Home LiteratureArticle Details
PMID: 8670881 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Intrinsic signaling function of APP as a novel target of three V642 mutations linked to familial Alzheimer's disease.

The EMBO journal ·Vol. 15 ·No. 15 ·1996-08-01 ·Pages 3769-77

Okamoto T, Takeda S, Giambarella U, Murayama Y, Matsui T, Katada T, Matsuura Y, Nishimoto I

Abstract

APP695 is a transmembrane precursor of Abeta amyloid. In familial Alzheimer's disease (FAD), three mutations V642I/F/G were discovered in APP695, which has been suggested by multiple studies to be a cell surface signaling receptor. We previously reported that normal APP695 encodes a potential GO-linked receptor with ligand-regulated function and that expression of the three FAD mutants (FAD-APPs), not normal APP, induces cellular outputs by GO-dependent mechanisms. This suggests that FAD-APPs are constitutively active GO-linked receptors. Here, we provide direct evidence for this notion. Reconstitution of either recombinant FAD-APP with GO vesicles induced activation of GO, which was inhibitable by pertussis toxin, sensitive to Mg2+ and proportional in quantity to the reconstituted amounts of FAD-APP. Consistent with the dominant inheritance of this type of FAD, this function was dominant over normal APP, because little activation was observed in APP695-GO vesicles. Experiments with antibody competition and sequence deletion indicated that His657-Lys676 of FAD-APP, which has been specified as the ligand-dependent GO-coupling domain of normal APP, was responsible for this constitutive activation, confirming that the three FAD-APPs are mutationally activated APP695. This study identifies the intrinsic signaling function of APP to be a novel target of hereditary Alzheimer's disease mutations, providing an in vitro system for the screening of potential FAD inhibitors.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amyloid beta-Protein Precursor/genetics,metabolism Baculoviridae Flavin-Adenine Dinucleotide/genetics,metabolism GTP-Binding Proteins/metabolism Guanosine 5'-O-(3-Thiotriphosphate) Humans Point Mutation Receptors, Cell Surface/metabolism Signal Transduction/genetics
Chemicals
Amyloid beta-Protein Precursor Receptors, Cell Surface Flavin-Adenine Dinucleotide Guanosine 5'-O-(3-Thiotriphosphate) GTP-Binding Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Okamoto T
Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Takeda S
Giambarella U
Murayama Y
Matsui T
Katada T
Matsuura Y
Nishimoto I
References (57)
57 references, click to expand
  1. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.
    Nature. 1995 Feb 9;373(6514):523-7 PMID: 7845465
  2. Distinctive regulation of the functional linkage between the human cation-independent mannose 6-phosphate receptor and GTP-binding proteins by insulin-like growth factor II and mannose 6-phosphate.
    J Biol Chem. 1990 Oct 15;265(29):17456-62 PMID: 2170379
  3. Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro.
    J Cell Biol. 1995 Mar;128(5):919-27 PMID: 7876315
  4. Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor.
    Nature. 1995 Mar 16;374(6519):272-6 PMID: 7885448
  5. Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans.
    Science. 1995 Mar 17;267(5204):1648-51 PMID: 7886454
  6. Participation of the protein Go in multiple aspects of behavior in C. elegans.
    Science. 1995 Mar 17;267(5204):1652-5 PMID: 7886455
  7. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.
    Cell. 1995 May 19;81(4):525-31 PMID: 7758106
  8. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
    Nature. 1995 Jun 29;375(6534):754-60 PMID: 7596406
  9. Direct control of exocytosis by receptor-mediated activation of the heterotrimeric GTPases Gi and G(o) or by the expression of their active G alpha subunits.
    EMBO J. 1995 Aug 1;14(15):3635-44 PMID: 7641683
  10. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.
    Nature. 1995 Aug 31;376(6543):775-8 PMID: 7651536
  11. Activation of a G protein complex by aggregation of beta-1,4-galactosyltransferase on the surface of sperm.
    Science. 1995 Sep 22;269(5231):1718-21 PMID: 7569899
  12. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene.
    Nature. 1995 Sep 28;377(6547):351-4 PMID: 7566091
  13. Signalling downstream of activated mammalian Notch.
    Nature. 1995 Sep 28;377(6547):355-8 PMID: 7566092
  14. In vivo coupling of insulin-like growth factor II/mannose 6-phosphate receptor to heteromeric G proteins. Distinct roles of cytoplasmic domains and signal sequestration by the receptor.
    J Biol Chem. 1995 Dec 8;270(49):29224-8 PMID: 7493951
  15. The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein.
    J Biol Chem. 1995 Dec 29;270(52):30853-6 PMID: 8537337
  16. Expression of V642 APP mutant causes cellular apoptosis as Alzheimer trait-linked phenotype.
    EMBO J. 1996 Feb 1;15(3):498-509 PMID: 8599933
  17. Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP.
    EMBO J. 1996 May 15;15(10):2468-75 PMID: 8665854
  18. Two guanine nucleotide-binding proteins in rat brain serving as the specific substrate of islet-activating protein, pertussis toxin. Interaction of the alpha-subunits with beta gamma-subunits in development of their biological activities.
    J Biol Chem. 1986 Jun 25;261(18):8182-91 PMID: 3087970
  19. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.
    Nature. 1987 Feb 19-25;325(6106):733-6 PMID: 2881207
