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doi: 10.1242/10.1242/jcs.00104

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Functional role of -actinin, PI 3-kinase and MEK1/2 in insulin-like growth factor I receptor kinase regulated motility of human breast carcinoma cells

¹ Department of Microbiology, University of Pennsylvania, 3610 Hamilton Walk, 211 Johnson Pavilion, Philadelphia PA 19104, USA
² MRC-Laboratory for Molecular Cell Biology and Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK
³ Department of Cell Biology, Building NC1, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA

^* Author for correspondence (e-mail: guvakova{at}mail.med.upenn.edu)

Accepted 19 August 2002

Within epithelial tissue, cells are held together by specialized lateral junctions. At particular stages of development and in pathological processes such as metastasis, cells break down the intercellular junctions, separate from the epithelial sheet and migrate individually. Despite the importance of these processes, little is understood about the regulatory mechanisms of active cell separation. In view of the effects of insulin-like growth factor I (IGF-I) on mammary gland development and cancer, we developed a model using MCF-7 human breast cancer cells in which the process of cell separation can be induced by IGF-I. The separation was enhanced in MCF-7 cells overexpressing the IGF-IR and blocked in the cells expressing a dead-kinase mutant of this receptor. Activation of the IGF-IR resulted in a rapid formation of motile actin microspikes at the regions of cell-cell contacts, disorganization of mature adherens junctions and the onset of cell migration. In cell separation, the signaling between the IGF-IR kinase and actin required phosphatidylinositol 3 (PI 3)-kinase-generated phospholipids but not MAP kinases and was mediated by -actinin. The activity of MEK1/2 kinases was needed for consecutive cell migration. This work also defined a new function for -actinin. Upon IGF-IR activation, green fluorescence protein (GFP)-labeled -actinin concentrated at the base of actin microspikes. Deletion of the N-terminal actin-binding domain of -actinin prevented this redistribution, indicating that this domain is necessary. Delection of the C-terminal tail of -actinin reduced the number of microspikes, showing that -actinin has a role in the development of microspikes and is not passively reorganized with filamentous actin. We suggest that the signaling pathway from the IGF-IR kinase through the PI-3 kinase to -actinin participates in the rapid organization of actin into microspikes at the cell-cell junctions and leads to active cell separation, whereas signaling through ERK1/2 MAP kinases controls cell migration following cell separation.

Key words: IGF-IR signaling, -actinin, Actin cytoskeleton, Breast cancer cell migration

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