Matrix metalloproteinases (MMPs) are a major group of enzymes that regulate cell matrix composition. In this paper, our results show that c-Myc significantly induced vascular smooth muscle cells (VSMCs) migration and invasion, compared with the results, the T58A had more effectively than WT c-Myc, which was associated with c-Myc increased MMP-2 gene expression and activity. Silenced c-Myc led to reduce MMP-2 gene expression and activity, as well as decrease VSMC migration and invasion, indicating c-Myc is required for MMP-2 mediated VSMC migration and invasion. However, S62A had no effect on VSMC migration and invasion, which was in line with S62A had no effect on the c-Myc transcriptional activity. To better understand whether Bcl2 cooperate with c-Myc on MMP-2 function, our data show that although Bcl2 had no effect on the MMP-2 activity, the coexpressing c-Myc and Bcl2 significantly increased MMP-2 gene expression and activity. Our results suggest that phosphorylation of Bcl2 (T70E and EEE) had more effectively on the MMP-2 activity, which resulted from T70E and EEE severely increased c-Myc transcriptional activity by directly binding to c-Myc. The findings show that phosphorylation of Bcl2 enhanced c-Myc-mediated MMP-2 activity.