Premium
Presenilin‐1 is an unprimed glycogen synthase kinase‐3β substrate
Author(s) -
Twomey Ciara,
McCarthy Justin V.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.06.035
Subject(s) - gsk 3 , glycogen synthase , presenilin , phosphorylation , gsk3b , biochemistry , kinase , chemistry , biology , microbiology and biotechnology , medicine , disease , alzheimer's disease
Previously we described presenilin‐1 (PS1) as a GSK‐3β substrate [Kirschenbaum, F., Hsu, S.C., Cordell, B. and McCarthy, J.V. (2001) Substitution of a glycogen synthase kinase‐3beta phosphorylation site in presenilin 1 separates presenilin function from beta‐catenin signalling. J. Biol. Chem. 276, 7366–7375; Kirschenbaum, F., Hsu, S.C., Cordell, B. and McCarthy, J.V. (2001) Glycogen synthase kinase‐3beta regulates presenilin 1 C‐terminal fragment levels. J. Biol. Chem. 276, 30701–30707], though it has not been determined whether PS1 is a primed or unprimed GSK‐3β substrate. A means of separating GSK‐3β activity toward primed and unprimed substrates was identified in the GSK‐3β‐R96A phosphate binding pocket mutant [Frame, S., Cohen, P. and Biondi, R.M. (2001) A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321–1327], which is unable to phosphorylate primed but retains the ability to phosphorylate unprimed GSK‐3β substrates. By using wild type GSK‐3β, GSK‐3β‐R96A, and a pharmacological modulator of GSK‐3β activity, we demonstrate that PS1 is an unprimed GSK‐3β substrate. These findings have important implications for regulation of PS1 function and the pathogenesis of Alzheimer's disease.