Role of Melanoma Inhibitor of Apoptosis (ML-IAP) Protein, a Member of the Baculoviral IAP Repeat (BIR) Domain Family, in the Regulation of C-RAF Kinase and Cell Migration*
Role of Melanoma Inhibitor of Apoptosis (ML-IAP) Protein, a Member of the Baculoviral IAP Repeat (BIR) Domain Family, in the Regulation of C-RAF Kinase and Cell Migration*
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DOI：
10.1074/jbc.m112.341297
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
Tripat Kaur Oberoi-Khanuja;C. Karreman;Sarit Larisch;U. Rapp;K. Rajalingam
中科院分区：
文献类型：
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作者：
Tripat Kaur Oberoi-Khanuja;C. Karreman;Sarit Larisch;U. Rapp;K. Rajalingam
背景：研究了ML-IAP在调节MAPK信号传导和细胞迁移中的可能作用。结果：ML-IAP直接结合C-RAF并靶向C-RAF进行蛋白酶体降解。ML-IAP的缺失导致MAPK活性和细胞迁移的增加。ML-IAP直接与XIAP交互。结论：ML-IAP调节C-RAF的稳定性和细胞迁移。意义：ML-IAP在调节细胞迁移和MAPK信号传导中有新的作用。iap存在于异质复合物中，并调节C-RAF的稳定性。凋亡抑制剂（IAPs）蛋白的特点是存在进化上保守的杆状病毒凋亡重复抑制剂（BIR）结构域，主要以其抑制半胱天蛋白酶的作用而闻名，从而导致细胞凋亡。我们之前已经证明含有多bir结构域的IAP、细胞IAP和X-linked IAP可以通过直接调节C-RAF激酶的蛋白稳定性来控制肿瘤细胞的迁移。在这里，我们将我们的观察扩展到包含IAP家族成员黑素瘤-IAP （ML-IAP）的单个BIR结构域。我们发现ML-IAP可以直接与C-RAF结合，并且ML-IAP的消耗导致黑色素瘤细胞中C-RAF蛋白水平的增加、MAPK激活和细胞迁移。因此，我们的研究结果揭示了ML-IAP在控制C-RAF稳定性和细胞迁移方面迄今未知的作用。
Background: The possible role of ML-IAP in regulating MAPK signaling and cell migration is examined. Results: ML-IAP directly binds to C-RAF and targets it for proteasomal degradation. Loss of ML-IAP leads to an increase in MAPK activity and cell migration. ML-IAP interacts directly with XIAP. Conclusion: ML-IAP regulates C-RAF stability and cell migration. Significance: There is a novel role of ML-IAP in regulating cell migration and MAPK signaling. IAPs exist in heteromeric complexes and regulate C-RAF stability. Inhibitor of apoptosis (IAPs) proteins are characterized by the presence of evolutionarily conserved baculoviral inhibitor of apoptosis repeat (BIR) domains, predominantly known for their role in inhibiting caspases and, thereby, apoptosis. We have shown previously that multi-BIR domain-containing IAPs, cellular IAPs, and X-linked IAP can control tumor cell migration by directly regulating the protein stability of C-RAF kinase. Here, we extend our observations to a single BIR domain containing IAP family member melanoma-IAP (ML-IAP). We show that ML-IAP can directly bind to C-RAF and that ML-IAP depletion leads to an increase in C-RAF protein levels, MAPK activation, and cell migration in melanoma cells. Thus, our results unveil a thus far unknown role for ML-IAP in controlling C-RAF stability and cell migration.