title: Differential roles of JIP scaffold proteins in the modulation of amyloid precursor protein metabolism.
abstract: We previously found that the JNK-interacting proteins JIP1b and JIP2 associate with the cytoplasmic domain of the Alzheimer's amyloid precursor protein (APP) (Taru, H., Iijima, K., Hase, M., Kirino, Y., Yagi, Y., and Suzuki, T. (2002) J. Biol. Chem. 277, 20070-20078). This interaction involves the carboxyl-terminal phosphotyrosine interaction (PI) domain of JIP1b or JIP2 and the GYENPTY motif in the APP cytoplasmic domain. The expression of JIP1b stabilizes immature APP and suppresses the production of a secreted large extracellular amino-terminal domain of APP, the generation of a cleaved intracellular carboxyl-terminal fragment of APP, and the secretion of beta-amyloid 40 and 42. Deletion of the PI domain or alteration of PI amino acid residues prevents JIP1b from interacting with APP and affecting its metabolism, but deletion of the JNK-binding domain of JIP1b has no effect. JIP2, a weaker APP-binding protein, does not influence the processing of APP, although it is known that both JIP1b and JIP2 equally regulate the JNK signaling cascade. The present results suggest that JIP1b can directly modulate APP metabolism by interacting with the APP cytoplasmic domain, independent of its regulation of the JNK signaling cascade.
authors.affiliation: Laboratory of Neurobiophysics, School of Pharmaceutical Sciences, the University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kirino
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; C490666:MAPK8IP1 protein, human; C408376:MAPK8IP2 protein, human; C490665:Mapk8ip protein, mouse; C486564:Mapk8ip2 protein, mouse; D020033:Protein Isoforms; D005982:Glutathione Transferase