Neuronal insulin signaling and resistance: a balancing act of kinases and phosphatases

in Journal of Endocrinology
Authors:
Medha Sharma Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India

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Yamini Yadav Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India

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Chinmoy Sankar Dey Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India

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https://orcid.org/0000-0003-0667-915X

Correspondence should be addressed to C S Dey: csdey@bioschool.iitd.ac.in

*(M Sharma and Y Yadav contributed equally to this work)

This paper forms part of a themed collection on Insulin Resistance and Type 2 Diabetes Mellitus. The Guest Editors for this collection were Matthias Blüher, Stefan Bornstein and Martin Haluzík.

DOI:
https://doi.org/10.1530/JOE-23-0151
Volume/Issue:
Volume 260: Issue 1
Article Type:
Review Article
Article ID:
e230151
Online Publication Date:
01 Dec 2023
Copyright:
© the author(s) 2023
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Insulin signaling cascade in peripheral insulin-sensitive tissues regulates whole-body glucose metabolism. Any deregulation in this pathway leads to insulin resistance, ultimately leading to metabolic diseases like type 1 diabetes, type 2 diabetes, and obesity. Insulin signaling in the brain has also been studied for many decades and associated with many primary functions like maintenance of synaptic plasticity, regulation of cognition, and circadian rhythm. Importantly, neuronal insulin signaling has also been associated with the regulation of neuronal glucose uptake. Any impairment in neuronal insulin signaling affecting neuronal glucose uptake has been associated with neurodegenerative disorders like Alzheimer’s disease, the process now being termed as type 3 diabetes. Since the criticality lies in proper signaling cascade, determining important points of deregulation is important. In this review, we have discussed some critical points of such deregulation, dividing them into two classes of enzymes: kinases and phosphatases. We have highlighted their individual roles in neuronal insulin signaling, along with their possible implications in neuronal insulin resistance. Future strategies targeting these nodes in neuronal insulin signaling might be helpful in exploring potential therapeutic opportunities to overcome neuronal insulin resistance and related neurodegenerative diseases.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2023
Article ID:
e230151
Article Type:
Review Article
Received Date:
13 May 2023
Accepted Date:
06 Nov 2023
Print Publication Date:
01 Jan 2024
Online Publication Date:
01 Dec 2023
Keywords:
neuronal insulin signaling; neuronal insulin resistance; kinase; phosphatase

  • Abdul-Ghani MA & & DeFronzo RA 2010 Pathogenesis of insulin resistance in skeletal muscle. Journal of Biomedicine and Biotechnology 2010 476279. (https://doi.org/10.1155/2010/476279)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Adeva-Andany MM, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C & & Pazos-García C 2016 Liver glucose metabolism in humans. Bioscience Reports 36 e00416. (https://doi.org/10.1042/BSR20160385)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Andreozzi F, Procopio C, Greco A, Mannino GC, Miele C, Raciti GA, Iadicicco C, Beguinot F, Pontiroli AE & Hribal ML et al. 2011 Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. Diabetologia 54 1879–1887. (https://doi.org/10.1007/s00125-011-2116-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Apolloni S, Parisi C, Pesaresi MG, Rossi S, Carrì MT, Cozzolino M, Volonté C & & D’Ambrosi N 2013 The NADPH oxidase pathway is dysregulated by the P2X7 receptor in the SOD1-G93A microglia model of amyotrophic lateral sclerosis. Journal of Immunology 190 5187–5195. (https://doi.org/10.4049/jimmunol.1203262)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL, et al.2006 Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Human Molecular Genetics 15 273–285. (https://doi.org/10.1093/hmg/ddi443)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bandyopadhyay G, Standaert ML, Galloway L, Moscat J & & Farese RV 1997 Evidence for involvement of protein kinase C (PKC)-zeta and noninvolvement of diacylglycerol-sensitive PKCs in insulin-stimulated glucose transport in L6 myotubes. Endocrinology 138 4721–4731. (https://doi.org/10.1210/endo.138.11.5473)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bandyopadhyay GK, Yu JG, Ofrecio J & & Olefsky JM 2005 Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54 2351–2359. (https://doi.org/10.2337/diabetes.54.8.2351)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bao Z, Duan C, Gong C, Wang L, Shen C, Wang C & & Cui G 2016 Protein phosphatase 1γ regulates the proliferation of human glioma via the NF-κB pathway. Oncology Reports 35 2916–2926. (https://doi.org/10.3892/or.2016.4644)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bashan N, Dorfman K, Tarnovscki