The Role of Actin Polymerization in Tumor Metastasis

Abstract

Abstract : Breast cancer is frequently associated with gene amplification of EMS1 or cortactin, a protein that regulates the assembly of filamentous actin (F-actin). Previous studies have demonstrated that overexpression of cortactin results in increase in metastases and invasion of breast tumor cells. The goal of this project is to reveal the potential to target cortactin in tumor metastasis with initial emphasis on the biological significance of the interaction of cortactin with phospholipids, which are known to play a critical role in the modulation of cell migration in response to extracellular stimuli and other cellular proteins. Cortactin binds to a subset of phosphatidylinositides, including phosphatidylinositol 5-phosphoate (PI(5) P), phosphatidylinoistol 4,5 biophosphoate (PI(4,5)P2) and phosphatidylinositol 4-phosphoate (PI(4)P). Interestingly, not all those phospholipids show a similar effect on the activity of cortactin. While PI(5)P increases the activity of cortactin for actin assembly, PI(4)P inhibits the cortactin mediated actin branching. This data indicates that the activity of cortactin is regulated by different types of membrane phospholipids. Our recent study has also identified that cortactin binds to missing in metastasis (MIM), which is frequently under expressed in many malignant cells. Binding of MIM to cortactin appears to be regulated by extracellular stimuli such as PDGF and requires tyrosine phosphorylation of cortactin. Furthermore, interaction with MIM potentiates the activity of cortactin but inhibits N-WASP for actin polymerization. More significantly, overexpression of MIM inhibits tumor cell motility. These data indicate that interaction between cortactin and MIM may play an important role in tumor metastasis.