BACKGROUND & AIMS:
:Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.
背景与目标:
: tau蛋白的磷酸化受几种激酶调节,尤其是糖原合酶激酶3β (GSK-3beta),细胞周期蛋白依赖性蛋白激酶5 (cdk5) 和cAMP依赖性蛋白激酶 (PKA)。PKA对tau的磷酸化使其被GSK-3beta磷酸化,但是尚未很好地研究通过预磷酸化对GSK-3beta-catalyzed tau磷酸化的位点特异性调节。在这里,我们发现PKA的预磷酸化促进了Thr181,Ser199,Ser202,Thr205,Thr217,Thr231,Ser396和Ser422的GSK-3beta-catalyzed tau磷酸化,但抑制了Thr212和ser404的磷酸化。相反,预磷酸化对其随后在Thr181,Ser199,Thr205,Thr231和Ser422处被cdk5磷酸化没有显着影响; 在Ser202,Thr212,Thr217和Ser404处抑制它; 并在ser396处略微促进它。这些研究揭示了三种主要tau激酶对tau磷酸化的相互调节的性质。