T, Harman-Boehm I, Liberty IF, Blüher M, Ovadia S, Maymon-Zilberstein T, Potashnik R, Stumvoll M, et al.2007 Mitogen-activated protein kinases, inhibitory-kappaB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology 148 2955–2962. (https://doi.org/10.1210/en.2006-1369)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bertrand L, Ginion A, Beauloye C, Hebert AD, Guigas B, Hue L & & Vanoverschelde J-L 2006 AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B. American Journal of Physiology. Heart and Circulatory Physiology 291 H239–H250. (https://doi.org/10.1152/ajpheart.01269.2005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bisht B & & Dey CS 2008 Focal adhesion kinase contributes to insulin-induced actin reorganization into a mesh harboring glucose transporter-4 in insulin resistant skeletal muscle cells. BMC Cell Biology 9 48. (https://doi.org/10.1186/1471-2121-9-48)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bisht B, Goel HL & & Dey CS 2007 Focal adhesion kinase regulates insulin resistance in skeletal muscle. Diabetologia 50 1058–1069. (https://doi.org/10.1007/s00125-007-0591-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bisht B, Srinivasan K & & Dey CS 2008 In vivo inhibition of focal adhesion kinase causes insulin resistance. Journal of Physiology 586 3825–3837. (https://doi.org/10.1113/jphysiol.2008.157107)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bokoch GM 2003 Biology of the p21-activated kinases. Annual Review of Biochemistry 72 743–781. (https://doi.org/10.1146/annurev.biochem.72.121801.161742)

  • Boonying W, Joselin A, Huang E, Qu D, Safarpour F, Iyirhiaro GO, Gonzalez YR, Callaghan SM, Slack RS, Figeys D, et al.2019 Pink1 regulates FKBP5 interaction with AKT/PHLPP and protects neurons from neurotoxin stress induced by MPP. Journal of Neurochemistry 150 312–329. (https://doi.org/10.1111/jnc.14683)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, Dani C, Hofman P, Pagès G, Pouysségur J, et al.2005 The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes 54 402–411. (https://doi.org/10.2337/diabetes.54.2.402)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou J-P, Laville M, Le Marchand-Brustel Y, Tanti J-F & & Vidal H 2003 Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52 1319–1325. (https://doi.org/10.2337/diabetes.52.6.1319)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bradley CA, Peineau S, Taghibiglou C, Nicolas CS, Whitcomb DJ, Bortolotto ZA, Kaang B-K, Cho K, Wang YT & & Collingridge GL 2012 A pivotal role of GSK-3 in synaptic plasticity. Frontiers in Molecular Neuroscience 5 13. (https://doi.org/10.3389/fnmol.2012.00013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bright MD, Garner AP & & Ridley AJ 2009 PAK1 and PAK2 have different roles in HGF-induced morphological responses. Cellular Signalling 21 1738–1747. (https://doi.org/10.1016/j.cellsig.2009.07.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Brognard J, Sierecki E, Gao T & & Newton AC 2007 PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Molecular Cell 25 917–931. (https://doi.org/10.1016/j.molcel.2007.02.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Buoso E, Biundo F, Lanni C, Aiello S, Grossi S, Schettini G, Govoni S & & Racchi M 2013 Modulation of Rack-1/PKCβII signalling by soluble AβPPα in SH-SY5Y cells. Current Alzheimer Research 10 697–705. (https://doi.org/10.2174/15672050113109990145)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Burgaya F, Toutant M, Studler J-M, Costa A, Bert ML, Gelman M & & Girault J-A 1997 Alternatively spliced focal adhesion kinase in rat brain with increased autophosphorylation activity. Journal of Biological Chemistry 272 28720–28725. (https://doi.org/10.1074/jbc.272.45.28720)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Callender JA & & Newton AC 2017 Conventional protein kinase C in the brain: 40 years later. Neuronal Signaling 1 NS20160005. (https://doi.org/10.1042/NS20160005)

  • Callender JA, Yang Y, Lordén G, Stephenson NL, Jones AC, Brognard J & & Newton AC 2018 Protein kinase Cα gain-of-function variant in Alzheimer’s disease displays enhanced catalysis by a mechanism that evades down-regulation. PNAS 115 E5497–E5505. (https://doi.org/10.1073/pnas.1805046115)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Caltagarone J, Jing Z & & Bowser R 2007 Focal adhesions regulate Aβ signaling and cell death in Alzheimer’s disease. Biochimica et Biophysica Acta 1772 438–445. (https://doi.org/10.1016/j.bbadis.2006.11.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Carlson CJ, Koterski S, Sciotti RJ, Poccard GB & & Rondinone CM 2003 Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes 52 634–641. (https://doi.org/10.2337/diabetes.52.3.634)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Carroll LS, Williams HJ, Walters J, Kirov G, O’Donovan MC & & Owen MJ 2011 Mutation screening of the 3q29 microdeletion syndrome candidate genes DLG1 and PAK2 in schizophrenia. