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Multisite tyrosine phosphorylation of the N‐terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein
Author(s) -
Dunning Christopher J. R.,
Black Hannah L.,
Andrews Katie L.,
Davenport Elizabeth C.,
Conboy Michael,
Chawla Sangeeta,
Dowle Adam A.,
Ashford David,
Thomas Jerry R.,
Evans Gareth J. O.
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13571
Subject(s) - phosphorylation , proto oncogene tyrosine protein kinase src , amyloid precursor protein , microbiology and biotechnology , tyrosine phosphorylation , protein tyrosine phosphatase , biology , receptor tyrosine kinase , tyrosine , tyrosine kinase , amyloid precursor protein secretase , chemistry , biochemistry , signal transduction , alzheimer's disease , medicine , disease , pathology
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 SH 2‐binding motif ( 202 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 .The regulation of amyloid precursor protein (APP) trafficking is poorly understood. We have discovered that the APP adapter, Mint1, is phosphorylated by C‐Src kinase. Mint1 causes APP accumulation in the trans‐Golgi network, whereas inhibition of Src or mutation of Mint1‐Y202 permits APP recycling. The phosphorylation status of Mint1 could impact on the pathological trafficking of APP in Alzheimer's disease.