RCE1 cleaves S-Farn proRAS proteins

After prenylation, RAS proteins undergo C-terminal endoproteolysis by RAS-converting enzyme I (RCE1), which removes the aaX residues of the CaaX motif (Otto et al, 1999; Hollander et al, 2000; reviewed in Hampton et al, 2018; Ahearn et al, 2018). RCE1-mediated cleavage is required for RAS plasma membrane localization and function (Michaelson et al, 2005). RCE1 is ubiquitinated in its active form, and deubiquitination by USP17L2 abrogates its catalytic activity and inhibits signaling through the RAS-RAF MAP kinase pathway (Burrows et al, 2009). RCE1 has thus been investigated as a potential therapeutic target in RAS driven disease. Despite some promising studies, the effects of RCE1 inactivation appear unpredictable and can lead to unexpected activation of RAS signaling through mechanisms that are not fully understood (Bergo et al, 2002; Aiyagari et al, 2003; Kim et al, 1999; Chen et al, 1998; Chen et al, 1999; Wahlstrom et al, 2007).

经丙基化处理后，RAS蛋白由RAS转化酶I（RCE1）进行C端内肽酶解，去除CaaX基序中的aaX残基（Otto et al, 1999；Hollander et al, 2000；Hampton et al, 2018综述；Ahearn et al, 2018）。RCE1介导的切割对于RAS蛋白在质膜上的定位和功能至关重要（Michaelson et al, 2005）。RCE1在其活性形式下发生泛素化，而USP17L2的去泛素化作用则消除了其催化活性并抑制了RAS-RAF MAP激酶途径的信号传导（Burrows et al, 2009）。因此，RCE1已被研究作为RAS驱动疾病的潜在治疗靶点。尽管有一些有希望的研究，但RCE1失活的效果似乎难以预测，并且可能通过尚未完全理解的机制意外激活RAS信号传导（Bergo et al, 2002；Aiyagari et al, 2003；Kim et al, 1999；Chen et al, 1998；Chen et al, 1999；Wahlstrom et al, 2007）。