Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis

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 beta 3. Integrin beta 3 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 beta 3 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.