Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Biology Department, Temple University, Philadelphia, PA, 19122, USA.
Istituto Somatogene Per la Ricerca Onco-Genomica, ISOPROG, Caltanissetta, 93100, Italy.
Oncogene. 2019 Aug;38(31):5987-6001. doi: 10.1038/s41388-019-0854-y. Epub 2019 Jul 3.
Malignant mesothelioma is a deadly disease with limited therapeutic options. EphB4 is an oncogenic tyrosine kinase receptor expressed in malignant mesothelioma as well as in a variety of cancers. It is involved in tumor microenvironment mediating angiogenesis and invasive cellular effects via both EphrinB2 ligand-dependent and independent mechanisms. The molecular network underlying EphB4 oncogenic effects is still unclear. Here we show that EphB4 expression in malignant mesothelioma cells is markedly decreased upon neutralization of cancer-secreted IGF-II. In particular, we demonstrate that EphB4 protein expression in malignant mesothelioma cells depend upon a degradation rescue mechanism controlled by the autocrine IGF-II-insulin receptor-A specific signaling axis. We show that the regulation of EphB4 expression is linked to a competing post-translational modification of its carboxy-terminal tail via phosphorylation of its tyrosine 987 by the Insulin receptor isoform-A kinase-associated activity in response to the autocrine IGF-II stimuli. Neutralization of this autocrine-induced EphB4-phosphorylation by IGF-II associates with the increased ubiquitination of EphB4 carboxy-terminal tail and with its rapid degradation. We also describe a novel Ubiquitin binding motif in the targeted region as part of the identified EphB4 phosphodegron and provide 3D modeling data supporting a possible model for the acute EphB4 PTM-driven regulation by IGF-II. Altogether, these findings disclose a novel molecular mechanism for the maintenance of EphB4-expression in malignant mesothelioma cells and other IGF-II-secreting cancers (IGF2omas).
恶性间皮瘤是一种致命疾病，治疗选择有限。EphB4 是一种致癌酪氨酸激酶受体，在恶性间皮瘤以及多种癌症中表达。它通过 EphrinB2 配体依赖性和非依赖性机制参与肿瘤微环境介导的血管生成和侵袭性细胞作用。EphB4 致癌作用的分子网络尚不清楚。在这里，我们表明，中和癌症分泌的 IGF-II 后，恶性间皮瘤细胞中 EphB4 的表达明显降低。特别是，我们证明恶性间皮瘤细胞中 EphB4 蛋白的表达依赖于由自分泌 IGF-II-胰岛素受体-A 特异性信号轴控制的降解挽救机制。我们表明，EphB4 表达的调节与其羧基末端尾巴的竞争翻译后修饰有关，通过胰岛素受体同工型-A 激酶相关活性对自分泌 IGF-II 刺激的酪氨酸 987 进行磷酸化。通过 IGF-II 中和这种自分泌诱导的 EphB4 磷酸化与 EphB4 羧基末端尾巴的泛素化增加及其快速降解有关。我们还描述了靶向区域中的一个新的泛素结合基序，作为鉴定的 EphB4 磷酸肽降解基序的一部分，并提供了支持 IGF-II 驱动的 EphB4 PTM 急性调节的可能模型的 3D 建模数据。总之，这些发现揭示了恶性间皮瘤细胞和其他分泌 IGF-II 的癌症（IGF2omas）中 EphB4 表达维持的新分子机制。
