Home LiteratureArticle Details
PMID: 9892651 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 2 ·1999-01-19 ·Pages 435-40

Tezuka T, Umemori H, Akiyama T, Nakanishi S, Yamamoto T

Abstract

Fyn, a member of the Src-family protein-tyrosine kinase (PTK), is implicated in learning and memory that involves N-methyl-D-aspartate (NMDA) receptor function. In this study, we examined how Fyn participates in synaptic plasticity by analyzing the physical and functional interaction between Fyn and NMDA receptors. Results showed that tyrosine phosphorylation of NR2A, one of the NMDA receptor subunits, was reduced in fyn-mutant mice. NR2A was tyrosine-phosphorylated in 293T cells when coexpressed with Fyn. Therefore, NR2A would be a substrate for Fyn in vivo. Results also showed that PSD-95, which directly binds to and coclusters with NMDA receptors, promotes Fyn-mediated tyrosine phosphorylation of NR2A. Different regions of PSD-95 associated with NR2A and Fyn, respectively, and so PSD-95 could mediate complex formation of Fyn with NR2A. PSD-95 also associated with other Src-family PTKs, Src, Yes, and Lyn. These results suggest that PSD-95 is critical for regulation of NMDA receptor activity by Fyn and other Src-family PTKs, serving as a molecular scaffold for anchoring these PTKs to NR2A.

