Packham S, Warsito D, Lin Y, Sadi S, Karlsson R, Sehat B, Larsson O
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Biosciences, Stockholm University, The Wenner-Gren Institute, Stockholm, Sweden.
Oncogene. 2015 Apr 23;34(17):2227-38. doi: 10.1038/onc.2014.165. Epub 2014 Jun 9.
Mounting evidence has shown that the insulin-like growth factor-1 receptor (IGF-1R) has critical roles in cancer cell growth. This has prompted pharmacological companies to develop agents targeting the receptor. Surprisingly, clinical trials using specific IGF-1R antibodies have, however, revealed disappointing results. Further understanding of the role of IGF-1R in cancer cells is therefore necessary for development of efficient therapeutic strategies. Recently, we showed that IGF-1R is sumoylated and translocated into the cell nucleus where it activates gene transcription. Several other studies have confirmed our findings and it has been reported that nuclear IGF-1R (nIGF-1R) has prognostic and predictive impact in cancer. To increase the understanding of IGF-1R in cancer cells, we here present the first study that proposes a pathway by which IGF-1R translocates into the cell nucleus. We could demonstrate that IGF-1R first associates with the dynactin subunit p150(Glued), which transports the receptor to the nuclear pore complex, where it co-localizes with importin-β followed by association with RanBP2. Sumoylation of IGF-1R seems to be required for interaction with RanBP2, which in turn may serve as the SUMO E3 ligase. In the context of sumoylation, we provided evidence that it may favor nIGF-1R accumulation by increasing the stability of the receptor. Taken together, topographic and functional interactions between dynactin, importin-β and RanBP2 are involved in nuclear translocation of IGF-1R. Our results provide new understanding of IGF-1R in cancer, which in turn may contribute to development of new therapeutic strategies.
越来越多的证据表明，胰岛素样生长因子-1受体（IGF-1R）在癌细胞生长中起关键作用。这促使制药公司开发针对该受体的药物。然而，令人惊讶的是，使用特异性IGF-1R抗体的临床试验结果却令人失望。因此，要开发有效的治疗策略，有必要进一步了解IGF-1R在癌细胞中的作用。最近，我们发现IGF-1R会发生SUMO化修饰并转移至细胞核内，在细胞核中它会激活基因转录。其他几项研究也证实了我们的发现，并且有报道称细胞核内的IGF-1R（nIGF-1R）在癌症中具有预后和预测作用。为了增进对IGF-1R在癌细胞中作用的了解，我们在此展示了第一项提出IGF-1R转移至细胞核途径的研究。我们能够证明，IGF-1R首先与动力蛋白激活蛋白亚基p150（Glued）结合，该亚基将受体转运至核孔复合体，在核孔复合体中它与输入蛋白-β共定位，随后与RanBP2结合。IGF-1R的SUMO化修饰似乎是与RanBP2相互作用所必需的，而RanBP2反过来可能充当SUMO E3连接酶。在SUMO化修饰的背景下，我们提供的证据表明，它可能通过增加受体的稳定性来促进nIGF-1R的积累。总之，动力蛋白激活蛋白、输入蛋白-β和RanBP2之间的拓扑和功能相互作用参与了IGF-1R的核转运。我们的研究结果为癌症中IGF-1R的作用提供了新的认识，这反过来可能有助于开发新的治疗策略。
