由Raf、MEK和ERK组成的激酶级联信号传导对于动物发育至关重要，并且在人类恶性肿瘤中经常被错误激活。我们试图确定控制Caenorhabditis elegans Raf同源物LIN-45介导的信号传导的因素。遗传筛选显示，LIN-45的降解需要E3/E4泛素连接酶UFD-2。无论是UFD-2还是其伴侣ATP依赖性分离酶CDC-48，都需要对LIN-45蛋白丰度进行发育调节。我们证明UFD-2与E3泛素连接酶SCFSEL-10在同一通路中作用，以降低LIN-45在Raf-MEK-ERK信号传导最活跃的细胞中的蛋白丰度。UFD-2还减少了携带相当于与癌相关的BRAF(V600E)突变的激活LIN-45的蛋白丰度。我们的结构功能研究显示，破坏介导蛋白质相互作用的LIN-45结构域（包括保守的富含半胱氨酸结构域和14-3-3结合基序）对于UFD-2独立的LIN-45降解是必需的。我们提出了一个模型，其中UFD-2和CDC-48在SCFSEL-10下游起作用，从蛋白质相互作用伙伴中清除LIN-45，并促进蛋白酶体靶向和降解。这些发现暗示UFD-2和CDC-48在哺乳动物细胞中正常和癌基因Ras和MAPK信号传导过程中，可能对Raf的降解起到重要作用。

Signaling by the kinase cascade composed of Raf, MEK, and ERK is critical for animal development and is often inappropriately activated in human malignancies. We sought to identify factors that control signaling mediated by the Caenorhabditis elegans Raf ortholog LIN-45. A genetic screen showed that the degradation of LIN-45 required the E3/E4 ubiquitin ligase UFD-2. Both UFD-2 and its partner, the ATP-dependent segregase CDC-48, were required for the developmental regulation of LIN-45 protein abundance. We showed that UFD-2 acted in the same pathway as the E3 ubiquitin ligase SCFSEL-10 to decrease LIN-45 abundance in cells in which Raf-MEK-ERK signaling was most highly active. UFD-2 also reduced the protein abundance of activated LIN-45 carrying a mutation equivalent to the cancer-associated BRAF(V600E) variant. Our structure-function studies showed that the disruption of LIN-45 domains that mediate protein-protein interactions, including the conserved cysteine-rich domain and 14-3-3 binding motifs, were required for UFD-2-independent degradation of LIN-45. We propose a model in which UFD-2 and CDC-48 act downstream of SCFSEL-10 to remove LIN-45 from its protein interaction partners and facilitate proteasomal targeting and degradation. These findings imply that UFD-2 and CDC-48 may be important for Raf degradation during normal and oncogenic Ras and MAPK signaling in mammalian cells.