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

In English

Författare

  • 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.

Publiceringsår

2016-05-01

Språk

Engelska

Sidor

518-527

Publikation/Tidskrift/Serie

Journal of Neurochemistry

Volym

137

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

Wiley-Blackwell

Ämne

  • Neurosciences

Nyckelord

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

Status

Published

Forskningsgrupp

  • Clinical Memory Research

ISBN/ISSN/Övrigt

  • ISSN: 0022-3042