Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau.
Protein phosphatase (PP)-2A, which regulates the phosphorylation of tau, is regulated by two endogenous inhibitor proteins, I(1)(PP2A) and I(2)(PP2A), in mammalian tissues. Here, we report the cloning of I(1)(PP2A) and I(2)(PP2A) from human brain, and show that in PC12 cells and in I(1)(PP2A)-GFP or I(2)(PP2A)-GFP transfected NIH3T3 and human neural progenitor cells, I(1)(PP2A) is localized mostly in the cell cytoplasm and I(2)(PP2A) mostly in the nucleus. The recombinant I(1)(PP-2A) and I(2)(PP-2A) inhibit PP-2A activity towards hyperphosphorylated tau in vitro; the dephosphorylation of the hyperphosphorylated tau at specific sites is selectively inhibited. Overexpression of I(1)(PP2A) as well as I(2)(PP2A) results in tau hyperphosphorylation and degeneration of PC 12 cells.
Tsujio
Ichiro
I
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA.
Zaidi
Tanweer
T
Xu
Jiliu
J
Kotula
Leszek
L
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry; D002467:Cell Nucleus / Q000737:chemistry / Q000276:immunology; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D056488:Histone Chaperones; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009474:Neurons / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D011506:Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors; D016875:tau Proteins / Q000032:analysis / Q000378:metabolism*
C087425:ANP32A protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C513473:SET protein, human; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2