Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen
Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen
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DOI：
10.1074/jbc.m110885200
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发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Reiss, K
中科院分区：
文献类型：
--
作者：
Lassak, A;Del Valle, L;Reiss, K
胰岛素受体底物1（Insulin receptor substrate 1，IRS-1）是胰岛素和胰岛素样生长因子I受体的主要信号传导分子，可传递代谢和促生长信号，在细胞中过表达时具有转化特性。在这里，我们表明，IRS-1易位到细胞核中的早期病毒蛋白T抗原的人多瘤病毒JC的存在。在T抗原阳性细胞系和诊断为髓母细胞瘤的患者的T抗原阳性活检中检测到核IRS-1。IRS-1与JC病毒T抗原直接结合的结构域位于IRS-1分子的N-末端部分，这种结合不依赖于IRS-1的酪氨酸磷酸化，并被IRS-1的丝氨酸磷酸化强烈抑制。此外，IRS-1的显性阴性突变体对IRS-1-T抗原结合的竞争抑制JC病毒T抗原转化细胞在非贴壁依赖性培养条件下的生长和存活。基于这些发现，我们提出了一个新的作用IRS-1-T抗原复合物在控制病毒感染过程中的细胞平衡。它可能涉及IRS-1从其表面受体解偶联，并将其功能转移到细胞核。
Insulin receptor substrate 1 (IRS-1) is the major signaling molecule for the insulin and insulin-like growth factor I receptors, which transduces both metabolic and growth-promoting signals, and has transforming properties when overexpressed in the cells. Here we show that IRS-1 is translocated to the nucleus in the presence of the early viral protein-T-antigen of the human polyomavirus JC. Nuclear IRS-1 was detected in T-antigen-positive cell lines and in T-antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JC virus T-antigen binding was localized within the N-terminal portion of IRS-1 molecule, and the binding was independent from IRS-1 tyrosine phosphorylation and was strongly inhibited by IRS-1 serine phosphorylation. In addition, competition for the IRS-1-T-antigen binding by a dominant negative mutant of IRS-1 inhibited growth and survival of JC virus T-antigen-transformed cells in anchorage-independent culture conditions. Based on these findings, we propose a novel role for the IRS-1-T-antigen complex in controlling cellular equilibrium during viral infection. It may involve uncoupling of IRS-1 from its surface receptor and translocation of its function to the nucleus.