Key Concepts of Section 16.5

• Many RTKs and cytokine receptors can initiate the IP₃/DAG signaling pathway by activating phospholipase C_γ (PLC_γ), a different PLC isoform than the one activated by G protein–coupled receptors.

• Activated RTKs and cytokine receptors also can initiate another phosphoinositide pathway by binding a PI-3 kinase, thereby allowing the enzyme access to its membrane-bound phosphoinositide substrates, which then become phosphorylated at the 3 position (PI 3-phosphates; see Figure 16-28).

• The PH domain in various proteins binds to PI 3-phosphates, forming signaling complexes associated with the cytosolic face of the plasma membrane.

• Protein kinase B (PKB) becomes partially activated by binding to PI 3-phosphates with its PH domain. Full activation of PKB requires phosphorylation by the kinase PDK1, which is also recruited to the membrane by binding to PI 3-phosphates, and by a second kinase, PDK2 (see Figure 16-29).

• Activated PKB promotes survival of many cells by directly phosphorylating and inactivating several pro-apoptotic proteins and by phosphorylating and inactivating the FOXO3a transcription factor, which otherwise induces synthesis of pro-apoptotic proteins.

• Signaling via the PI-3 kinase pathway is terminated by the PTEN phosphatase, which hydrolyzes the 3-phosphate in PI 3-phosphates. Loss of PTEN, a common occurrence in human tumors, promotes cell survival and proliferation.