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Biochem J. Dec 15, 1996; 320(Pt 3): 957–963.
PMCID: PMC1218021

Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism.

Abstract

Secretory cleavage of the amyloid precursor protein (APP), a process that releases soluble APP derivatives (APPs) into the extracellular space, is stimulated by the activation of muscarinic receptors coupled to phosphoinositide hydrolysis. The signalling pathways involved in the release process exhibit both protein kinase C- and protein tyrosine phosphorylation-dependent components [Slack, Breu, Petryniak, Srivastava and Wurtman (1995) J. Biol. Chem. 270, 8337-8344]. The possibility that elevations in intracellular Ca2+ concentration initiate the tyrosine phosphorylation-dependent release of APPs was examined in human embryonic kidney cells expressing muscarinic m3 receptors. Inhibition of protein kinase C with the bisindolylmaleimide GF 109203X decreased the carbachol-evoked release of APPs by approx. 30%, as shown previously. The residual response was further decreased, in an additive manner, by the Ca2+ chelator EGTA, or by the tyrosine kinase inhibitor tyrphostin A25. The Ca2+ ionophore, ionomycin, like carbachol, stimulated both the release of APPs and the tyrosine phosphorylation of several proteins, one of which was identified as paxillin, a component of focal adhesions. The effects of ionomycin on APPs release and on protein tyrosine phosphorylation were concentration-dependent, and occurred over similar concentration ranges; both effects were inhibited only partly by GF 109203X, but were abolished by EGTA or by tyrosine kinase inhibitors. The results demonstrate for the first time that ionophore-induced elevations in intracellular Ca2+ levels elicit APPs release via increased tyrosine phosphorylation. Part of the increase in APPs release evoked by muscarinic receptor activation might be attributable to a similar mechanism.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Weidemann A, König G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 1989 Apr 7;57(1):115–126. [PubMed]
  • Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990 Jun 1;248(4959):1122–1124. [PubMed]
  • Sisodia SS, Koo EH, Beyreuther K, Unterbeck A, Price DL. Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing. Science. 1990 Apr 27;248(4954):492–495. [PubMed]
  • Wang R, Meschia JF, Cotter RJ, Sisodia SS. Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells. J Biol Chem. 1991 Sep 5;266(25):16960–16964. [PubMed]
  • Estus S, Golde TE, Kunishita T, Blades D, Lowery D, Eisen M, Usiak M, Qu XM, Tabira T, Greenberg BD, et al. Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science. 1992 Feb 7;255(5045):726–728. [PubMed]
  • Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature. 1992 Jun 11;357(6378):500–503. [PubMed]
  • Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science. 1992 Feb 7;255(5045):728–730. [PubMed]
  • Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, et al. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992 Sep 24;359(6393):322–325. [PubMed]
  • Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, et al. Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature. 1992 Sep 24;359(6393):325–327. [PubMed]
  • Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992 Oct 2;258(5079):126–129. [PubMed]
  • Buxbaum JD, Koo EH, Greengard P. Protein phosphorylation inhibits production of Alzheimer amyloid beta/A4 peptide. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9195–9198. [PMC free article] [PubMed]
  • Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ. Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem. 1993 Nov 5;268(31):22959–22962. [PubMed]
  • Gabuzda D, Busciglio J, Yankner BA. Inhibition of beta-amyloid production by activation of protein kinase C. J Neurochem. 1993 Dec;61(6):2326–2329. [PubMed]
  • Fuller SJ, Storey E, Li QX, Smith AI, Beyreuther K, Masters CL. Intracellular production of beta A4 amyloid of Alzheimer's disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein. Biochemistry. 1995 Jun 27;34(25):8091–8098. [PubMed]
  • Mattson MP, Barger SW, Cheng B, Lieberburg I, Smith-Swintosky VL, Rydel RE. beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease. Trends Neurosci. 1993 Oct;16(10):409–414. [PubMed]
  • Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I, Rydel RE. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron. 1993 Feb;10(2):243–254. [PubMed]
  • Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992 Oct 9;258(5080):304–307. [PubMed]
  • Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10075–10078. [PMC free article] [PubMed]
  • Wolf BA, Wertkin AM, Jolly YC, Yasuda RP, Wolfe BB, Konrad RJ, Manning D, Ravi S, Williamson JR, Lee VM. Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J Biol Chem. 1995 Mar 3;270(9):4916–4922. [PubMed]
  • Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science. 1992 Oct 23;258(5082):607–614. [PubMed]
  • Caporaso GL, Gandy SE, Buxbaum JD, Ramabhadran TV, Greengard P. Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3055–3059. [PMC free article] [PubMed]
  • Gillespie SL, Golde TE, Younkin SG. Secretory processing of the Alzheimer amyloid beta/A4 protein precursor is increased by protein phosphorylation. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1285–1290. [PubMed]
  • Slack BE, Nitsch RM, Livneh E, Kunz GM, Jr, Breu J, Eldar H, Wurtman RJ. Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C alpha. J Biol Chem. 1993 Oct 5;268(28):21097–21101. [PubMed]
