Internalization-defective mutants prevent invasion.

The ability of tumor cells to migrate through the body and invade new tissues is a major focus for research that could leadto new cancer therapies. On page 1345, Uekita et al. demonstrate that the membrane-bound matrix metalloproteinase MT1-MMP, which functions in both migration and invasion, must be recycled continuously from the cell surface to sustain both processes. Blocking the recycling process inhibits the invasive phenotype.

Previous work had shown that MT1-MMP localizes at the migration edge, but it remained unclear how the enzyme was regulated. The authors show that specific sequences in the cytoplasmic tail of MT1-MMP bind to a component of clathrin-coated pits, and that mutations in these sequences prevent internalization and cause the enzyme to accumulate on the cell surface. Although the internalization-defective enzyme specifically accumulates at the migration edge, it does not promote migration or invasion in various assay systems, indicating that the protein must turn over to remain active.

The authors hypothesize that inactivation of MT1-MMP on the cell surface by degradation or inhibitors necessitates continuous replacement of the enzyme; as front-line troops wear out, they are replaced by new recruits. By defining the small motif required for this recycling process, the authors have also identified a potential molecular target for drugs that might inhibit tumor cell metastasis. ▪