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 156B 844–849. (https://doi.org/10.1002/ajmg.b.31231)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Charest DL, Mordret G, Harder KW, Jirik F & & Pelech SL 1993 Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1. Molecular and Cellular Biology 13 4679–4690. (https://doi.org/10.1128/mcb.13.8.4679-4690.1993)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen WS, Xu P-Z, Gottlob K, Chen M-L, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, et al.2001 Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene. Genes and Development 15 2203–2208. (https://doi.org/10.1101/gad.913901)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen H-K, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EMC, Orr HT, Botas J, et al.2003 Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113 457–468. (https://doi.org/10.1016/s0092-8674(0300349-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen WS, Peng X-D, Wang Y, Xu P-Z, Chen M-L, Luo Y, Jeon S-M, Coleman K, Haschek WM, Bass J, et al.2009 Leptin deficiency and beta-cell dysfunction underlie type 2 diabetes in compound Akt knockout mice. Molecular and Cellular Biology 29 3151–3162. (https://doi.org/10.1128/MCB.01792-08)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen B, Van Winkle JA, Lyden PD, Brown JH & & Purcell NH 2013 PHLPP1 gene deletion protects the brain from ischemic injury. Journal of Cerebral Blood Flow and Metabolism 33 196–204. (https://doi.org/10.1038/jcbfm.2012.150)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cheung AT, Wang J, Ree D, Kolls JK & & Bryer-Ash M 2000 Tumor necrosis factor-alpha induces hepatic insulin resistance in obese Zucker (fa/fa) rats via interaction of leukocyte antigen-related tyrosine phosphatase with focal adhesion kinase. Diabetes 49 810–819. (https://doi.org/10.2337/diabetes.49.5.810)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cho H, Thorvaldsen JL, Chu Q, Feng F & & Birnbaum MJ 2001 Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. Journal of Biological Chemistry 276 38349–38352. (https://doi.org/10.1074/jbc.C100462200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chung YH, Joo KM, Lim HC, Cho MH, Kim D, Lee WB & & Cha CI 2005 Immunohistochemical study on the distribution of phosphorylated extracellular signal-regulated kinase (ERK) in the central nervous system of SOD1G93A transgenic mice. Brain Research 1050 203–209. (https://doi.org/10.1016/j.brainres.2005.05.060)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LGD, Clements M, Al-Qassab H, Heffron H & Xu AW et al. 2007 AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. Journal of Clinical Investigation 117 2325–2336. (https://doi.org/10.1172/JCI31516)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cleasby ME, Reinten TA, Cooney GJ, James DE & & Kraegen EW 2007 Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Molecular Endocrinology 21 215–228. (https://doi.org/10.1210/me.2006-0154)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Colin E, Régulier E, Perrin V, Dürr A, Brice A, Aebischer P, Déglon N, Humbert S & & Saudou F 2005 Akt is altered in an animal model of Huntington’s disease and in patients. European Journal of Neuroscience 21 1478–1488. (https://doi.org/10.1111/j.1460-9568.2005.03985.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Comerford KM, Leonard MO, Cummins EP, Fitzgerald KT, Beullens M, Bollen M & & Taylor CT 2006 Regulation of protein phosphatase 1gamma activity in hypoxia through increased interaction with NIPP1: implications for cellular metabolism. Journal of Cellular Physiology 209 211–218. (https://doi.org/10.1002/jcp.20726)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cozzone D, Fröjdö S, Disse E, Debard C, Laville M, Pirola L & & Vidal H 2008 Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients. Diabetologia 51 512–521. (https://doi.org/10.1007/s00125-007-0913-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Crary JF, Shao CY, Mirra SS, Hernandez AI & & Sacktor TC 2006 Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease. Journal of Neuropathology and Experimental Neurology 65 319–326. (https://doi.org/10.1097/01.jnen.0000218442.07664.04)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Crews CM, Alessandrini A & & Erikson RL 1992 The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258 478–480. (https://doi.org/10.1126/science.1411546)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • da Cruz e Silva EF, Fox CA, Ouimet CC, Gustafson E, Watson SJ & & Greengard P 1995 Differential expression of protein phosphatase 1 isoforms in mammalian brain. Journal of Neuroscience 15 3375–3389. (https://doi.org/10.1523/JNEUROSCI.15-05-03375.1995)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Culmsee C, Monnig J, Kemp BE & Mattson MP 2001 AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. Journal of Molecular Neuroscience  17 45–58. (https://doi.org/10.1385/JMN:17:1:45)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR & & Mandarino LJ 2000 Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. Journal of Clinical Investigation 105 311–320. (https://doi.org/10.1172/JCI7535)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Das AK, Helps NR, Cohen PT & & Barford D 1996 Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 a resolution. EMBO Journal 15 6798–6809. (https://doi.org/10.1002/j.1460-2075.1996.tb01071.