Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling.
Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling.
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DOI：
10.1038/onc.2009.336
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发表时间：
2010-01-21
期刊：
影响因子：
8
通讯作者：
Der, C. J.
中科院分区：
文献类型：
--
作者：
Hanker, A. B.;Mitin, N.;Wilder, R. S.;Henske, E. P.;Tamanoi, F.;Cox, A. D.;Der, C. J.
关键词：
Rheb 1和Rheb 2小GTP酶及其效应子mTOR在人类癌症中被异常激活，并且是抗癌药物发现的有吸引力的靶点。Rheb通过其C-末端CAAX（C =半胱氨酸，A =脂肪族，X =末端氨基酸）基序（法呢基类异戊二烯的翻译后修饰底物）靶向内膜。法尼基化后，Rheb经历了两个额外的CAAX信号处理步骤，Rce 1催化的AAX残基裂解和Icmt介导的法尼基化半胱氨酸羧甲基化。然而，这些异戊二烯化后加工步骤是否是通过mTOR的Rheb信号传导所需的尚不清楚。我们发现Rheb 1和Rheb 2主要定位于内质网和高尔基体。我们确定，Icmt和Rce 1加工是Rheb定位所需的，但对于Rheb诱导的mTOR底物p70 S6激酶（S6 K）的激活是不必要的。最后，我们评估了法尼基硫代水杨酸（FTS）是否阻断Rheb的定位和功能。令人惊讶的是，FTS阻止了由组成型活性mTOR突变体诱导的S6 K活化，表明FTS在Rheb下游水平抑制mTOR。我们得出结论，Icmt和Rce 1的抑制剂不会阻断Rheb的功能，但FTS可能是Rheb和mTOR依赖性癌症的有希望的治疗方法。
The Rheb1 and Rheb2 small GTPases and their effector mTOR are aberrantly activated in human cancer and are attractive targets for anti-cancer drug discovery. Rheb is targeted to endomembranes via its C-terminal CAAX (C = cysteine, A = aliphatic, X = terminal amino acid) motif, a substrate for posttranslational modification by a farnesyl isoprenoid. Following farnesylation, Rheb undergoes two additional CAAX-signaled processing steps, Rce1-catalyzed cleavage of the AAX residues and Icmt-mediated carboxylmethylation of the farnesylated cysteine. However, whether these post-prenylation processing steps are required for Rheb signaling through mTOR is not known. We found that Rheb1 and Rheb2 localize primarily to the endoplasmic reticulum and Golgi apparatus. We determined that Icmt and Rce1 processing is required for Rheb localization, but is dispensable for Rheb-induced activation of the mTOR substrate p70 S6 kinase (S6K). Finally, we evaluated whether farnesylthiosalicylic acid (FTS) blocks Rheb localization and function. Surprisingly, FTS prevented S6K activation induced by a constitutively active mTOR mutant, indicating that FTS inhibits mTOR at a level downstream of Rheb. We conclude that inhibitors of Icmt and Rce1 will not block Rheb function, but FTS could be a promising treatment for Rheb- and mTOR-dependent cancers.
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