c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK

Shuji Matsuda, Takashi Yasukawa, Yasuko Homma, Yuko Ito, Takako Niikura, Takako Hiraki, Shuichi Hirai, Shigeo Ohno, Yoshiko Kita, Masaoki Kawasumi, Keisuke Koyama, Tokuo Yamamoto, John M. Kyriakis, Ikuo Nishimoto

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Abstract

Using a yeast two-hybrid method, we searched for amyloid precursor protein (APP)-interacting molecules by screening mouse and human brain libraries. In addition to known interacting proteins containing a phosphotyrosine-interaction-domain (PID) - Fe65, Fe65L, Fe65L2, X11, and mDab1, we identified, as a novel APP-interacting molecule, a PID-containing isoform of mouse JNK-interacting protein-1 (JIP-1b) and its human homolog IB1, the established scaffold proteins for JNK. The APP amino acids Tyr682, Ash684, and Tyr687 in the G681YENPTY687 region were all essential for APP/JIP-1b interaction, but neither Tyr653 nor Thr668 was necessary. APP-interacting ability was specific for this additional isoform containing PID and was shared by both human and mouse homologs. JIP-1b expressed by mammalian cells was efficiently precipitated by the cytoplasmic domain of APP in the extreme Gly681-Asn695 domain-dependent manner. Reciprocally, both full-length wild-type and familial Alzheimer's disease mutant APPs were precipitated by PID-containing JIP constructs. Antibodies raised against the N and C termini of JIP-1b coprecipitated JIP-1b and wild-type or mutant APP in nonneuronal and neuronal cells. Moreover, human JNK1β1 formed a complex with APP in a JIP-1b-dependent manner. Confocal microscopic examination demonstrated that APP and JIP-1b share similar subcellular localization in transfected cells. These data indicate that JIP-1b/IB1 scaffolds APP with JNK, providing a novel insight into the role of the JNK scaffold protein as an interface of APP with intracellular functional molecules.

Original languageEnglish
Pages (from-to)6597-6607
Number of pages11
JournalJournal of Neuroscience
Volume21
Issue number17
Publication statusPublished - 2001 Sep 1

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Keywords

  • Amyloid precursor protein
  • c-Jun N-terminal kinase
  • JIP-1b/IB1
  • Phosphotyrosine-interaction-domain
  • Scaffolding protein

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Matsuda, S., Yasukawa, T., Homma, Y., Ito, Y., Niikura, T., Hiraki, T., Hirai, S., Ohno, S., Kita, Y., Kawasumi, M., Koyama, K., Yamamoto, T., Kyriakis, J. M., & Nishimoto, I. (2001). c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK. Journal of Neuroscience, 21(17), 6597-6607.