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Abstract：
Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor signal. Mechanistically, the growth factor-triggered phosphorylation inhibits the degron domain present in the regulated RTK, blocking access to a specific degradation complex. This ultimately rescues the RTK from rapid ubiquitin-proteasome-system-mediated degradation and, most importantly, causes its cellular overexpression. This mechanism, which has been here assigned the new functional name \"Over-Expression by Degradation Rescue\" (OEDR), provides an additional layer and potentially preferential tool for the control of RTKs expression in cancer, in addition to other mechanisms acting at the transcriptional and messenger transcript stabilization levels. We propose this newly defined phosphorylation/ubiquitination switch-dependent signal to bear wider unexploited relevance in cell biology and human pathophysiology. The recently identified mechanism underlying an OEDR-regulated RTK is discussed herein in the context of physiological endocrine circuits and cancer.
摘要：
最近发表的工作提供了恶性肿瘤相关调节机制的第一个已知证据，功能性连接嵌入受体酪氨酸激酶（RTK）中的磷酸调节的degron结构域，它在癌症中的异位表达，以特定的自分泌生长因子信号为条件。机械上,生长因子触发的磷酸化抑制调节的RTK中存在的Degron结构域，阻止访问特定的降解复合体。这最终挽救了RTK从快速泛素-蛋白酶体系统介导的降解，最重要的是,导致其细胞过度表达。这个机制,已在此处分配了新的功能名称“通过退化救援过度表达”(OEDR)，为控制癌症中的RTKs表达提供了额外的层和潜在的优先工具，除了在转录和信使转录物稳定水平起作用的其他机制。我们建议这种新定义的磷酸化/泛素化开关依赖性信号在细胞生物学和人类病理生理学中具有更广泛的未被利用的相关性。本文在生理内分泌回路和癌症的背景下讨论了最近鉴定的OEDR调节的RTK的潜在机制。
