Model of spatiotemporal regulation of Kit activation and Kit-dependent activation of PI3-K. (A) In unstimulated cells, Kit is present in the plasma membrane. Lipid rafts contain SFKs, PTEN, and p110. Before stimulation, p85, PDK1, and Akt are located in the cytosol. Upon KL stimulation wild-type Kit is recruited to lipid rafts, leading to interaction with SFKs. Association of Kit with p85 leads to assembly of the PI3-K complex. Diffusion of PI-3K-generated PIP₃ to the cytosol and binding to PDK1 and Akt via PH domains results in translocation of PDK1 and Akt to the plasma membrane, where they become activated. Activation of Akt mediates Kit-dependent proliferation. PTEN translocates from lipid rafts to the cytosol where it deactivates cytosolic PIP₃. (C) Oncogenic Kit is initially located in lipid rafts in a tyrosine kinase-dependent manner. Some Kit protein is also present in the membrane (not shown). Association of oncogenic Kit with p85 in lipid rafts leads to constitutive activation of PI3-K and Akt. PTEN is located primarily in the cytosol.