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • de la Monte SM & & Wands JR 2008 Alzheimer’s disease is Type 3 diabetes–evidence reviewed. Journal of Diabetes Science and Technology 2 1101–1113. (https://doi.org/10.1177/193229680800200619)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Díaz González M, Buberman A, Morales M, Ferrer I & & Knafo S 2021 Aberrant synaptic PTEN in symptomatic Alzheimer’s patients may link synaptic depression to network failure. Frontiers in Synaptic Neuroscience 13 683290. (https://doi.org/10.3389/fnsyn.2021.683290)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Diez H, Garrido JJ & & Wandosell F 2012 Specific Roles of Akt iso Forms in Apoptosis and Axon Growth Regulation in Neurons. PLoS One 7 e32715. (https://doi.org/10.1371/journal.pone.0032715)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dourlen P, Fernandez-Gomez FJ, Dupont C, Grenier-Boley B, Bellenguez C, Obriot H, Caillierez R, Sottejeau Y, Chapuis J, Bretteville A, et al.2017 Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology. Molecular Psychiatry 22 874–883. (https://doi.org/10.1038/mp.2016.59)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Draffin JE, Sánchez-Castillo C, Fernández-Rodrigo A, Sánchez-Sáez X, Ávila J, Wagner FF & & Esteban JA 2021 GSK3α, not GSK3β, drives hippocampal NMDAR-dependent LTD via tau-mediated spine anchoring. EMBO Journal 40 e105513. (https://doi.org/10.15252/embj.2020105513)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dummler B, Tschopp O, Hynx D, Yang Z-Z, Dirnhofer S & & Hemmings BA 2006 Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Molecular and Cellular Biology 26 8042–8051. (https://doi.org/10.1128/MCB.00722-06)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dunning CJ, McGauran G, Willén K, Gouras GK, O’Connell DJ & & Linse S 2015 Direct high affinity interaction between Aβ42 and GSK3α stimulates hyperphosphorylation of tau: a new molecular link in Alzheimer’s disease? ACS Chemical Neuroscience 7 161–170. (https://doi.org/10.1021/acschemneuro.5b00262)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Eldar-Finkelman H, Argast GM, Foord O, Fischer EH & & Krebs EG 1996 Expression and characterization of glycogen synthase kinase-3 mutants and their effect on glycogen synthase activity in intact cells. PNAS 93 10228–10233. (https://doi.org/10.1073/pnas.93.19.10228)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M & & Gogos JA 2004 Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nature Genetics 36 131–137. (https://doi.org/10.1038/ng1296)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M & Zarrabi A et al. 2022 AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: a pre-clinical and clinical investigation. Biomedicine & Pharmacotherapy 146 112563. (https://doi.org/10.1016/j.biopha.2021.112563)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Farese RV, Standaert ML, Ishizuka T, Yu B, Hernandez H, Waldron C, Watson J, Farese JP, Cooper DR & & Wickstrom E 1991 Antisense DNA downregulates protein kinase C isozymes (beta and alpha) and insulin-stimulated 2-deoxyglucose uptake in rat adipocytes. Antisense Research and Development 1 35–42. (https://doi.org/10.1089/ard.1991.1.35)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ferrer I, Blanco R, Carmona M, Ribera R, Goutan E, Puig B, Rey MJ, Cardozo A, Viñals F & & Ribalta T 2001 Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. Brain Pathology 11 144–158. (https://doi.org/10.1111/j.1750-3639.2001.tb00387.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Furlong RM, Lindsay A, Anderson KE, Hawkins PT, Sullivan AM & & O’Neill C 2019 The Parkinson’s disease gene PINK1 activates Akt via PINK1 kinase-dependent regulation of the phospholipid PI(3,4,5)P3. Journal of Cell Science 132 jcs233221. (https://doi.org/10.1242/jcs.233221)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gabbouj S, Natunen T, Koivisto H, Jokivarsi K, Takalo M, Marttinen M, Wittrahm R, Kemppainen S, Naderi R, Posado-Fernández A, et al.2019a Intranasal insulin activates Akt2 signaling pathway in the hippocampus of wild-type but not in APP/PS1 Alzheimer model mice. Neurobiology of Aging 75 98–108. (https://doi.org/10.1016/j.neurobiolaging.2018.11.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gabbouj S, Ryhänen S, Marttinen M, Wittrahm R, Takalo M, Kemppainen S, Martiskainen H, Tanila H, Haapasalo A, Hiltunen M, et al.2019b Altered insulin signaling in Alzheimer’s disease brain – special emphasis on PI3K-Akt pathway. Frontiers in Neuroscience 13 629. (https://doi.org/10.3389/fnins.2019.00629)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gao T, Furnari F & & Newton AC 2005 PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Molecular Cell 18 13–24. (https://doi.org/10.1016/j.molcel.2005.03.