Objectives: We set out to investigate the role of ADAMTS-4 (aggrecanase) in cell-surface binding and to analyse the effects of over-expressing ADAMTS-4 domain deletion mutants on regulating cellular morphology. Methods: For this purpose, isogenic clonal CHO-cell lines were established using the Invitrogen Flp-IN system that expressed wild type ADAMTS-4, E362-A ADAMTS-4 and various C-terminal domain deletion mutants of ADAMTS-4. Results: Over-expression of wild type ADAMTS-4 resulted in a marked change in cellular morphology with prominent loss of focal adhesions and establishment of a cortical actin cytoskeleton. These changes were dependent on enzymatic activity, as incubation with TIMP-3 reversed these cytoskeletal changes. Furthermore, cell lines expressing an inactive E362-A ADAMTS-4 mutant showed the same morphology as untransfected cells or cells expressing C-terminal deletion mutants of ADAMTS-4. The underlying mechanism that regulate the morphological changes observed in the cell line expressing wild type ADAMTS-4 was further analysed using a variety of metalloproteinase and signalling inhibitors. Conclusions: ADAMTS-4 induces a signalling pathway that conveys an increased motility to CHO-cells dependent on a small aminoacid sequence motif in its C-terminal domain and proteolytic activity.