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Multisite tyrosine phosphorylation of the N-terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein

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Author

  • Christopher J R Dunning
  • Hannah L. Black
  • Katie L. Andrews
  • Elizabeth C. Davenport
  • Michael Conboy
  • Sangeeta Chawla
  • Adam A. Dowle
  • David Ashford
  • Jerry R. Thomas
  • Gareth J O Evans

Summary, in English

Mint/X11 is one of the four neuronal trafficking adaptors that interact with amyloid precursor protein (APP) and are linked with its cleavage to generate β-amyloid peptide, a key player in the pathology of Alzheimer's disease. How APP switches between adaptors at different stages of the secretory pathway is poorly understood. Here, we show that tyrosine phosphorylation of Mint1 regulates the destination of APP. A canonical SH2-binding motif (202YEEI) was identified in the N-terminus of Mint1 that is phosphorylated on tyrosine by C-Src and recruits the active kinase for sequential phosphorylation of further tyrosines (Y191 and Y187). A single Y202F mutation in the Mint1 N-terminus inhibits C-Src binding and tyrosine phosphorylation. Previous studies observed that co-expression of wild-type Mint1 and APP causes accumulation of APP in the trans-Golgi. Unphosphorylatable Mint1 (Y202F) or pharmacological inhibition of Src reduced the accumulation of APP in the trans-Golgi of heterologous cells. A similar result was observed in cultured rat hippocampal neurons where Mint1(Y202F) permitted the trafficking of APP to more distal neurites than the wild-type protein. These data underline the importance of the tyrosine phosphorylation of Mint1 as a critical switch for determining the destination of APP.

Publishing year

2016-05-01

Language

English

Pages

518-527

Publication/Series

Journal of Neurochemistry

Volume

137

Issue

4

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Neurosciences

Keywords

  • amyloid precursor protein
  • intracellular trafficking
  • Mint1
  • protein phosphorylation
  • Src
  • tyrosine kinase

Status

Published

Research group

  • Clinical Memory Research

ISBN/ISSN/Other

  • ISSN: 0022-3042