Induction of fascin spikes in breast cancer cells by activation of the insulin-like growth factor-I receptor

Abstract

Insulin-like growth factor-I receptor (IGF-IR) signaling contributes to the formation of mammary carcinomas and has chiefly been studied with regard to the proliferative and anti-apoptotic effects of IGF-IR signaling. However, IGF-IR activation also affects the actin cytoskeleton and alterations in cell migratory behavior are of known importance for the malignant conversion and metastasis of epithelial cells. The actin-binding protein fascin is found in cell projections and spikes that are involved in the locomotion of mesenchymal cells. Fascin expression is typically low in normal epithelial cells, but is markedly upregulated in several types of carcinomas. Here, we also demonstrate increased fascin expression in breast carcinoma cell lines and adopt MCF-7 human mammary carcinoma cells that over-express wild-type or kinase-inactivated forms of the IGF-IR as a model system to test the hypothesis that IGF-IR activation induces fascin projections. We show that the time-dependent dissociation of cell colonies that occurs upon receptor activation by IGF-I involves the formation of dynamic, fascin-containing lateral cell projections that co-localize with ruffling membranes in association with protrusive activity and cell migratory phenotype. The molecular mechanism of these effects is completely dependent on IGF-IR tyrosine kinase activity and is mediated by a phosphatidylinositol (PI) 3-kinase-dependent process. In demonstrating transduction of fascin spike assembly by activation of a peptide growth factor receptor, these novel data reveal a wide role for fascin spikes in cell motility and provide new insight into the complex effects of IGF-IR signaling on actin cytoskeletal organization.