The C-terminal region of membrane type matrix metalloproteinase is a functional transmembrane domain required for pro-gelatinase A activation.
We identified a new matrix metalloproteinase (membrane type matrix metalloproteinase (MT-MMP)) that has a potential transmembrane (TM) domain at the C terminus and reported its expression on the surface of invasive tumor cells. The expression of MT-MMP induced specific activation of 72-kDa pro-gelatinase A (Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) Nature 370, 61-65). Thus, MT-MMP on the cell surface is thought to play an important role in various physiological and pathological processes accompanying tissue remodeling. In this study, we demonstrated that the potential TM domain deduced from the amino acid sequence functions as a membrane linker when it is fused to a secretory protein, tissue inhibitor of matrix metalloproteinases-1. The pro-gelatinase A activation function of MT-MMP was abolished by truncation of the TM domain and recovered by fusing the MT-MMP mutant with the TM domain of interleukin 2 receptor alpha-chain. The truncated MT-MMP was released from the cells into the medium and detected as processed or modified forms. In spite of the deletion of the TM domain some portions of the mutant MT-MMP were still retained on the surface of cells. Thus, MT-MMP has an additional device to keep it on the cell surface. The TM domain however, plays an essential role in the pro-gelatinase A activation function of MT-MMP, probably regulating its fine orientation or the localization that is necessary to interact with substrate.
Cao
J
J
Department of Molecular Virology and Oncology, School of Medicine, Kanazawa University, Ishikawa, Japan.
Sato
H
H
Takino
T
T
Seiki
M
M
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D018076:DNA, Complementary; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism*
D018076:DNA, Complementary; D004792:Enzyme Precursors; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase