MIM (Missing-in-Metastasis), also known as MTSS1 (metastasis suppressor 1), is a scaffold protein that is down-regulated in multiple metastatic cancer cell lines compared with non-metastatic counterparts. MIM regulates cytoskeletal dynamics and actin polymerization, and has been implicated in the control of cell motility and invasion. MIM has also been shown to bind to a receptor PTP (protein tyrosine phosphatase), PTPdelta, an interaction that may provide a link between tyrosine-phosphorylation-dependent signalling and metastasis. We used shRNA-mediated gene silencing to investigate the consequences of loss of MIM on the migration and invasion of the MCF10A mammary epithelial cell model of breast cancer. We observed that suppression of MIM by RNAi enhanced migration and invasion of MCF10A cells, effects that were associated with increased levels of PTPdelta. Furthermore, analysis of human clinical data indicated that PTPdelta was elevated in breast cancer samples when compared with normal tissue. We demonstrated that the SRC protein tyrosine kinase is a direct substrate of PTPdelta and, upon suppression of MIM, we observed changes in the phosphorylation status of SRC; in particular, the inhibitory site (Tyr527) was hypophosphorylated, whereas the activating autophosphorylation site (Tyr416) was hyperphosphorylated. Thus the absence of MIM led to PTPdelta-mediated activation of SRC. Finally, the SRC inhibitor SU6656 counteracted the effects of MIM suppression on cell motility and invasion. The present study illustrates that both SRC and PTPdelta have the potential to be therapeutic targets for metastatic tumours associated with loss of MIM.
School of Medicine