Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis
Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis
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DOI：
10.1038/ncomms5804
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发表时间：
2014-09-01
影响因子：
16.6
通讯作者：
Wang, Yi-Ching
中科院分区：
文献类型：
--
作者：
Tsai, Chung-Han;Cheng, Hung-Chi;Wang, Yi-Ching
Rab小GTP酶是膜运输和引导囊泡靶向的主要调节剂。最近的出版物表明，Rab-controlled贩运途径在肿瘤发生过程中发生改变。然而，是否有任何Rabs发挥转移抑制作用的探索最少。在这里，我们解决的转移抑制功能的人Rab 37（hRAB 37）使用分泌组学，细胞，动物和临床分析。我们发现，金属蛋白酶组织抑制剂1（TIMP 1），一种分泌的糖蛋白，抑制细胞外基质周转，是一种新的货物hRAB 37。hRAB 37以核苷酸依赖的方式调节TIMP 1的胞吐作用，从而在体外和体内抑制基质金属蛋白酶9（MMP 9）迁移轴。hRAB 37或TIMP 1的功能障碍消除了转移抑制。转移和生存率差的肺癌患者显示低hRAB 37蛋白表达与肿瘤中的低TIMP 1一致。我们的研究结果确定hRAB 37作为一种新的转移抑制因子Rab，通过TIMP 1-MMP 9途径发挥作用，并具有显着的预后能力。
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.