Fig. 9. (a) Scheme showing which IGF-IR signaling pathways were blocked using a molecular genetic approach (dead kinase IGF-IR) and the pharmacological compounds LY 294002, UO 126, PD 98059 and PI analog. ^*D3 phospholipids: PtdIns(3)P, PtdIns(3,4)P₂, PtdIns(3,5)P₂, PtdIns(3,4,5)P₂; (b) A model of biphasic motility responses regulated by the IGF-IR kinase in MCF-7 cells. Non-motile polarized epithelial cells develop mature adherens junctions and prominent stress fibers; apical ruffles and actin microspikes are not present. The initial stage of cell motility, active cell separation, is characterized by a loss of adherens junctions, disassembly of stress fibers, increased membrane ruffling and formation of actin microspikes; these processes are blocked by the inhibitors of the PI 3-kinase but not of MEK1/2 signaling. The subsequent transition of the cells from separating to migrating is characterized by re-assembly of stress fibers, development of the long membrane protrusions and translocation of the cell body over substratum. MEK1/2 inhibitor blocks all these processes.