Welcker Markus, Wang Baiyun, Rusnac Domniţa-Valeria, Hussaini Yasser, Swanger Jherek, Zheng Ning, Clurman Bruce E
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Sci Adv. 2022 Jan 28;8(4):eabl7872. doi: 10.1126/sciadv.abl7872.
c-Myc (hereafter, Myc) is a cancer driver whose abundance is regulated by the SCF ubiquitin ligase and proteasomal degradation. Fbw7 binds to a phosphorylated Myc degron centered at threonine 58 (T58), and mutations of Fbw7 or T58 impair Myc degradation in cancers. Here, we identify a second Fbw7 phosphodegron at Myc T244 that is required for Myc ubiquitylation and acts in concert with T58 to engage Fbw7. While Ras-dependent Myc serine 62 phosphorylation (pS62) is thought to stabilize Myc by preventing Fbw7 binding, we find instead that pS62 greatly enhances Fbw7 binding and is an integral part of a high-affinity degron. Crystallographic studies revealed that both degrons bind Fbw7 in their diphosphorylated forms and that the T244 degron is recognized via a unique mode involving Fbw7 arginine 689 (R689), a mutational hotspot in cancers. These insights have important implications for Myc-associated tumorigenesis and therapeutic strategies targeting Myc stability.
c-Myc（以下简称Myc）是一种癌症驱动因子，其丰度受SCF泛素连接酶和蛋白酶体降解调控。Fbw7与以苏氨酸58（T58）为中心的磷酸化Myc降解结构域结合，Fbw7或T58的突变会损害癌症中Myc的降解。在此，我们在Myc的T244位点鉴定出第二个Fbw7磷酸化降解结构域，它是Myc泛素化所必需的，并且与T58协同作用以结合Fbw7。虽然依赖Ras的Myc丝氨酸62磷酸化（pS62）被认为通过阻止Fbw7结合来稳定Myc，但我们发现pS62反而极大地增强了Fbw7的结合，并且是高亲和力降解结构域的一个组成部分。晶体学研究表明，两个降解结构域均以其二磷酸化形式结合Fbw7，并且T244降解结构域通过涉及Fbw7精氨酸689（R689，癌症中的一个突变热点）的独特模式被识别。这些见解对与Myc相关的肿瘤发生以及针对Myc稳定性的治疗策略具有重要意义。
