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. 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.
Roghi
Christian
C
Cancer Research UK Cambridge Research Institute, The Li Ka Shing Centre, UK. chr26@cam.ac.uk
Jones
Louise
L
Gratian
Matthew
M
English
William R
WR
Murphy
Gillian
G
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
D004792:Enzyme Precursors; C122048:GORASP2 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D045683:Furin; D053511:Matrix Metalloproteinase 14