The Novel Functions of High-Molecular-Mass Complexes Containing Insulin Receptor Substrates in Mediation and Modulation of Insulin-Like Activities: Emerging Concept of Diverse Functions by IRS-Associated Proteins.
The Novel Functions of High-Molecular-Mass Complexes Containing Insulin Receptor Substrates in Mediation and Modulation of Insulin-Like Activities: Emerging Concept of Diverse Functions by IRS-Associated Proteins.
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DOI：
10.3389/fendo.2015.00073
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发表时间：
2015
影响因子：
5.2
通讯作者：
Takahashi S
中科院分区：
文献类型：
--
作者：
Hakuno F;Fukushima T;Yoneyama Y;Kamei H;Ozoe A;Yoshihara H;Yamanaka D;Shibano T;Sone-Yonezawa M;Yu BC;Chida K;Takahashi S
胰岛素样肽，如胰岛素样生长因子（IGFs）和胰岛素，诱导多种生物活性，如生长，分化，存活，增加的亲和力，并在许多细胞类型和体内减少catalysts。通常，IGF或胰岛素与IGF-I受体（IGF-IR）或胰岛素受体（IR）结合，激活受体酪氨酸激酶。胰岛素受体底物（IRS）是受体激酶的主要底物，介导IGF/胰岛素信号以指导生物活性。最近，我们发现即使没有IGF/胰岛素刺激，IRSs也能形成高分子量复合物（这里称为IRSomes）。这些复合物含有蛋白质（此处称为IRSAP; IRS相关蛋白），其通过受体激酶调节IRS的酪氨酸磷酸化，控制IRS稳定性，并确定IRS的细胞内定位。此外，在这些复合物中，我们不仅发现了参与RNA代谢的蛋白质，而且还发现了RNA本身。因此，IRSAP可能有助于调节IGF/胰岛素生物活性。由于已经确定胰岛素样活性的调节障碍导致包括癌症在内的各种年龄相关疾病，因此我们可以提出IRSome是治疗这些疾病的重要靶标。
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 (IGF-IR) or insulin receptor (IR), 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. 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, and determine intracellular localization of IRSs. In addition, in these complexes, we found not only proteins that are involved in RNA metabolism but also RNAs themselves. Thus, IRSAPs possibly contribute to modulation of IGF/insulin bioactivities. Since it is established that disorder of modulation of insulin-like activities causes various age-related diseases including cancer, we could propose that the IRSome is an important target for treatment of these diseases.
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