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gao T, Brognard J & & Newton AC 2008 The phosphatase PHLPP controls the cellular levels of protein kinase C. Journal of Biological Chemistry 283 6300–6311. (https://doi.org/10.1074/jbc.M707319200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gauron MC, Lorden G, Prokopenko D, Tanzi R & & Newton A 2022 Novel PKC signaling in Alzheimer’s disease. FASEB Journal 36. (https://doi.org/10.1096/fasebj.2022.36.S1.R3731)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Giraud J, Haas M, Feener EP, Copps KD, Dong X, Dunn SL & & White MF 2007 Phosphorylation of Irs1 at SER-522 inhibits insulin signaling. Molecular Endocrinology 21 2294–2302. (https://doi.org/10.1210/me.2007-0159)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Goel HL & & Dey CS 2002 Insulin stimulates spreading of skeletal muscle cells involving the activation of focal adhesion kinase, phosphatidylinositol 3-kinase and extracellular signal regulated kinases. Journal of Cellular Physiology 193 187–198. (https://doi.org/10.1002/jcp.10161)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gonzalez E & & McGraw TE 2009 The Akt kinases: isoform specificity in metabolism and cancer. Cell Cycle 8 2502–2508. (https://doi.org/10.4161/cc.8.16.9335)

  • Grace EA & & Busciglio J 2003 Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy. Journal of Neuroscience 23 493–502. (https://doi.org/10.1523/JNEUROSCI.23-02-00493.2003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Greco SJ, Sarkar S, Johnston JM & & Tezapsidis N 2009 Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. Biochemical and Biophysical Research Communications 380 98–104. (https://doi.org/10.1016/j.bbrc.2009.01.041)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Greco SJ, Hamzelou A, Johnston JM, Smith MA, Ashford JW & & Tezapsidis N 2011 Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons. Biochemical and Biophysical Research Communications 414 170–174. (https://doi.org/10.1016/j.bbrc.2011.09.050)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Grinder-Hansen L, Ribel-Madsen R, Wojtaszewski JFP, Poulsen P, Grunnet LG & & Vaag A 2016 A common variation of the PTEN gene is associated with peripheral insulin resistance. Diabetes & Metabolism 42 280–284. (https://doi.org/10.1016/j.diabet.2016.03.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gupta A & & Dey CS 2009 PTEN and SHIP2 regulates PI3K/Akt pathway through focal adhesion kinase. Molecular and Cellular Endocrinology 309 55–62. (https://doi.org/10.1016/j.mce.2009.05.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gupta A & & Dey CS 2012 PTEN, a widely known negative regulator of insulin/PI3K signaling, positively regulates neuronal insulin resistance. Molecular Biology of the Cell 23 3882–3898. (https://doi.org/10.1091/mbc.E12-05-0337)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gupta A, Bisht B & & Dey CS 2011 Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology 60 910–920. (https://doi.org/10.1016/j.neuropharm.2011.01.033)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gupta A, Bisht B & & Dey CS 2012 Focal adhesion kinase negatively regulates neuronal insulin resistance. Biochimica et Biophysica Acta 1822 1030–1037. (https://doi.org/10.1016/j.bbadis.2012.02.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hardie DG, Ross FA & & Hawley SA 2012 AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Reviews. Molecular Cell Biology 13 251–262. (https://doi.org/10.1038/nrm3311)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Heide LPVD, Hoekman MF, Biessels GJ & & Gispen WH 2003 Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3-kinase (PI3) kinase-dependent manner in Neuro2a cells. Journal of Neurochemistry 86 86–91. (https://doi.org/10.1046/j.1471-4159.2003.01828.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Himmelstein DS, Ward SM, Lancia JK, Patterson KR & & Binder LI 2012 Tau as a therapeutic target in neurodegenerative disease. Pharmacology and Therapeutics 136 8–22. (https://doi.org/10.1016/j.pharmthera.2012.07.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O & & Woodgett JR 2000 Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406 86–90. (https://doi.org/10.1038/35017574)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hough C, Radu M & & Doré JJE 2012 TGF-beta induced Erk phosphorylation of Smad linker region regulates Smad signaling. PLoS One 7 e42513. (https://doi.org/10.1371/journal.pone.0042513)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hribal ML, Mancuso E, Arcidiacono GP, Greco A, Musca D, Procopio T, Ruffo M & & Sesti G 2020 The phosphatase PHLPP2 plays a key role in the regulation of pancreatic beta-cell survival. International Journal of Endocrinology 2020 e1027386. (https://doi.org/10.1155/2020/1027386)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huang D, Cheung AT, Parsons JT & & Bryer-Ash M 2002 Focal adhesion kinase (FAK) regulates insulin-stimulated glycogen synthesis in hepatocytes. Journal of Biological