Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

Chung Han Tsai, Hung Chi Cheng, Yu Shiuan Wang, Pinpin Lin, Jayu Jen, I. Ying Kuo, Ying Hua Chang, Pao Chi Liao, Ruey Hwa Chen, Wei Chien Yuan, Han Shui Hsu, Muh Hwa Yang, Ming Ta Hsu, Chu Yi Wu, Yi Ching Wang

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Rab small GTPases are master regulators of membrane trafficking and guide vesicle targeting. Recent publications show that Rab-controlled trafficking pathways are altered during tumorigenesis. However, whether any of the Rabs plays a metastasis suppressor role is least explored. Here we address the metastasis suppressive function of human Rab37 (hRAB37) using secretomics, cell, animal and clinical analyses. We show that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted glycoprotein that inhibits extracellular matrix turnover, is a novel cargo of hRAB37. hRAB37 regulates the exocytosis of TIMP1 in a nucleotide-dependent manner to inactivate matrix metalloproteinase 9 (MMP9) migration axis in vitro and in vivo. Dysfunction of hRAB37 or TIMP1 abrogates metastasis suppression. Lung cancer patients with metastasis and poor survival show low hRAB37 protein expression coinciding with low TIMP1 in tumours. Our findings identify hRAB37 as a novel metastasis suppressor Rab that functions through the TIMP1-MMP9 pathway and has significant prognostic power.

Original languageEnglish
Article number4804
JournalNature communications
Volume5
DOIs
Publication statusPublished - 2014 Sep 3

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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