Tau phosphorylation and proteolysis: insights and perspectives.
In 1992 little was known about the specific protein kinases that phosphorylate tau and the proteases that regulate tau turnover. Although we had already demonstrated that tau was a substrate of the calcium-activated protease calpain (Johnson et al. (1989), Biochem Biophys Res Commun 163, 1505-1511), our publication entitled, "Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain" (Litersky and Johnson (1992), J Biol Chem 267, 1563-1568) was the first demonstration that phosphorylation by a specific kinase could inhibit the proteolysis of tau by calpain. At the time these findings suggested that the abnormal phosphorylation of tau in Alzheimer's disease brain could result in impaired tau turnover and thus result in an abnormal accumulation of the protein that could contribute to the formation of pathological lesions. Since this initial finding, much has been learned about the proteolysis of tau, not only by calpain, but by other proteases as well. However, much remains unknown about how phosphorylation regulates tau turnover in vivo and the specific proteases involved. In this article we give a brief history of our initial findings and then discuss subsequent studies from our laboratory, as well as others, on tau proteolysis and modulation by phosphorylation and how these findings contribute to our understanding of the posttranslational processing of tau in Alzheimer's disease.
Johnson
Gail V W
GV
Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. gvwj@uab.edu
D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D000242:Cyclic AMP; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D002118:Calcium