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

Publication ,  Journal Article
Do, MT; Chai, TF; Casey, PJ; Wang, M
Published in: Oncogene
October 12, 2017

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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Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

October 12, 2017

Volume

36

Issue

41

Start / End Page

5757 / 5767

Location

England

Related Subject Headings

  • rab4 GTP-Binding Proteins
  • Protein Processing, Post-Translational
  • Protein Methyltransferases
  • Oncology & Carcinogenesis
  • Neoplasms
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Mice
  • Integrin beta3
  • Humans
 

Citation

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Do, M. T., Chai, T. F., Casey, P. J., & Wang, M. (2017). Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis. Oncogene, 36(41), 5757–5767. https://doi.org/10.1038/onc.2017.183
Do, M. T., T. F. Chai, P. J. Casey, and M. Wang. “Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis.Oncogene 36, no. 41 (October 12, 2017): 5757–67. https://doi.org/10.1038/onc.2017.183.
Do, M. T., et al. “Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis.Oncogene, vol. 36, no. 41, Oct. 2017, pp. 5757–67. Pubmed, doi:10.1038/onc.2017.183.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

October 12, 2017

Volume

36

Issue

41

Start / End Page

5757 / 5767

Location

England

Related Subject Headings

  • rab4 GTP-Binding Proteins
  • Protein Processing, Post-Translational
  • Protein Methyltransferases
  • Oncology & Carcinogenesis
  • Neoplasms
  • Neoplasm Metastasis
  • Neoplasm Invasiveness
  • Mice
  • Integrin beta3
  • Humans