Journal
PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES
Volume 97, Issue 4, Pages 145-160Publisher
JAPAN ACAD
DOI: 10.2183/pjab.97.009
Keywords
TRAF6; NF-kappa B; signal transduction; ubiquitin
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology Japan [16H06575]
- Japan Society for the Promotion of Science [18K15235, 20K07610, 20H03441]
- Japan Agency for Medical Research and Development [JP20wm0125002]
- Grants-in-Aid for Scientific Research [20H03441, 20K07610, 18K15235, 16H06575] Funding Source: KAKEN
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NF-kappa B is a transcription factor that plays crucial roles in cell proliferation, differentiation, and apoptosis, as well as in various physiological processes such as development, organogenesis, immunity, inflammation, and neurological functions. TRAF family proteins are key players in the signaling pathways activating NF-kappa B, revealing the significance of ubiquitin in NF-kappa B signaling and other biological systems. The discovery of the nonproteolytic functions of ubiquitin in cellular signaling has revolutionized the field of ubiquitin studies.
NF-kappa B was first identified in 1986 as a B cell-specific transcription factor inducing immunoglobulin kappa light chain expression. Subsequent studies revealed that NF-kappa B plays important roles in development, organogenesis, immunity, inflammation, and neurological functions by spatiotemporally regulating cell proliferation, differentiation, and apoptosis in several cell types. Furthermore, studies on the signal pathways that activate NF-kappa B led to the discovery of TRAF family proteins with E3 ubiquitin ligase activity, which function downstream of the receptor. This discovery led to the proposal of an entirely new signaling mechanism concept, wherein K63-ubiquitin chains act as a scaffold for the signaling complex to activate downstream kinases. This concept has revolutionized ubiquitin studies by revealing the importance of the nonproteolytic functions of ubiquitin not only in NF-kappa B signaling but also in a variety of other biological systems. TRAF6 is the most diverged among the TRAF family proteins, and our studies uncovered its notable physiological and pathological functions.
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