Signaling by extracellular signaling proteins of the ephrin family provides an example of how RTKs can activate a Rho GTPase. Ephrins bind and thereby activate members of the Eph family of RTKs (see Figure 15–43). One member of the Eph family is found on the surface of motor neurons and helps guide the migrating tip of the axon (called a growth cone) to its muscle target. The binding of a cell-surface ephrin protein activates the Eph receptor, causing the growth cones to collapse, thereby repelling them from inappropriate regions and keeping them on track. The response depends on a Rho-GEF called ephexin, which is stably associated with the cytosolic tail of the Eph receptor. When ephrin binding activates the Eph receptor, the receptor activates a cytoplasmic tyrosine kinase that phosphorylates ephexin on a tyrosine, enhancing the ability of ephexin to activate the Rho protein RhoA. The activated RhoA (RhoA-GTP) then regulates various downstream target proteins, including some effector proteins that control the actin cytoskeleton, causing the growth cone to collapse (Figure 15–51).
Having considered how RTKs use GEFs and monomeric GTPases to relay signals into the cell, we now consider a second major strategy that RTKs use that depends on a quite different intracellular relay mechanism.
Figure 15–51 Growth cone collapse mediated by Rho family GTPases.
The binding of ephrin A1 proteins on an adjacent cell activates EphA4 RTKs on the growth cone. Phosphotyrosines on the activated Eph receptors recruit and activate a cytoplasmic tyrosine kinase to phosphorylate the receptor-associated Rho-GEF ephexin on a tyrosine. This enhances the ability of the ephexin to activate RhoA. RhoA then induces the growth cone to collapse by stimulating the myosin-dependent contraction of the actin cytoskeleton.
PI 3-Kinase Produces Lipid Docking Sites in the Plasma Membrane
As mentioned earlier, one of the proteins that binds to the intracellular tail of RTK molecules is the plasma-membrane-bound enzyme phosphoinositide 3-kinase (PI 3-kinase). This kinase principally phosphorylates inositol phospholipids rather than proteins, and both RTKs and GPCRs can activate it. It plays a central part in promoting cell survival and growth.
Phosphatidylinositol (PI) is unique among membrane lipids because it can undergo reversible phosphorylation at multiple sites on its inositol head group to generate a variety of phosphorylated PI lipids called phosphoinositides. When activated, PI 3-kinase catalyzes phosphorylation at the 3 position of the inositol ring to generate several phosphoinositides (Figure 15–52). The production of PI(3,4,5)P3 matters most because it can serve as a docking site for various intracellular signaling proteins, which assemble into signaling complexes that relay the signal into the cell from the cytosolic face of the plasma membrane (see Figure 15–10C).