  20. Pertussis toxin suppresses long-term potentiation of hippocampal mossy fiber synapses.
    Neurosci Lett. 1988 Jul 19;90(1-2):181-5 PMID: 3412640
  21. Oncogenic activation of p185neu stimulates tyrosine phosphorylation in vivo.
    Mol Cell Biol. 1988 Sep;8(9):3969-73 PMID: 2464744
  22. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein.
    Cell. 1989 Apr 7;57(1):115-26 PMID: 2649245
  23. A pertussis toxin-sensitive G protein in hippocampal long-term potentiation.
    Science. 1989 May 26;244(4907):980-3 PMID: 2543072
  24. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
    Nature. 1991 Feb 21;349(6311):704-6 PMID: 1671712
  25. Isolation of baculovirus-derived secreted and full-length beta-amyloid precursor protein.
    J Biol Chem. 1991 Apr 15;266(11):7285-90 PMID: 1901866
  26. Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion.
    J Neurosci Res. 1991 Jan;28(1):90-100 PMID: 1645774
  27. Mis-sense mutation Val----Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease.
    Lancet. 1991 Apr 20;337(8747):978-9 PMID: 1678058
  28. The 717Val----Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups.
    Biochem Biophys Res Commun. 1991 Aug 15;178(3):1141-6 PMID: 1908231
  29. Morphoregulatory activities of NCAM and N-cadherin can be accounted for by G protein-dependent activation of L- and N-type neuronal Ca2+ channels.
    Cell. 1991 Oct 4;67(1):21-33 PMID: 1680564
  30. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.
    Science. 1991 Oct 4;254(5028):97-9 PMID: 1925564
  31. An intracellular guanine nucleotide release protein for G0. GAP-43 stimulates isolated alpha subunits by a novel mechanism.
    J Biol Chem. 1991 Nov 25;266(33):22465-71 PMID: 1834672
  32. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.
    Nature. 1991 Oct 31;353(6347):844-6 PMID: 1944558
  33. Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation.
    J Biol Chem. 1992 Jan 25;267(3):1430-3 PMID: 1346134
  34. Localization of Alzheimer beta A4 amyloid precursor protein at central and peripheral synaptic sites.
    Brain Res. 1991 Nov 1;563(1-2):184-94 PMID: 1786532
  35. Detection of G protein-activator regions in M4 subtype muscarinic, cholinergic, and alpha 2-adrenergic receptors based upon characteristics in primary structure.
    J Biol Chem. 1992 Apr 25;267(12):8342-6 PMID: 1314825
  36. Role of amyloid precursor protein (APP): study with antisense transfection of human neuroblastoma cells.
    J Neurosci Res. 1992 Apr;31(4):635-45 PMID: 1578514
  37. The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth.
    Neuron. 1992 Jul;9(1):129-37 PMID: 1632967
  38. Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene.
    Neurology. 1992 Aug;42(8):1445-53 PMID: 1520398
  39. Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor.
    Nature. 1992 Sep 3;359(6390):64-7 PMID: 1301020
  40. IL-8 induces the locomotion of human IL-2-activated natural killer cells. Involvement of a guanine nucleotide binding (Go) protein.
    J Immunol. 1993 Feb 15;150(4):1524-34 PMID: 8381837
  41. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
    J Biol Chem. 1993 Mar 5;268(7):4625-36 PMID: 8095262
  42. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o)
    Nature. 1993 Mar 4;362(6415):75-9 PMID: 8446172
  43. GAP-43 augments G protein-coupled receptor transduction in Xenopus laevis oocytes.
    Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5327-31 PMID: 7685122
  44. Intraneuronal compartments of the amyloid precursor protein.
    J Neurosci. 1993 Jul;13(7):3112-23 PMID: 8331388
  45. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas.
    Nature. 1993 Oct 14;365(6447):649-51 PMID: 8413627
  46. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.
    Nature. 1993 Oct 14;365(6447):652-4 PMID: 7692306
  47. A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth.
    J Neurosci. 1994 Apr;14(4):2117-27 PMID: 8158260
  48. Activated mutants of the alpha subunit of G(o) promote an increased number of neurites per cell.
    J Neurosci. 1994 Apr;14(4):2327-38 PMID: 8158271
  49. An intrinsic guanine nucleotide exchange inhibitor in Gi2 alpha. Significance of G-protein self-suppression which antagonizes receptor signal.
    J Biol Chem. 1994 May 13;269(19):13756-9 PMID: 8188651
  50. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants.
    Science. 1994 May 27;264(5163):1336-40 PMID: 8191290
  51. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension.
    J Neurosci. 1994 Sep;14(9):5461-70 PMID: 8083748
  52. CREB: a mediator of long-term memory from mollusks to mammals.
    Cell. 1994 Oct 7;79(1):5-8 PMID: 7923377
  53. Neural cell adhesion molecules influence second messenger systems.
    Neuron. 1989 Jul;3(1):13-20 PMID: 2559759
  54. Expression of the Alzheimer amyloid precursor gene transcripts in the human brain.
    Neuron. 1988 Oct;1(8):669-77 PMID: 2908447
  55. G0 is a major growth cone protein subject to regulation by GAP-43.
    Nature. 1990 Apr 26;344(6269):836-41 PMID: 2158629
  56. A simple structure encodes G protein-activating function of the IGF-II/mannose 6-phosphate receptor.
    Cell. 1990 Aug 24;62(4):709-17 PMID: 2167177
  57. Ligand-dependent G protein coupling function of amyloid transmembrane precursor.
    J Biol Chem. 1995 Mar 3;270(9):4205-8 PMID: 7876177
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-08-01
Pages
3769-77
Language
English
Region
England
NLM ID
8208664
PMCID
PMC452057
Subset
IM
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2