title: Multisite tyrosine phosphorylation of the N-terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein.
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 ((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.
authors: Department of Biology, University of York, York, UK.
authors: Christopher J R
authors: CJ
authors: Dunning
authors: Department of Biology, University of York, York, UK.
authors: Hannah L
authors: HL
authors: Black
authors: Department of Biology, University of York, York, UK.
authors: Katie L
authors: KL
authors: Andrews
authors: Department of Biology, University of York, York, UK.
authors: Elizabeth C
authors: EC
authors: Davenport
authors: Department of Biology, University of York, York, UK.
authors: Michael
authors: M
authors: Conboy
authors: Department of Biology, University of York, York, UK.
authors: Sangeeta
authors: S
authors: Chawla
authors: Department of Biology, University of York, York, UK.
authors: Adam A
authors: AA
authors: Dowle
authors: Department of Biology, University of York, York, UK.
authors: David
authors: D
authors: Ashford
authors: Department of Biology, University of York, York, UK.
authors: Jerry R
authors: JR
authors: Thomas
authors: Department of Biology, University of York, York, UK.
authors: Gareth J O
authors: 0000-0003-2573-7001
authors: GJ
authors: Evans
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; 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 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism*
chemical_list: C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C513072:Apba1 protein, mouse; D009419:Nerve Tissue Proteins; D014443:Tyrosine; D019061:src-Family Kinases
keywords: Mint1; Src; amyloid precursor protein; intracellular trafficking; protein phosphorylation; tyrosine kinase