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Molecular & Cellular Proteomics 5:97-113, 2006.
© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

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

Chiara D’Ambrosio^,, Simona Arena^,, Gabriella Fulcoli^,, Meir H. Scheinfeld^¶, Dawang Zhou^¶, Luciano D’Adamio^¶,|| and Andrea Scaloni^,**

From the Proteomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Naples, Italy, ^¶ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, and ^|| Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy

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 ß-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- 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, ß-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.

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