Chemistry 277 18151–18160. (https://doi.org/10.1074/jbc.M104252200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huang D, Khoe M, Ilic D & & Bryer-Ash M 2006 Reduced expression of focal adhesion kinase disrupts insulin action in skeletal muscle cells. Endocrinology 147 3333–3343. (https://doi.org/10.1210/en.2005-0382)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Humbert S, Bryson EA, Cordelières FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME & & Saudou F 2002 The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves huntingtin phosphorylation by Akt. Developmental Cell 2 831–837. (https://doi.org/10.1016/S1534-5807(0200188-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hurtado DE, Molina-Porcel L, Carroll JC, Macdonald C, Aboagye AK, Trojanowski JQ & & Lee VM-Y 2012 Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models of Alzheimer’s disease. Journal of Neuroscience 32 7392–7402. (https://doi.org/10.1523/JNEUROSCI.0889-12.2012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R, et al.2006 Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metabolism 3 267–275. (https://doi.org/10.1016/j.cmet.2006.02.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Iqbal K, Liu F & & Gong C-X 2016 Tau and neurodegenerative disease: the story so far. Nature Reviews. Neurology 12 15–27. (https://doi.org/10.1038/nrneurol.2015.225)

  • Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q & & Czech MP 2003 Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. PNAS 100 7569–7574. (https://doi.org/10.1073/pnas.1332633100)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jope RS, Yuskaitis CJ & & Beurel E 2007 Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochemical Research 32 577–595. (https://doi.org/10.1007/s11064-006-9128-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kahn BB 2019 Adipose tissue, inter-organ communication, and the path to Type 2 diabetes: the 2016 Banting medal for scientific achievement lecture. Diabetes 68 3–14. (https://doi.org/10.2337/dbi18-0035)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kaidanovich-Beilin O & & Eldar-Finkelman H 2006 Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. Journal of Pharmacology and Experimental Therapeutics 316 17–24. (https://doi.org/10.1124/jpet.105.090266)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kajno E, McGraw TE & & Gonzalez E 2015 Development of a new model system to dissect isoform specific Akt signalling in adipocytes. Biochemical Journal 468 425–434. (https://doi.org/10.1042/BJ20150191)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Khurana A & & Dey CS 2002 Subtype specific roles of mitogen activated protein kinases in L6E9 skeletal muscle cell differentiation. Molecular and Cellular Biochemistry 238 27–39. (https://doi.org/10.1023/a:1019957602038)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Khurana A & & Dey CS 2004 Involvement of c-Jun N-terminal kinase activities in skeletal muscle differentiation. Journal of Muscle Research and Cell Motility 25 645–655. (https://doi.org/10.1007/s10974-004-7099-1)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim K, Ryu D, Dongiovanni P, Ozcan L, Nayak S, Ueberheide B, Valenti L, Auwerx J & & Pajvani UB 2017 Degradation of PHLPP2 by KCTD17, via a glucagon-dependent pathway, promotes hepatic steatosis. Gastroenterology 153 1568-1580.e10. (https://doi.org/10.1053/j.gastro.2017.08.039)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kim K, Kang JK, Jung YH, Lee SB, Rametta R, Dongiovanni P, Valenti L & & Pajvani UB 2021 Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver. Nature Communications 12 1822. (https://doi.org/10.1038/s41467-021-22106-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kimura T, Suzuki A, Fujita Y, Yomogida K, Lomeli H, Asada N, Ikeuchi M, Nagy A, Mak TW & & Nakano T 2003 Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development 130 1691–1700. (https://doi.org/10.1242/dev.00392)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Knafo S, Sánchez-Puelles C, Palomer E, Delgado I, Draffin JE, Mingo J, Wahle T, Kaleka K, Mou L, Pereda-Perez I, et al.2016 PTEN recruitment controls synaptic and cognitive function in Alzheimer’s models. Nature Neuroscience 19 443–453. (https://doi.org/10.1038/nn.4225)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kovacic S, Soltys C-LM, Barr AJ, Shiojima I, Walsh K & & Dyck JRB 2003 Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. Journal of Biological Chemistry 278 39422–39427. (https://doi.org/10.1074/jbc.M305371200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Krook A, Björnholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, Wallberg-Henriksson H & & Zierath JR 2000 Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49 284–292. (https://doi.org/10.2337/diabetes.49.2.284)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kumar S, Sieghart W & & Morrow AL 2002 Association of protein kinase C with GABA(A) receptors containing alpha1 and alpha4 subunits in the cerebral cortex: selective effects of chronic ethanol consumption. Journal of Neurochemistry 82 110–117. (https://doi.org/10.1046/j.1471-4159.2002.00943.