Membrane type 1 matrix metalloproteinase (MT1-MMP) ubiquitination at Lys581 increases cellular invasion through type I collagen.
Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP14) is a zinc-dependent type I transmembrane metalloproteinase playing pivotal roles in the regulation of pericellular proteolysis and cellular migration. Elevated expression levels of MT1-MMP have been demonstrated to correlate with a poor prognosis in cancer. MT1-MMP has a short intracellular domain (ICD) that has been shown to play important roles in cellular migration and invasion, although these ICD-mediated mechanisms remain poorly understood. In this study, we report that MT1-MMP is mono-ubiquitinated at its unique lysine residue (Lys(581)) within the ICD. Our data suggest that this post-translational modification is involved in MT1-MMP trafficking as well as in modulating cellular invasion through type I collagen matrices. By using an MT1-MMP Y573A mutant or the Src family inhibitor PP2, we observed that the previously described Src-dependent MT1-MMP phosphorylation is a prerequisite for ubiquitination. Taken together, these findings show for the first time an additional post-translational modification of MT1-MMP that regulates its trafficking and cellular invasion, which further emphasizes the key role of the MT1-MMP ICD.
Department of Oncology, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, University of Cambridge, Cambridge CB2 0RE, United Kingdom. eisenach@biochem.mpg.de
Patricia A
PA
Eisenach
Pedro Corrêa
PC
de Sampaio
Gillian
G
Murphy
Christian
C
Roghi
D045744:Cell Line, Tumor; D002465:Cell Movement; D024042:Collagen Type I / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008239:Lysine; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D054875:Ubiquitination
D024042:Collagen Type I; D016392:Proto-Oncogene Proteins pp60(c-src); D053511:Matrix Metalloproteinase 14; D008239:Lysine