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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 4804 (Sep 03 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25183545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TIMP1 protein, human
• Tissue Inhibitor of Metalloproteinase-1
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Rab37 protein, human
• rab GTP-Binding Proteins

Topics

• Adenocarcinoma (genetics, metabolism, mortality, pathology)
• Animals
• COS Cells
• Cell Line, Tumor
• Cell Movement
• Chlorocebus aethiops
• Epithelial Cells (metabolism, pathology)
• Exocytosis (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Injections, Intravenous
• Lung Neoplasms (genetics, metabolism, mortality, pathology)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Signal Transduction
• Survival Analysis
• Tail
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Transport Vesicles (metabolism)
• rab GTP-Binding Proteins (genetics, metabolism)