Akt1 phosphorylates Nicastrin to regulate its protein stability and activity

作者：Jo Eun Hye; Ahn Ji Seon; Mo Jung Soon; Yoon Ji Hye; Ann Eun Jung; Baek Hyeong Jin; Lee Hye Jin; Kim Seol Hee; Kim Mi Yeon; Park Hee Sae^*

来源：Journal of Neurochemistry, 2015, 134(5): 799-810.

DOI：10.1111/jnc.13173

• Akt1
• co-localization
• lysosome
• Nicastrin
• phosphorylation
• proteasome

The gamma-secretase is a multiprotein complex that cleaves many type-I membrane proteins, such as the Notch receptor and the amyloid precursor protein. Nicastrin (NCT) is an essential component of the multimeric gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we found that Akt1 markedly regulated the protein stability of NCT. Importantly, the kinase activity of Akt1 was essential for the inhibition of gamma-secretase activity through degradation of NCT. Notably, the protein level of endogenous NCT was higher in shAkt1-expressing cells than in shCon-expressing cells. Akt1 physically interacted with NCT and mediated its degradation through proteasomal and lysosomal pathways. We also found that Akt1 phosphorylates NCT at Ser437, resulting in a significant reduction in NCT protein stability. Importantly, a phospho-deficient mutation in NCT at Ser437 stabilized its protein levels. Collectively, our results reveal that Akt1 functions as a negative regulator of the gamma-secretase activity through phosphorylation and degradation of NCT.

• 出版日期2015-9