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lachén-Montes M, González-Morales A, de Morentin XM, Pérez-Valderrama E, Ausín K, Zelaya MV, Serna A, Aso E, Ferrer I, Fernández-Irigoyen J, et al.2016 An early dysregulation of FAK and MEK/ERK signaling pathways precedes the β-amyloid deposition in the olfactory bulb of APP/PS1 mouse model of Alzheimer’s disease. Journal of Proteomics 148 149–158. (https://doi.org/10.1016/j.jprot.2016.07.032)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lalatsa A, Sun Y, Gamboa JI & & Knafo S 2020 Preformulation studies of a stable PTEN-PDZ lipopeptide able to cross an in vitro blood-brain-barrier model as a potential therapy for Alzheimer’s disease. Pharmaceutical Research 37 183. (https://doi.org/10.1007/s11095-020-02915-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lammers T & & Lavi S 2007 Role of type 2C protein phosphatases in growth regulation and in cellular stress signaling. Critical Reviews in Biochemistry and Molecular Biology 42 437–461. (https://doi.org/10.1080/10409230701693342)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lauterborn JC, Cox CD, Chan SW, Vanderklish PW, Lynch G & & Gall CM 2020 Synaptic actin stabilization protein loss in down syndrome and Alzheimer disease. Brain Pathology 30 319–331. (https://doi.org/10.1111/bpa.12779)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lawrence JC & & Roach PJ 1997 New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46 541–547. (https://doi.org/10.2337/diab.46.4.541)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lee FHF, Kaidanovich-Beilin O, Roder JC, Woodgett JR & & Wong AHC 2011 Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice. Schizophrenia Research 129 74–79. (https://doi.org/10.1016/j.schres.2011.03.032)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Leng Y, Steiler TL & & Zierath JR 2004 Effects of insulin, contraction, and phorbol esters on mitogen-activated protein kinase signaling in skeletal muscle from lean and ob/ob mice. Diabetes 53 1436–1444. (https://doi.org/10.2337/diabetes.53.6.1436)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Leroy K, Boutajangout A, Authelet M, Woodgett JR, Anderton BH & & Brion J-P 2002 The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer’s disease. Acta Neuropathologica 103 91–99. (https://doi.org/10.1007/s004010100435)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Levenga J, Wong H, Milstead RA, Keller BN, LaPlante LE & & Hoeffer CA 2017 AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity. eLife 6. (https://doi.org/10.7554/eLife.30640)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu Y, Qin L, Li G, Zhang W, An L, Liu B & & Hong J-S 2003a Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. Journal of Pharmacology and Experimental Therapeutics 305 212–218. (https://doi.org/10.1124/jpet.102.043166)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu F, Su Y, Li B & & Ni B 2003b Regulation of amyloid precursor protein expression and secretion via activation of ERK1/2 by hepatocyte growth factor in HEK293 cells transfected with APP751. Experimental Cell Research 287 387–396. (https://doi.org/10.1016/s0014-4827(0300152-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu A, Zhu Y, Chen W, Merlino G & & Yu Y 2022 PTEN dual lipid- and protein-phosphatase function in tumor progression. Cancers 14 3666. (https://doi.org/10.3390/cancers14153666)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lordén G, Wozniak JM, Doré K, Dozier LE, Cates-Gatto C, Patrick GN, Gonzalez DJ, Roberts AJ, Tanzi RE & & Newton AC 2022 Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model. Nature Communications 13 7200. (https://doi.org/10.1038/s41467-022-34679-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ma Q-L, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, Beech W, Frautschy SA & & Cole GM 2008 P21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. Journal of Biological Chemistry 283 14132–14143. (https://doi.org/10.1074/jbc.M708034200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • MacAulay K, Doble BW, Patel S, Hansotia T, Sinclair EM, Drucker DJ, Nagy A & & Woodgett JR 2007 Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism. Cell Metabolism 6 329–337. (https://doi.org/10.1016/j.cmet.2007.08.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Maesako M, Uemura K, Kubota M, Hiyoshi K, Ando K, Kuzuya A, Kihara T, Asada M, Akiyama H & & Kinoshita A 2011 Effect of glycogen synthase kinase 3 β-mediated presenilin 1 phosphorylation on amyloid β production is negatively regulated by insulin receptor cleavage. Neuroscience 177 298–307. (https://doi.org/10.1016/j.neuroscience.2010.12.