1Department of Oncology and Pathology, Karolinska Institutet, Cancer Center Karolinska, R8:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Sci Signal. 2010 Feb 9;3(108):ra10. doi: 10.1126/scisignal.2000628.
The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues-Lys(1025), Lys(1100), and Lys(1120)-in the beta subunit of the receptor. Mutation of these SUMO-1 sites abolished the ability of IGF-1R to translocate to the nucleus and activate transcription but did not alter its kinase-dependent signaling. Thus, we demonstrate a SUMOylation-mediated mechanism of IGF-1R signaling that has potential implications for gene regulation.
胰岛素样生长因子 1 受体 (IGF-1R) 在发育和癌症生物学中发挥着关键作用。其大部分生物学效应归因于其酪氨酸激酶活性，该活性通过磷脂酰肌醇 3-激酶和丝裂原活化蛋白激酶途径传播信号。在这里，我们报告 IGF-1 促进小泛素样修饰蛋白-1 (SUMO-1) 对 IGF-1R 的修饰及其向核内的易位。核内 IGF-1R 与增强子样元件结合，并在报告基因检测中增加转录。IGF-1R 的 SUMOylation 位点被鉴定为受体β亚基中的三个进化上保守的赖氨酸残基-Kys(1025)、Kys(1100)和 Kys(1120)。这些 SUMO-1 位点的突变消除了 IGF-1R 向核内易位和激活转录的能力，但不改变其激酶依赖性信号。因此，我们证明了 IGF-1R 信号的 SUMOylation 介导机制，这可能对基因调控具有重要意义。
