Metastasis is a devastating aspect of malignant cells. Infiltration of surrounding breast tissue by malignant cells is the initial stage of cancer invasiveness. Dictyostelium cell motility and chemotaxis is used as a model for understanding these processes in normal and diseased human cells. Our work has shown that CaM is essential for chemotaxis and specific CaMBPs are linked to cAMP chemotaxis (Gauthier & O'Day, 2001). We also have examined the importance of CaM and its binding proteins in cell spreading of the human metastatic breast cancer cell line, MDA-MB-231, after being induced by epidermal growth factor (EGF) and by transforming growth factor beta (TGFβ). Inhibitors of CaM, prevent cell spreading induced by these growth factors and we have identified numerous CaMBPs in MDA-MB-231 cells and some of these undergo specific changes during factor-induced spreading (Gauthier & O'Day, unpublished). The EGF receptor (EGFR) has been shown to be a CaMBP but its factor-induced autophosphorylation, an essential initial step in signal transduction, is not affected by CaM inhibitors indicating that this initial event is not the target of CaM inhibition of cell spreading. What are the critical CaM-dependent pathways that mediate cell spreading?
Previous work by others has shown that the EGF receptor itself is a CaMBP. Another related component of the calcium signaling pathway is protein kinase C alpha. We have shown that PKCα is a negative regulator of cell spreading and motility in MDA-MB-231 cells. This regulation is somehow linked to EGFR function since immunolocalization studies show that EGF, EGFR and PKCα all co-localize when cells are stimulated to spread and move by EGF.
Gauthier, Mona L., & Danton H. O'Day, 2001. Detection of Calmodulin-Binding Proteins and Calmodulin-Dependent Phosphorylation Linked to Calmodulin-Dependent Chemotaxis to Folic and cAMP in Dictyostelium. Cellular Signalling 13: 575-584.
Gauthier, Mona L., Cheryl Torretto, John Ly, Valerie Francescutti, and Danton H. O'Day, 2003. Protein Kinase Cα Negatively Regulates Cell Spreading and Motility in MDA-MB-231 Human Breast Cancer Cells Downstream of Epidermal Growth Factor Receptor. Biochemical Biophysical Research Communications 307: 839-846.
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