title: 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.
abstract: 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 LLY(573) 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 with furin, thus leading to the activation of the zymogen.
authors.affiliation: Cancer Research UK Cambridge Research Institute, The Li Ka Shing Centre, UK. chr26@cam.ac.uk
authors.forename: Christian
authors.initials: C
authors.lastname: Roghi
authors.forename: Louise
authors.initials: L
authors.lastname: Jones
authors.forename: Matthew
authors.initials: M
authors.lastname: Gratian
authors.forename: William R
authors.initials: WR
authors.lastname: English
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
mesh_terms: D045744:Cell Line, Tumor; D003593:Cytoplasm; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D045683:Furin / Q000378:metabolism*; D000077614:Golgi Matrix Proteins; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes
chemical_list: D004792:Enzyme Precursors; C122048:GORASP2 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D045683:Furin; D053511:Matrix Metalloproteinase 14