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mallick A, Sharma M & & Dey CS 2022 Emerging roles of PHLPP phosphatases in the nervous system. Molecular and Cellular Neurosciences 123 103789. (https://doi.org/10.1016/j.mcn.2022.103789)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Masliah E, Mallory M, Hansen L, Alford M, Albright T, DeTeresa R, Terry R, Baudier J & & Saitoh T 1991 Patterns of aberrant sprouting in Alzheimer’s disease. Neuron 6 729–739. (https://doi.org/10.1016/0896-6273(9190170-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Masson GR & & Williams RL 2020 Structural mechanisms of PTEN regulation. Cold Spring Harbor Perspectives in Medicine 10 a036152. (https://doi.org/10.1101/cshperspect.a036152)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Maurin H, Lechat B, Dewachter I, Ris L, Louis JV, Borghgraef P, Devijver H, Jaworski T & & Van Leuven F 2013 Neurological characterization of mice deficient in GSK3α highlight pleiotropic physiological functions in cognition and pathological activity as Tau kinase. Molecular Brain 6 27. (https://doi.org/10.1186/1756-6606-6-27)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McGowan CH & & Cohen P 1988 [39] Protein phosphatase-2C from rabbit skeletal muscle and liver: an Mg2+-dependent enzyme. Methods in Enzymology 159 416–426. (https://doi.org/10.1016/0076-6879(8859041-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R & & Alessi DR 2005 Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO Journal 24 1571–1583. (https://doi.org/10.1038/sj.emboj.7600633)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N, Nuzzo CMA, Vaccaro V, Vari S, Cognetti F, et al.2015 PTEN: multiple functions in human malignant tumors. Frontiers in Oncology 5 24.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mishra D & & Dey CS 2019 Protein kinase C attenuates insulin signalling cascade in insulin-sensitive and insulin-resistant Neuro-2a cells. Journal of Molecular Neuroscience 69 470–477. (https://doi.org/10.1007/s12031-019-01377-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mishra D & & Dey CS 2021 PKCα: prospects in regulating insulin resistance and AD. Trends in Endocrinology and Metabolism 32 341–350. (https://doi.org/10.1016/j.tem.2021.03.006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mishra D, Reddy I & & Dey CS 2023 PKCα isoform inhibits insulin signaling and aggravates neuronal insulin resistance. Molecular Neurobiology 60 6642–6659. (https://doi.org/10.1007/s12035-023-03486-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Miyamoto S, Purcell NH, Smith JM, Gao T, Whittaker R, Huang K, Castillo R, Glembotski CC, Sussman MA & Newton ACet al. 2010 PHLPP-1 negatively regulates Akt activity and survival in the heart. Circulation Research 107 476–484. (https://doi.org/10.1161/CIRCRESAHA.109.215020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moc C, Taylor AE, Chesini GP, Zambrano CM, Barlow MS, Zhang X, Gustafsson ÅB & & Purcell NH 2015 Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy. Cardiovascular Research 105 160–170. (https://doi.org/10.1093/cvr/cvu243)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morales-Garcia JA, Luna-Medina R, Alonso-Gil S, Sanz-Sancristobal M, Palomo V, Gil C, Santos A, Martinez A & & Perez-Castillo A 2012 Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo. ACS Chemical Neuroscience 3 963–971. (https://doi.org/10.1021/cn300110c)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, Ávila J & & Llorens-Martín M 2019 Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature Medicine 25 554–560. (https://doi.org/10.1038/s41591-019-0375-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Müller G, Wied S & & Frick W 2000 Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes. Molecular and Cellular Biology 20 4708–4723. (https://doi.org/10.1128/MCB.20.13.4708-4723.2000)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Murphy LO & & Blenis J 2006 MAPK signal specificity: the right place at the right time. Trends in Biochemical Sciences 31 268–275. (https://doi.org/10.1016/j.tibs.2006.03.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R & & Tonks NK 1997 P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. PNAS 94 9052–9057. (https://doi.org/10.1073/pnas.94.17.9052)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Newton AC 2018 Protein kinase C: perfectly balanced. Critical Reviews in Biochemistry and Molecular Biology 53 208–230. (https://doi.org/10.1080/10409238.2018.1442408)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nguyen T-VV, Galvan V, Huang W, Banwait S, Tang H, Zhang J & & Bredesen DE 2008 Signal transduction in Alzheimer disease: p21-activated kinase signaling requires C-terminal cleavage of APP at Asp664. Journal of Neurochemistry 104 1065–1080. (https://doi.org/10.1111/j.1471-4159.2007.05031.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L & & Henry RR 2000 Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49 263–271. (https://doi.org/10.2337/diabetes.49.2.263)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nitsche C, Edderkaoui M, Moore RM, Eibl G, Kasahara N, Treger J, Grippo PJ, Mayerle J, Lerch MM & & Gukovskaya AS 2012 The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 142 377–87.e1. (https://doi.org/10.1053/j.gastro.2011.10.026)