Page 154 - ebook

[B. Cell Biology/Stem Cell] B-12

Akt1 interrupts the interaction between Nicastrin and APP

through degradation of NCT

Eun-Hye Jo¹, Mi-Yeon Kim¹, So-I Noh¹, Hyung-Ju Lee¹, Hee-Sae Park¹*

¹School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea

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 gammasecretase 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.