One especially important PH-domain-containing protein is the serine/threonine protein kinase Akt. The PI-3-kinase–Akt signaling pathway is the major pathway activated by the hormone insulin. It also plays a key part in promoting the survival and growth of many cell types in both invertebrates and vertebrates, as we now discuss.
The PI-3-Kinase–Akt Signaling Pathway Stimulates Animal Cells to Survive and Grow
As discussed earlier, extracellular signals are usually required for animal cells to grow and divide, as well as to survive (see Figure 15–4). Members of the insulin-like growth factor (IGF) family of signal proteins, for example, stimulate many types of animal cells to survive and grow. They bind to specific RTKs (see Figure 15–43), which activate PI 3-kinase to produce PI(3,4,5)P3. The PI(3,4,5)P3 recruits two protein kinases to the plasma membrane via their PH domains—Akt (also called protein kinase B, or PKB) and phosphoinositide-dependent protein kinase 1 (PDK1), and this leads to the activation of Akt (Figure 15–53). Once activated,
PI(3,4,5)P3 PI(4,5)P2 PH domains CYTOSOL activated receptor tyrosine kinase activated PI 3-kinase PDK1 Akt phosphorylation and activation of Akt by PDK1 and mTOR dissociation active Akt Bad inactive apoptosis-inhibitory protein inactivated Bad INHIBITION OF APOPTOSIS PHOSPHORYLATION OF Bad 14-3-3 protein mTOR (in complex 2)P P P P P P P P P P P P P P P P P P
Figure 15–53 One way in which signaling through PI 3-kinase promotes cell survival. An extracellular survival signal activates an RTK, which recruits and activates PI 3-kinase. The PI 3-kinase produces PI(3,4,5)P3, which serves as a docking site for two serine/threonine kinases with PH domains—Akt and the phosphoinositide-dependent kinase PDK1—and brings them into proximity at the plasma membrane. The Akt is phosphorylated on a serine by a third kinase (usually mTOR in complex 2), which alters the conformation of the Akt so that it can be phosphorylated on a threonine by PDK1, which activates the Akt. The activated Akt now dissociates from the plasma membrane and phosphorylates various target proteins, including the Bad protein. When unphosphorylated, Bad holds one or more apoptosis-inhibitory proteins (of the Bcl2 family—discussed in Chapter 18) in an inactive state. Once phosphorylated, Bad releases the inhibitory proteins, which now can block apoptosis and thereby promote cell survival. As shown, the phosphorylated Bad binds to a ubiquitous cytosolic protein called 14-3-3, which keeps Bad out of action.
Akt phosphorylates various target proteins at the plasma membrane, as well as in the cytosol and nucleus. The effect on most of the known targets is to inactivate them; but the targets are such that these actions of Akt all conspire to enhance cell survival and growth, as illustrated for one cell survival pathway in Figure 15–53.