  • Slack BE, Breu J, Petryniak MA, Srivastava K, Wurtman RJ. Tyrosine phosphorylation-dependent stimulation of amyloid precursor protein secretion by the m3 muscarinic acetylcholine receptor. J Biol Chem. 1995 Apr 7;270(14):8337–8344. [PubMed]
  • Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4489–4493. [PMC free article] [PubMed]
  • Yeo EJ, Exton JH. Stimulation of phospholipase D by epidermal growth factor requires protein kinase C activation in Swiss 3T3 cells. J Biol Chem. 1995 Feb 24;270(8):3980–3988. [PubMed]
  • Olivier AR, Parker PJ. Identification of multiple PKC isoforms in Swiss 3T3 cells: differential down-regulation by phorbol ester. J Cell Physiol. 1992 Aug;152(2):240–244. [PubMed]
  • Gusovsky F, Lueders JE, Kohn EC, Felder CC. Muscarinic receptor-mediated tyrosine phosphorylation of phospholipase C-gamma. An alternative mechanism for cholinergic-induced phosphoinositide breakdown. J Biol Chem. 1993 Apr 15;268(11):7768–7772. [PubMed]
  • Felder CC, MacArthur L, Ma AL, Gusovsky F, Kohn EC. Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1706–1710. [PMC free article] [PubMed]
  • Slunt HH, Thinakaran G, Von Koch C, Lo AC, Tanzi RE, Sisodia SS. Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). J Biol Chem. 1994 Jan 28;269(4):2637–2644. [PubMed]
  • Peralta EG, Ashkenazi A, Winslow JW, Ramachandran J, Capon DJ. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature. 1988 Aug 4;334(6181):434–437. [PubMed]
  • Sandmann J, Peralta EG, Wurtman RJ. Coupling of transfected muscarinic acetylcholine receptor subtypes to phospholipase D. J Biol Chem. 1991 Apr 5;266(10):6031–6034. [PubMed]
  • da Cruz e Silva OA, Iverfeldt K, Oltersdorf T, Sinha S, Lieberburg I, Ramabhadran TV, Suzuki T, Sisodia SS, Gandy S, Greengard P. Regulated cleavage of Alzheimer beta-amyloid precursor protein in the absence of the cytoplasmic tail. Neuroscience. 1993 Dec;57(4):873–877. [PubMed]
  • Hung AY, Selkoe DJ. Selective ectodomain phosphorylation and regulated cleavage of beta-amyloid precursor protein. EMBO J. 1994 Feb 1;13(3):534–542. [PMC free article] [PubMed]
  • Schmidt M, Hüwe SM, Fasselt B, Homann D, Rümenapp U, Sandmann J, Jakobs KH. Mechanisms of phospholipase D stimulation by m3 muscarinic acetylcholine receptors. Evidence for involvement of tyrosine phosphorylation. Eur J Biochem. 1994 Oct 15;225(2):667–675. [PubMed]
  • Querfurth HW, Selkoe DJ. Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry. 1994 Apr 19;33(15):4550–4561. [PubMed]
  • Vostal JG, Jackson WL, Shulman NR. Cytosolic and stored calcium antagonistically control tyrosine phosphorylation of specific platelet proteins. J Biol Chem. 1991 Sep 5;266(25):16911–16916. [PubMed]
  • Tepel M, Kühnapfel S, Theilmeier G, Teupe C, Schlotmann R, Zidek W. Filling state of intracellular Ca2+ pools triggers trans plasma membrane Na+ and Ca2+ influx by a tyrosine kinase-dependent pathway. J Biol Chem. 1994 Oct 21;269(42):26239–26242. [PubMed]
  • Sargeant P, Farndale RW, Sage SO. ADP- and thapsigargin-evoked Ca2+ entry and protein-tyrosine phosphorylation are inhibited by the tyrosine kinase inhibitors genistein and methyl-2,5-dihydroxycinnamate in fura-2-loaded human platelets. J Biol Chem. 1993 Aug 25;268(24):18151–18156. [PubMed]
  • Lee KM, Toscas K, Villereal ML. Inhibition of bradykinin- and thapsigargin-induced Ca2+ entry by tyrosine kinase inhibitors. J Biol Chem. 1993 May 15;268(14):9945–9948. [PubMed]
  • Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. [PubMed]
  • Soltoff SP, Toker A. Carbachol, substance P, and phorbol ester promote the tyrosine phosphorylation of protein kinase C delta in salivary gland epithelial cells. J Biol Chem. 1995 Jun 2;270(22):13490–13495. [PubMed]
  • Jockusch BM, Bubeck P, Giehl K, Kroemker M, Moschner J, Rothkegel M, Rüdiger M, Schlüter K, Stanke G, Winkler J. The molecular architecture of focal adhesions. Annu Rev Cell Dev Biol. 1995;11:379–416. [PubMed]
  • Burridge K, Turner CE, Romer LH. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol. 1992 Nov;119(4):893–903. [PMC free article] [PubMed]
  • Rankin S, Rozengurt E. Platelet-derived growth factor modulation of focal adhesion kinase (p125FAK) and paxillin tyrosine phosphorylation in Swiss 3T3 cells. Bell-shaped dose response and cross-talk with bombesin. J Biol Chem. 1994 Jan 7;269(1):704–710. [PubMed]
  • Zachary I, Sinnett-Smith J, Turner CE, Rozengurt E. Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation of the focal adhesion-associated protein paxillin in Swiss 3T3 cells. J Biol Chem. 1993 Oct 15;268(29):22060–22065. [PubMed]
  • Mönning U, Sandbrink R, Weidemann A, Banati RB, Masters CL, Beyreuther K. Extracellular matrix influences the biogenesis of amyloid precursor protein in microglial cells. J Biol Chem. 1995 Mar 31;270(13):7104–7110. [PubMed]
  • Schubert D, Jin LW, Saitoh T, Cole G. The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion. Neuron. 1989 Dec;3(6):689–694. [PubMed]
  • Chen M, Yankner BA. An antibody to beta amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types. Neurosci Lett. 1991 Apr 29;125(2):223–226. [PubMed]
  • Huckle WR, Dy RC, Earp HS. Calcium-dependent increase in tyrosine kinase activity stimulated by angiotensin II. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8837–8841. [PMC free article] [PubMed]
  • Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature. 1995 Aug 31;376(6543):737–745. [PubMed]

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