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Oncogene
10 12, 2017;36 (41): 5757-5767.

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

M T Do, T F Chai, P J Casey, M Wang
Author Information
  1. M T Do: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
  2. T F Chai: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
  3. P J Casey: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
  4. M Wang: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
PMID: 28604748 DOI: 10.1038/onc.2017.183

Abstract

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.

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MeSH Term

Animals
Cell Line, Tumor
Cell Movement
Cell Polarity
Chickens
Endosomes
Humans
Integrin beta3
Mice
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasms
Protein Methyltransferases
Protein Processing, Post-Translational
rab4 GTP-Binding Proteins

Chemicals

Integrin beta3
Protein Methyltransferases
protein-S-isoprenylcysteine O-methyltransferase
rab4 GTP-Binding Proteins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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