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 () and Yi-Ching Wang ()
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Chung-Han Tsai: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1
Hung-Chi Cheng: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1
Yu-Shiuan Wang: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1
Pinpin Lin: National Health Research Institutes
Jayu Jen: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1
I-Ying Kuo: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1
Ying-Hua Chang: College of Medicine, National Cheng Kung University
Pao-Chi Liao: College of Medicine, National Cheng Kung University
Ruey-Hwa Chen: Institute of Biological Chemistry, Academia Sinica
Wei-Chien Yuan: Institute of Biological Chemistry, Academia Sinica
Han-Shui Hsu: Taipei Veterans General Hospital, Institute of Emergency and Critical Care Medicine, National Yang-Ming University
Muh-Hwa Yang: Institute of Clinical Medicine, College of Medicine, National Yang-Ming University
Ming-Ta Hsu: Institute of Biochemistry and Molecular Biology and Genome Center, College of Medicine, National Yang-Ming University
Chu-Yi Wu: College of Medicine, National Cheng Kung University
Yi-Ching Wang: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5804

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