Multisite tyrosine phosphorylation of the N-terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein.
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 ((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.
['Dunning|Christopher J R|CJ|', 'Black|Hannah L|HL|', 'Andrews|Katie L|KL|', 'Davenport|Elizabeth C|EC|', 'Conboy|Michael|M|', 'Chawla|Sangeeta|S|', 'Dowle|Adam A|AA|', 'Ashford|David|D|', 'Thomas|Jerry R|JR|', 'Evans|Gareth J O|GJ|0000-0003-2573-7001']
D048868:Adaptor Proteins, Signal Transducing D000595:Amino Acid Sequence D016564:Amyloid beta-Protein Precursor D000818:Animals D019556:COS Cells D002478:Cells, Cultured D002522:Chlorocebus aethiops D005260:Female D006367:HeLa Cells D006801:Humans D008297:Male D051379:Mice D009419:Nerve Tissue Proteins D010766:Phosphorylation D021381:Protein Transport D051381:Rats D017208:Rats, Wistar D014443:Tyrosine D019061:src-Family Kinases D021601:trans-Golgi Network
Mint1 Src amyloid precursor protein intracellular trafficking protein phosphorylation tyrosine kinase