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

• Published in: Nature communications Vol. 5; no. 1; p. 4804
• Main Authors: Tsai, Chung-Han, Cheng, Hung-Chi, Wang, Yu-Shiuan, Lin, Pinpin, Jen, Jayu, Kuo, I-Ying, Chang, Ying-Hua, Liao, Pao-Chi, Chen, Ruey-Hwa, Yuan, Wei-Chien, Hsu, Han-Shui, Yang, Muh-Hwa, Hsu, Ming-Ta, Wu, Chu-Yi, Wang, Yi-Ching
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.09.2014; Nature Publishing Group
• Subjects: 13; 13/109; 13/51; 14; 14/19; 14/28; 38; 59; 631/67/322; 631/80/313; 631/80/86; 64; 64/60; 82/58; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Animals; Biochemistry; Cell adhesion & migration; Cell Line, Tumor; Cell Movement; Cercopithecus aethiops; COS Cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Exocytosis - genetics; Extracellular matrix; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Injections, Intravenous; Localization; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Medical schools; Medicine; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular biology; Motility; multidisciplinary; Neoplasm Metastasis; Neoplasm Transplantation; Proteins; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; Survival Analysis; Tail; Thoracic surgery; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transport Vesicles - metabolism; Taiwan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5804

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. Rab-controlled trafficking pathways have been implicated in tumourigenesis. Here the authors show that Rab37 suppresses metastasis by regulating the exocytosis of tissue inhibitor of metalloproteinase 1 to repress matrix metalloproteinase 9 and represents a novel prognostic marker for lung cancer.