title: 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.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Chung-Han
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: 1] Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan [2] Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Yu-Shiuan
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 35, Keyan Road, Zhunan 350, Taiwan.
authors.forename: Pinpin
authors.initials: P
authors.lastname: Lin
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Jayu
authors.initials: J
authors.lastname: Jen
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: I-Ying
authors.initials: IY
authors.lastname: Kuo
authors.affiliation: Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Pao-Chi
authors.initials: PC
authors.lastname: Liao
authors.affiliation: 1] Institute of Biological Chemistry, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan [2] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 100, Taiwan.
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
authors.affiliation: 1] Institute of Biological Chemistry, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, Taiwan [2] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 100, Taiwan.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Yuan
authors.affiliation: Division of Thoracic Surgery, Taipei Veterans General Hospital, Institute of Emergency and Critical Care Medicine, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 112, Taiwan.
authors.forename: Han-Shui
authors.initials: HS
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 112, Taiwan.
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.affiliation: Institute of Biochemistry and Molecular Biology and Genome Center, College of Medicine, National Yang-Ming University, No. 155, Section 2, Linong Street, Taipei 112, Taiwan.
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Chu-Yi
authors.initials: CY
authors.lastname: Wu
authors.affiliation: 1] Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan [2] Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005089:Exocytosis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D016019:Survival Analysis; D013623:Tail; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C571080:Rab37 protein, human; D020691:rab GTP-Binding Proteins