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

Dunning, Christopher J R LU ; Black, Hannah L.; Andrews, Katie L.; Davenport, Elizabeth C.; Conboy, Michael; Chawla, Sangeeta; Dowle, Adam A.; Ashford, David; Thomas, Jerry R. and Evans, Gareth J O (2016) In Journal of Neurochemistry 137(4). p.518-527
Abstract

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... (More)

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.

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Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amyloid precursor protein, intracellular trafficking, Mint1, protein phosphorylation, Src, tyrosine kinase
in
Journal of Neurochemistry
volume
137
issue
4
pages
10 pages
publisher
Wiley-Blackwell
external identifiers
  • Scopus:84959304721
ISSN
0022-3042
DOI
10.1111/jnc.13571
language
English
LU publication?
yes
id
ffb0edfd-b313-49d4-8412-d96656fd83d1
date added to LUP
2016-09-21 13:32:03
date last changed
2016-09-22 17:09:11
@misc{ffb0edfd-b313-49d4-8412-d96656fd83d1,
  abstract     = {<p>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 (<sup>202</sup>YEEI) 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.</p>},
  author       = {Dunning, Christopher J R and Black, Hannah L. and Andrews, Katie L. and Davenport, Elizabeth C. and Conboy, Michael and Chawla, Sangeeta and Dowle, Adam A. and Ashford, David and Thomas, Jerry R. and Evans, Gareth J O},
  issn         = {0022-3042},
  keyword      = {amyloid precursor protein,intracellular trafficking,Mint1,protein phosphorylation,Src,tyrosine kinase},
  language     = {eng},
  month        = {05},
  number       = {4},
  pages        = {518--527},
  publisher    = {ARRAY(0xa311010)},
  series       = {Journal of Neurochemistry},
  title        = {Multisite tyrosine phosphorylation of the N-terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein},
  url          = {http://dx.doi.org/10.1111/jnc.13571},
  volume       = {137},
  year         = {2016},
}