Hyperphosphorylation of JNK-interacting Protein 1, a Protein Associated with Alzheimer Disease

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed li...

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Bibliographic Details
Published in:Molecular & cellular proteomics 2006-01, Vol.5 (1), p.97-113
Main Authors: D'Ambrosio, Chiara, Arena, Simona, Fulcoli, Gabriella, Scheinfeld, Meir H, Zhou, Dawang, D'Adamio, Luciano, Scaloni, Andrea
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Alzheimer Disease - metabolism
Amino Acid Motifs
Amino Acid Sequence
Amyloid beta-Peptides - metabolism
Anisomycin - pharmacology
Cells, Cultured
Chromatography, Affinity
Humans
Immunoprecipitation
MAP Kinase Kinase 4 - metabolism
Mitogen-Activated Protein Kinase Kinases - metabolism
Molecular Sequence Data
Peptide Fragments - analysis
Phosphorylation
Protein Binding
Proto-Oncogene Proteins c-akt - metabolism
Serine - chemistry
Signal Transduction
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Threonine - chemistry
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Summary:The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with β-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-α Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, β-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins.
ISSN:1535-9476
1535-9484
DOI:10.1074/mcp.M500226-MCP200