Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease

Mol Cell Proteomics. 2006 Jan;5(1):97-113. doi: 10.1074/mcp.M500226-MCP200. Epub 2005 Sep 29.


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 beta-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-alpha 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, beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • MAPK8IP1 protein, human
  • Peptide Fragments
  • Threonine
  • Serine
  • Anisomycin
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases