Fig. 5

Importance of the type I IGF receptor and PI3-kinase\Akt pathway in the IGF-protection from anoikis. Representations of the alpha and beta integrins (cyan and light purple) and their activation of Akt via the focal adhesion and FAK signal transduction pathway (green) (a). The homo-tetrameric type I IGF receptor (IGF-IR, pink) has the α-chains of each receptor coloured lighter than the β-chains. The extracellular ligands: insulin (orange), IGF-2 (ochre) and IGF-1 (pale yellow) are shown. Signal transduction from the activated receptor is depicted through IRS-1 via the PI3-kinase, PIP3, mTOR2, PDPK1 and Akt pathway (pink) or the Grb2, SOS, Ras, Raf, MEK1 and MEK2, ERK1 and ERK2 pathway (purple). The downward pointing grey arrow indicates constitutive activation of ERK1 and ERK2. The downward pointing metallic blue arrows indicate that a signal has been transduced from each pathway. The pale gold spheres represent phosphorylated moieties. The GTP on activated Ras is a light yellow sphere and the GDP on inactive Ras an ivory sphere. Uncleaved inactive caspase 3 is shown as a small bright yellow sphere and uncleaved active PARP as a large bright yellow sphere. Cleaved active caspase 3 and cleaved inactive PARP are shown as the equivalent fragmented spheres. Downward pointing larger blue arrows indicate that cell survival and downward pointing red arrows indicate that cell death ensues. Kinase inhibitors (brick red) that inhibit PI3-kinase, LY294002, or Akt, GSK 690693, abrogate the protective effect of IGF on cell survival of unattached cells (b) whereas the MEK1 and MEK2 kinase inhibitor, U0126, does not (c). Inhibition of the type I IGF receptor with the specific inhibitory antibody, figitumumab (brick red), induces anoikis in IGF-stimulated cells or in cells grown in serum (d)