MeSH Terms
Animals Cell Line Disks Large Homolog 4 Protein Guanylate Kinases Humans Intracellular Signaling Peptides and Proteins Membrane Proteins Mice Mice, Knockout Mutation/genetics N-Methylaspartate/metabolism Nerve Tissue Proteins/metabolism Phosphorylation Phosphotyrosine/metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-fyn Synaptosomes/metabolism Transfection/genetics src Homology Domains/genetics
Chemicals
Disks Large Homolog 4 Protein Dlg4 protein, mouse Intracellular Signaling Peptides and Proteins Membrane Proteins Nerve Tissue Proteins Proto-Oncogene Proteins postsynaptic density proteins Phosphotyrosine N-Methylaspartate FYN protein, human Fyn protein, mouse Proto-Oncogene Proteins c-fyn Guanylate Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tezuka T
Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Umemori H
Akiyama T
Nakanishi S
Yamamoto T
References (51)
51 references, click to expand
  1. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice.
    Science. 1992 Dec 18;258(5090):1903-10 PMID: 1361685
  2. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein.
    Neuron. 1992 Nov;9(5):929-42 PMID: 1419001
  3. Molecular cloning and characterization of the rat NMDA receptor.
    Nature. 1991 Nov 7;354(6348):31-7 PMID: 1834949
  4. yes-related protooncogene, syn, belongs to the protein-tyrosine kinase family.
    Proc Natl Acad Sci U S A. 1986 Aug;83(15):5459-63 PMID: 3526330
  5. Rapid and efficient site-specific mutagenesis without phenotypic selection.
    Proc Natl Acad Sci U S A. 1985 Jan;82(2):488-92 PMID: 3881765
  6. Isolation and characterization of postsynaptic densities from various brain regions: enrichment of different types of postsynaptic densities.
    J Cell Biol. 1980 Sep;86(3):831-45 PMID: 7410481
  7. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases.
    Nature. 1995 Nov 2;378(6552):85-8 PMID: 7477295
  8. NMDA receptor subunits epsilon 1 (NR2A) and epsilon 2 (NR2B) are substrates for Fyn in the postsynaptic density fraction isolated from the rat brain.
    Biochem Biophys Res Commun. 1995 Nov 13;216(2):582-8 PMID: 7488151
  9. Initial events of myelination involve Fyn tyrosine kinase signalling.
    Nature. 1994 Feb 10;367(6463):572-6 PMID: 7509042
  10. The major tyrosine-phosphorylated protein in the postsynaptic density fraction is N-methyl-D-aspartate receptor subunit 2B.
    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3954-8 PMID: 7513428
  11. Regulation of NMDA receptors by tyrosine kinases and phosphatases.
    Nature. 1994 May 19;369(6477):233-5 PMID: 7514272
  12. Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner.
    J Biol Chem. 1994 Jul 1;269(26):17749-55 PMID: 7517401
  13. Protein modules and signalling networks.
    Nature. 1995 Feb 16;373(6515):573-80 PMID: 7531822
  14. Focal adhesion kinase in the brain: novel subcellular localization and specific regulation by Fyn tyrosine kinase in mutant mice.
    Genes Dev. 1995 Aug 1;9(15):1909-21 PMID: 7544314
  15. Differential tyrosine phosphorylation of N-methyl-D-aspartate receptor subunits.
    J Biol Chem. 1995 Aug 25;270(34):20036-41 PMID: 7544350
  16. Modulation of GABAA receptors by tyrosine phosphorylation.
    Nature. 1995 Sep 28;377(6547):344-8 PMID: 7566089
  17. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95.
    Science. 1995 Sep 22;269(5231):1737-40 PMID: 7569905
  18. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit.
    Nature. 1995 Jan 12;373(6510):151-5 PMID: 7816096
  19. Increased fearfulness of Fyn tyrosine kinase deficient mice.
    Brain Res Mol Brain Res. 1994 Nov;27(1):179-82 PMID: 7877449
  20. The Drosophila tumor suppressor gene dlg is required for normal synaptic bouton structure.
    Neuron. 1994 Oct;13(4):823-35 PMID: 7946331
  21. Characterization of p59fyn-mediated signal transduction on T cell activation.
    Int Immunol. 1994 Aug;6(8):1245-55 PMID: 7981151
  22. N-methyl-D-aspartic acid receptor structure and function.
    Physiol Rev. 1994 Jul;74(3):723-60 PMID: 8036251
  23. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae.
    Cell. 1994 Aug 12;78(3):499-512 PMID: 8062390
  24. Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons.
    Nature. 1994 Apr 28;368(6474):853-6 PMID: 8159245
  25. Functional and physical interaction of protein-tyrosine kinases Fyn and Csk in the T-cell signaling system.
    J Biol Chem. 1993 Dec 25;268(36):27413-9 PMID: 8262983
  26. A role for Fyn tyrosine kinase in the suckling behaviour of neonatal mice.
    Nature. 1993 Dec 23-30;366(6457):742-5 PMID: 8264796
  27. Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits.
    J Biol Chem. 1993 Feb 5;268(4):2836-43 PMID: 8428958
  28. Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases.
    J Neurosci. 1996 Apr 1;16(7):2157-63 PMID: 8601796
  29. Molecular glue: kinase anchoring and scaffold proteins.
    Cell. 1996 Apr 5;85(1):9-12 PMID: 8620541
  30. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains.
    Cell. 1996 Mar 8;84(5):757-67 PMID: 8625413
  31. Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling.
    J Exp Med. 1996 Feb 1;183(2):675-80 PMID: 8627181
  32. Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein.
    Science. 1996 May 17;272(5264):1020-3 PMID: 8638125
  33. Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins.
    Neuron. 1996 Jul;17(1):103-13 PMID: 8755482
  34. Enhanced tyrosine phosphorylation of the 2B subunit of the N-methyl-D-aspartate receptor in long-term potentiation.
    Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10452-6 PMID: 8816821
  35. Long-term potentiation increases tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit 2B in rat dentate gyrus in vivo.
    Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10457-60 PMID: 8816822
  36. Binding of the inward rectifier K+ channel Kir 2.3 to PSD-95 is regulated by protein kinase A phosphorylation.
    Neuron. 1996 Oct;17(4):759-67 PMID: 8893032
  37. Beta-tubulin binds Src homology 2 domains through a region different from the tyrosine-phosphorylated protein-recognizing site.
    J Biol Chem. 1996 Nov 1;271(44):27931-5 PMID: 8910394
  38. Susceptibility to drug-induced seizures of Fyn tyrosine kinase-deficient mice.
    Neuroreport. 1996 Nov 4;7(15-17):2723-6 PMID: 8981455
  39. Essential role for dlg in synaptic clustering of Shaker K+ channels in vivo.
    J Neurosci. 1997 Jan 1;17(1):152-9 PMID: 8987744
  40. Requirement for the PDZ domain protein, INAD, for localization of the TRP store-operated channel to a signaling complex.
    Neuron. 1997 Jan;18(1):95-105 PMID: 9010208
  41. Subtype-specific regulation of recombinant NMDA receptor-channels by protein tyrosine kinases of the src family.
    J Physiol. 1996 Apr 15;492 ( Pt 2):445-52 PMID: 9019541
  42. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules.
    J Cell Biol. 1997 Feb 10;136(3):669-78 PMID: 9024696
  43. NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn).
    J Biol Chem. 1997 Mar 28;272(13):8310-9 PMID: 9079653
  44. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density.
    J Biol Chem. 1997 May 2;272(18):11943-51 PMID: 9115257
  45. Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90.
    J Biol Chem. 1997 May 16;272(20):12885-8 PMID: 9148889
  46. NMDA receptor and the tyrosine phosphorylation of its 2B subunit in taste learning in the rat insular cortex.
    J Neurosci. 1997 Jul 1;17(13):5129-35 PMID: 9185550
  47. DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95.
    Genes Cells. 1997 Jun;2(6):415-24 PMID: 9286858
  48. Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes.
    J Biol Chem. 1997 Oct 24;272(43):26899-904 PMID: 9341123
  49. Fyn-kinase as a determinant of ethanol sensitivity: relation to NMDA-receptor function.
    Science. 1997 Oct 24;278(5338):698-701 PMID: 9381182
  50. Src activation in the induction of long-term potentiation in CA1 hippocampal neurons.
    Science. 1998 Feb 27;279(5355):1363-7 PMID: 9478899
  51. PDZ proteins organize synaptic signaling pathways.
    Cell. 1998 May 15;93(4):495-8 PMID: 9604925
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.2.435
Published
1999-01-19
Pages
435-40
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC15154
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.96.2.435 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