Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau's ability to bind and stabilize microtubules

葛兰素史克-3 磷酸化 微管 τ蛋白 GSK3B公司 激酶 乙酰化 化学 糖原合酶 微管蛋白 细胞生物学 生物 分子生物学 生物化学 内科学 医学 疾病 基因 阿尔茨海默病
作者
Jae‐Hyeon Cho,Gail V.W. Johnson
出处
期刊:Journal of Neurochemistry [Wiley]
卷期号:88 (2): 349-358 被引量:221
标识
DOI:10.1111/j.1471-4159.2004.02155.x
摘要

Abstract Site‐specific phosphorylation of tau negatively regulates its ability to bind and stabilize microtubule structure. Although tau is a substrate of glycogen synthase kinase 3β (GSK3β), the exact sites on tau that are phosphorylated by this kinase in situ have not yet been established, and the effect of these phosphorylation events on tau–microtubule interactions have not been fully elucidated. GSK3β phosphorylates both primed and unprimed sites on tau, but only primed phosphorylation events significantly decrease the ability of tau to bind microtubules. The focus of the present study is on determining the importance of the GSK3β‐mediated phosphorylation of a specific primed site, Thr231, in regulating tau's function. Pre‐phosphorylation of Ser235 primes tau for phosphorylation by GSK3β at Thr231. Phosphorylation by GSK3β of wild‐type tau or tau with Ser235 mutated to Ala decreases tau–microtubule interactions. However, when Thr231 alone or Thr231 and Ser235 in tau were mutated to Ala, phosphorylation by GSK3β did not decrease the association of tau with the cytoskeleton. Further, T231A tau was still able to efficiently bind microtubules after phosphorylation by GSK3β. Expression of each tau construct alone increased tubulin acetylation, a marker of microtubule stability. However, when cells were cotransfected with wild‐type tau and GSK3β, the level of tubulin acetylation was decreased to vector‐transfected levels. In contrast, coexpression of GSK3β with mutated tau (T231A/S235A) did not significantly decrease the levels of acetylated tubulin. These results strongly indicate that phosphorylation of Thr231 in tau by GSK3β plays a critical role in regulating tau's ability to bind and stabilize microtubules.
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