Novel Function of Insulin Receptor Substrates (IRSs) as Scaffold Proteins
Shin-Ichiro Takahashi, Ph.D.
Professor, Graduate School of Agriculture and Life Sciences.
The University of Tokyo, Tokyo. Japan
Insulin-like peptides, such as insulin-like growth factors (IGFs) and insulin, induce a variety of bioactivities, such as growth, differentiation, survival, increased anabolism, and decreased catabolism in many cell types and in vivo. In general, IGFs or insulin bind to IGF-I receptor or insulin receptor, activating the receptor tyrosine kinase. Insulin receptor substrates (IRSs) are known to be major substrates of receptor kinases, mediating IGF/insulin signals to direct bioactivities. Despite the profuseness and diversity of these effects of IGFs, the in vitro biological effects of IGFs are relatively weak and often are not demonstrable except in the presence of other hormones or growth factors. These findings suggest that IGFs act as permissive factors to augment the signals of other factors. This mechanism is very important in order that IGF induces specific bioactivities in the right tissues at the right times. Accordingly, elucidating how IGF action is potentiated by other intercellular signaling molecules is essential for revealing IGF significance in target tissues. We found that ubiquitin ligase Nedd4 associates with IRS-2 and Nedd4 conjugates mono-ubiquitin to the IRS-2 C-terminal region. Ubiquitinated IRS-2 is in turn recognized by Epsin1, which possibly recruited IRS-2 to the plasma membrane. Consequently, IGF-induced tyrosine phosphorylation of IRS-2 is enhanced by IGF-I receptor kinase, which leads to the augmentation of IGF signals and mitogenic activities. Our further study demonstrated that this novel mechanism plays important roles to induce somatic growth as well as cancer growth and regulate metabolism in response to IGFs/insulin. Recently, we discovered that IRSs form high-molecular-mass complexes (referred to here as IRSomes) even without IGF/insulin stimulation. These complexes contain proteins (referred to here as IRSAPs; IRS-associated proteins), which modulate tyrosine phosphorylation of IRSs by receptor kinases, control IRS stability, determine the intracellular localization of IRSs, and induce novel bioactivities. In addition to around 50 IRSAPs, IRSomes contain various RNAs. New findings of ours suggest that IRSs function as not only signaling mediators which are generally accepted but also as scaffold proteins that are conventional hubs to converge important physiological signals.
■Contact
Laboratory of Cell Regulation,
Departments of Animal Sciences and
Applied Biological Chemistry,
Graduate School of Agricultural and
Life Sciences, The University of Tokyo
1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657,
Japan
TEL#: +81-(0)3-5841-8152 or 1310
FAX#: +81-(0)3-5841-1311
E-mail address: atkshin(at)g.ecc.u-tokyo.ac.jp
Lab HP URL: http://endo.ar.a.u-tokyo.ac.jp
■Education
1987 Ph.D. (Doctor of Agriculture), The University of Tokyo
■Career
1987-1988 Instructor, Laboratory of Biochemistry, Department of Agricultural Chemistry, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Japan
1988-1990 Research Fellow, Pediatric Endocrinology, Faculty of Medicine, University of North Carolina, NC, USA
1990-1994 Associate Professor, Laboratory of Nutritional Biochemistry, Department of Agricultural Chemistry, Faculty of Agriculture, The University of Tokyo, Japan
1994-2018 Associate Professor, Laboratory of Cell Regulation, Department of Animal Resources Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan
2001-2003 Program Officer, Department of Research Promotion, Ministry of Education, Culture, Sports, Sciences and Technology, Japan
2017 Starting of One Earth Guardians Development Program (https://www.one-earth-g.a.u-tokyo.ac.jp/news/)
2018 Professor, Laboratory of Cell Regulation, Departments of Applied Animal Sciences and Applied Biological Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan
■Major Research Interest
1) To elucidate molecular mechanisms of potentiation of bioactivities of insulin-like growth factors by other extracellular factors such as growth factors, hormones and extracellular matrix.
2) To elucidate molecular mechanisms of insulin and/or insulin-like growth factors resistance.
3) To elucidate the physiological significance of insulin-like growth factors and/or insulin under various physiological conditions and diseases.
4) To identify the novel metabolism-regulatory amino acid signals
■Selected Recent Publications
