PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations
PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations
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DOI：
10.1038/sj.emboj.7600251
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发表时间：
2004-07-07
期刊：
影响因子：
11.4
通讯作者：
Robakis, NK
中科院分区：
文献类型：
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作者：
Baki, L;Shioi, J;Robakis, NK
磷脂酰肌醇3-激酶（PI 3 K）通过激活其下游效应子Akt激酶来促进细胞存活和通讯。在这里，我们表明PSI，一种参与家族性阿尔茨海默病（FAD）的蛋白质，通过激活PI 3 K/Akt细胞存活信号促进细胞存活。PSI的这种功能不受γ-分泌酶抑制剂的影响。药理学和遗传学证据表明PSI作用于Akt的上游，在PI 3 K激酶处或之前。PSI与PI 3 K的p85亚基形成复合物并促进钙粘蛋白/PI 3 K缔合。此外，抑制这种关联的条件阻止PSI诱导的PI 3 K/Akt活化，表明PSI通过促进钙粘蛋白/PI 3 K关联来刺激PI 3 K/Akt信号传导。通过激活PI 3 K/Akt信号，PSI促进糖原合成酶激酶-3（GSK-3）的磷酸化/失活，抑制AD中过度磷酸化残基处tau的GSK-3依赖性磷酸化，并防止融合细胞的凋亡。PSI FAD突变抑制PSI依赖的PI 3 K/Akt活化，从而促进GSK-3活性和AD相关残基处的tau过度磷酸化。我们的数据提出了PSI可能通过激活PI 3 K/Akt信号通路来预防AD病理学发展的可能性。相反，FAD突变可能通过抑制该途径促进AD病理。
Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PSI, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PSI is unaffected by gamma-secretase inhibitors. Pharmacological and genetic evidence indicates that PSI acts upstream of Akt, at or before PI3K kinase. PSI forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PSI-induced PI3K/Akt activation, indicating that PSI stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PSI promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PSI FAD mutations inhibit the PSI-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PSI may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.