuo M. Cellular/Molecular Impaired Presynaptic Long-Term Potentiation in the Anterior Cingulate Cortex of Fmr1 Knock-out Mice J. Neurosci. 2015 35 2033 2043 10.1523/JNEUROSCI.2644-14.2015 25653361 PMC6705363 · DOI
  181. [204]Sears J.C. Choi W.J. Broadie K. Fragile X Mental Retardation Protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry Neurobiol. Dis. 2019 127 53 64 10.1016/j.nbd.2019.02.004 30771457 PMC6588493 · DOI
  182. [205]Sears J.C. Broadie K. FMRP-PKA Activity Negative Feedback Regulates RNA Binding-Dependent Fibrillation in Brain Learning and Memory Circuitry Cell Rep. 2020 33 108266 10.1016/j.celrep.2020.108266 33053340 PMC7590955 · DOI
  183. [206]Jiang A. Wang L. Lu J.Y.D. Freeman A. Campbell C. Su P. Wong A.H.C. Liu F. Sex Differences in Dopamine Receptor Signaling in Fmr1 Knockout Mice: A Pilot Study Brain Sci. 2021 11 1398 10.3390/brainsci11111398 34827397 PMC8615700 · DOI
  184. [207]Webb B.L.J. Hirst S.J. Giembycz M.A. Protein kinase C isoenzymes: A review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis Br. J. Pharmacol. 2000 130 1433 10.1038/sj.bjp.0703452 10928943 PMC1572212 · DOI
  185. [208]Black A.R. Black J.D. Protein kinase C signaling and cell cycle regulation Front. Immunol. 2012 3 423 10.3389/fimmu.2012.00423 23335926 PMC3547298 · DOI
  186. [209]Mochly-Rosen D. Das K. Grimes K. V Protein kinase C, an elusive therapeutic target? Nat. Rev. Drug Discov. 2012 11 937 957 10.1038/nrd3871 23197040 PMC3760692 · DOI
  187. [210]Zhang W. Xu C. Tu H. Wang Y. Sun Q. Hu P. Hu Y. Rondard P. Liu J. GABA B receptor upregulates fragile X mental retardation protein expression in neurons Sci. Rep. 2015 5 10468 10.1038/srep10468 26020477 PMC4447080 · DOI
  188. [211]Zhao W. Wang J. Song S. Li F. Yuan F. Reduction of α1GABAA receptor mediated by tyrosine kinase C (PKC) phosphorylation in a mouse model of fragile X syndrome Int. J. Clin. Exp. Med. 2015 8 13219 13226 26550246 PMC4612931
  189. [212]Deng P.Y. Klyachko V.A. Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout Mice Cell Rep. 2016 16 3157 3166 10.1016/j.celrep.2016.08.046 27653682 PMC5055130 · DOI
  190. [213]Roberts P.J. Der C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer Oncogene 2007 26 3291 3310 10.1038/sj.onc.1210422 17496923 · DOI · Paper page
  191. [214]Chen R.H. Sarnecki C. Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases Mol. Cell. Biol. 1992 12 915 927 10.1128/MCB.12.3.915-927.1992 1545823 PMC369523 · DOI
  192. [215]Richards S.A. Dreisbach V.C. Murphy L.O. Blenis J. Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1 Mol. Cell. Biol. 2001 21 7470 7480 10.1128/MCB.21.21.7470-7480.2001 11585927 PMC99919 · DOI
  193. [216]Fisher T.L. Blenis J. Evidence for two catalytically active kinase domains in pp90rsk Mol. Cell. Biol. 1996 16 1212 1219 10.1128/MCB.16.3.1212 8622665 PMC231103 · DOI
  194. [217]Bjorbaek C. Zhao Y. Moller D.E. Divergent functional roles for p90rsk kinase domains J. Biol. Chem. 1995 270 18848 18852 10.1074/jbc.270.32.18848 7642538 · DOI
  195. [218]Jensen C.J. Buch M.B. Krag T.O. Hemmings B.A. Gammeltoft S. Frödin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1 J. Biol. Chem. 1999 274 27168 27176 10.1074/jbc.274.38.27168 10480933 · DOI
  196. [219]Sutherland C. Campbell D.G. Cohen P. Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2. Identification of two threonines phosphorylated during activation by mitogen-activated protein kinase Eur. J. Biochem. 1993 212 581 588 10.1111/j.1432-1033.1993.tb17696.x 8444194 · DOI
  197. [220]Marques Pereira P. Schneider A. Pannetier S. Heron D. Hanauer A. Coffin-Lowry syndrome Eur. J. Hum. Genet. 2010 18 627 633 10.1038/ejhg.2009.189 19888300 PMC2987346 · DOI
  198. [221]Sala C. Vicidomini C. Bigi I. Mossa A. Verpelli C. Shank synaptic scaffold proteins: Keys to understanding the pathogenesis of autism and other synaptic disorders J. Neurochem. 2015 135 849 858 10.1111/jnc.13232 26338675 · DOI
  199. [222]Hall M.N. mTOR-what does it do? Transplantation Proceedings Elsevier Amsterdam, The Netherlands 2008 Volume 40 S5 S8 10.1016/J.TRANSPROCEED.2008.10.009 19100909 · DOI
  200. [223]Tavares M.R. Pavan I.C.B. Amaral C.L. Meneguello L. Luchessi A.D. Simabuco F.M. The S6K protein family in health and disease Life Sci. 2015 131 1 10 10.1016/j.lfs.2015.03.001 25818187 · DOI

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Authors
D’Incal, C., Broos, J., Torfs, T., Kooy, R. F., & Vanden Berghe, W.
Affiliations
  • University of Antwerp (BE)
  • Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2022-04-13
Volume
11
Issue
8
Pages
1325
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11081325
PMC
PMC9029738
OpenAlex
W4223902965
Cited by
29
References
255
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 1
FWCI
0.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • FRAXA Research Foundation
  • Universiteit Antwerpen (FFB190208)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
fragile X syndrome, FMRP, kinase inhibitors, phosphatase, autism spectrum disorder, intellectual disability, GABA receptors, Akt, ERK, mTOR, glycogen synthase kinase-3, phosphoproteomics, therapeutic target
MeSH terms
Animals, Autistic Disorder, Fibroblasts, Fragile X Syndrome, Phosphoric Monoester Hydrolases, Glycogen Synthase Kinase 3, Mice, Fragile X Messenger Ribonucleoprotein 1

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