PDF(Pubmed)
Abstract：
Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid-liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion-related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion-driven diseases.
摘要：
转染期间重排（RET）重排癌蛋白介导的Ras/MAPK信号级联在癌症中组成性激活。这里,我们展示了一个独特的信号生态位。生态位是基于嵌合RET液-液相分离的三元复合物。复合物包含重排的激酶（RET融合）；衔接子（GRB2），和效应子(SHC1)。一起,他们协调Ras/MAPK信号级联，依赖于酪氨酸激酶。CCDC6-RET融合经历LLPS,需要其激酶结构域和其融合配偶体。CCDC6-RET融合LLPS促进RET融合的自磷酸化,具有增强的激酶活性，这是信号生态位形成所必需的。在信号利基内，组成成分之间的相互作用得到加强，并且信号转导效率被放大。特定的RET融合相关信号生态位阐明了Ras/MAPK信号通路组成型激活的机制。除了关注RET融合本身，三元复合物的探索可能为设计旨在治疗RET融合驱动疾病的治疗策略提供了有希望的途径。
