tailieunhanh - Báo cáo khoa học: Golgi reassembly stacking protein 55 interacts with membrane-type (MT) 1-matrix metalloprotease (MMP) and furin and plays a role in the activation of the MT1-MMP zymogen

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a proteinase involved in the remodelling of extracellular matrix and the cleavage of a number of substrates. MT1-MMP is synthesized as a zymogen that requires intracellular post-translational cleavage to gain biological activity. Furin, a member of the pro-protein convertase family, has been implicated in the proteolytic removal of the MT1-MMP prodomain sequence. | ễFEBS Journal Golgi reassembly stacking protein 55 interacts with membrane-type MT 1-matrix metalloprotease MMP and furin and plays a role in the activation of the MT1-MMP zymogen Christian Roghi1 2 Louise Jones2 Matthew Gratian2 William R. English1 2 and Gillian Murphy1 2 1 Cancer Research UK Cambridge Research Institute The Li Ka Shing Centre UK 2 Cambridge Institute for MedicalResearch UK Keywords furin GRASP55 intracellular traffic MT1-MMP protease Correspondence C. Roghi Cancer Research UK Cambridge Research Institute The Li Ka Shing Centre Robinson Way Cambridge CB2 0RE UK Fax 44 0 1223 404573 Tel 44 0 1223 404472 E-mail chr26@ Present address KuDOS Pharmaceuticals Ltd Cambridge Science Park UK Received 25 March 2010 revised 14 May 2010 accepted 28 May 2010 doi Membrane-type 1 matrix metalloproteinase MT1-MMP is a proteinase involved in the remodelling of extracellular matrix and the cleavage of a number of substrates. MT1-MMP is synthesized as a zymogen that requires intracellular post-translational cleavage to gain biological activity. Furin a member of the pro-protein convertase family has been implicated in the proteolytic removal of the MT1-MMP prodomain sequence. In the present study we demonstrate a role for the peripheral Golgi matrix protein GRASP55 in the furin-dependent activation of MT1-MMP. MT1-MMP and furin were found to co-localize with Golgi reassembly stacking protein 55 GRASP55 . Further analysis revealed that GRASP55 associated with the cytoplasmic domain of both proteases and that the LLY573 motif in the MT1-MMP intracellular domain was crucial for the interaction with GRASP55. Overexpression of GRASP55 was found to enhance the formation of a complex between MT1-MMP and furin. Finally we report that disruption of the interaction between GRASP55 and furin led to a reduction in pro-MT1-MMP activation. Taken together these data suggest that GRASP55 may function as an adaptor protein coupling MT1-MMP .