MT1-MMP shedding involves an ADAM and is independent of its localization in lipid rafts.
The membrane type 1-matrix metalloproteinase (MT1-MMP) is a membrane-anchored protease that its entire ectodomain is shed from the cell surface. Here we show that in HT1080 cells MT1-MMP is shed as two soluble forms of approximately 52 and approximately 50kDa. Analyses in purified HT1080 plasma membranes show that release of these species is a two-step time-dependent process that is mediated by integral membrane metalloprotease(s). Differential sensitivity to TIMP-3 inhibition of the shedding process suggests that the second cleavage step leading to the formation of the 50-kDa soluble species is mediated by an ADAM. We also show that shedding of MT1-MMP is independent of its partition into lipid rafts because both wild type and glycosylphosphatidylinositol (GPI)-anchored MT1-MMP are shed. These studies provide new insights into the process of MT1-MMP ectodomain shedding, which may regulate pericellular proteolysis.
Toth
Marta
M
Department of Chemistry and Biochemistry and the Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN 46556, USA.
Sohail
Anjum
A
Mobashery
Shahriar
S
Fridman
Rafael
R
D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000032:analysis / Q000378:metabolism*; D021962:Membrane Microdomains / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology
D011480:Protease Inhibitors; D051722:ADAM Proteins; D053511:Matrix Metalloproteinase 14