FIG. 9.

Multiple TCR-stimulated signaling pathways are sensitive to the level of D3-phosphorylated phosphoinositides. Opposing activities of PI3K (heavy green arrow) and PTEN (red arrow) are shown regulating the pool of D3-phosphorylated phosphoinositides. The potential for D3-phosphorylated phosphoinositides to regulate signaling molecules activated in response to TCR activation is depicted by light green arrows. Of the signaling proteins indicated, Itk, Tec, PLC-γ1, Akt, and Vav all contain PH domains that preferentially bind to PI-3,4,5-P₃. Ras does not contain a PH domain, but it is subject to regulation by SOS and Ras-GAP, which both contain PI-3,4,5-P₃-binding PH domains. Likewise, the various isozymes of PKC do not possess PH domains but are all phosphorylated upon their activation loop by PDK1, which has a PH domain that binds PI-3,4,5-P₃ with high affinity.