2022-06-29

Abstract:

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.