Pro-oncogenic function of HIP-55/Drebrin-like (DBNL) through Ser269/Thr291-phospho-sensor motifs.
Pro-oncogenic function of HIP-55/Drebrin-like (DBNL) through Ser269/Thr291-phospho-sensor motifs.
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DOI：
10.18632/oncotarget.1900
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发表时间：
2014-05-30
期刊：
影响因子：
--
通讯作者：
Fu H
中科院分区：
文献类型：
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作者：
Li Z;Park HR;Shi Z;Li Z;Pham CD;Du Y;Khuri FR;Zhang Y;Han Q;Fu H
HIP-55（55 kDa的HPK 1相互作用蛋白，也称为DBNL，SH 3 P7和mAbp 1）是一种多结构域衔接蛋白，对器官发育和免疫反应至关重要。在这里，我们报告的耦合HIP-55细胞生长控制通过其14-3-3结合磷酸-Ser/Thr-传感器网站。通过亲和层析，我们发现HIP-55与14-3-3蛋白形成复合物，揭示了磷酸化Ser/Thr介导的信号网络中的一个新节点。此外，我们证明了HIP-55是适当的细胞生长控制所必需的。加强HIP-55表达促进肺癌细胞的增殖、集落形成、迁移和侵袭，而HIP-55沉默逆转这些作用。重要的是，发现HIP-55在肺癌细胞系和肺癌患者的肿瘤组织中上调。在异种移植动物模型中，需要上调的HIP-55来促进肿瘤的生长。然而，具有S269 A/T291 A突变的HIP-55（其消除14-3-3结合）的肿瘤表现出显著减小的尺寸，支持HIP-55/14-3-3蛋白相互作用节点在传递致癌信号中的重要作用。从机制上讲，HIP-55介导的肿瘤发生活性似乎部分是通过拮抗HPK 1的肿瘤抑制功能介导的。因此，HIP-55介导的致癌途径，通过S269/T291，可用于开发新的治疗策略。
HIP-55 (HPK1-interacting protein of 55 kDa, also named DBNL, SH3P7, and mAbp1) is a multidomain adaptor protein that is critical for organ development and the immune response. Here, we report the coupling of HIP-55 to cell growth control through its 14-3-3-binding phospho-Ser/Thr-sensor sites. Using affinity chromatography, we found HIP-55 formed a complex with 14-3-3 proteins, revealing a new node in phospho-Ser/Thr-mediated signaling networks. In addition, we demonstrated that HIP-55 is required for proper cell growth control. Enforced HIP-55 expression promoted proliferation, colony formation, migration, and invasion of lung cancer cells while silencing of HIP-55 reversed these effects. Importantly, HIP-55 was found to be upregulated in lung cancer cell lines and in tumor tissues of lung cancer patients. Upregulated HIP-55 was required to promote the growth of tumors in a xenograft animal model. However, tumors with S269A/T291A-mutated HIP-55, which ablates 14-3-3 binding, exhibited significantly reduced sizes, supporting a vital role of the HIP-55/14-3-3 protein interaction node in transmitting oncogenic signals. Mechanistically, HIP-55-mediated tumorigenesis activity appears to be in part mediated by antagonizing the tumor suppressor function of HPK1. Thus, the HIP-55–mediated oncogenic pathway, through S269/T291, may be exploited for the development of new therapeutic strategies.