Do M T, Chai T F, Casey P J, Wang M
Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Oncogene. 2017 Oct 12;36(41):5757-5767. doi: 10.1038/onc.2017.183. Epub 2017 Jun 12.
Isoprenylcysteine carboxylmethyltransferase (ICMT) catalyzes the post-translational modification of RAB GTPases that contain C-terminal CXC motifs. However, the functional impact of this modification on RAB proteins has not been actively explored. We found that inhibition of ICMT significantly reduced cell migration in vitro and cancer invasion and metastasis in vivo. This role of ICMT was found to be mediated by RAB4A, an essential regulator of the fast recycling of integrin β3. Integrin β3 regulates cell polarity and migration when localized appropriately to the plasma membrane, thereby having an essential role in cancer metastasis. ICMT catalyzed carboxylmethylation is critical for RAB4A activation and interaction with effectors, its localization to endosomes and recycling vesicles, and hence important for RAB4A-dependent integrin β3 recycling to plasma membrane. These findings bring attention to the effects of C-terminal carboxylmethylation on RAB GTPases and provide a rationale for targeting ICMT in the treatment of metastatic cancer.
异戊烯基半胱氨酸羧甲基转移酶（ICMT）催化含有C末端CXC基序的RAB GTP酶的翻译后修饰。然而，这种修饰对RAB蛋白的功能影响尚未得到积极探索。我们发现，抑制ICMT可显著降低体外细胞迁移以及体内癌症的侵袭和转移。发现ICMT的这一作用是由RAB4A介导的，RAB4A是整合素β3快速循环的关键调节因子。当整合素β3适当地定位于质膜时，它调节细胞极性和迁移，因此在癌症转移中起重要作用。ICMT催化的羧甲基化对于RAB4A的激活及其与效应器的相互作用、其在内体和循环小泡中的定位至关重要，因此对于RAB4A依赖的整合素β3循环到质膜也很重要。这些发现引起了人们对C末端羧甲基化对RAB GTP酶影响的关注，并为在转移性癌症治疗中靶向ICMT提供了理论依据。
