The control of cell growth by the PI-3-kinase–Akt pathway depends in part on a large protein kinase called TOR (named as the target of rapamycin, a bacterial toxin that inactivates the kinase and is used clinically as both an immunosuppressant and anticancer drug). TOR was originally identified in yeasts in genetic screens for rapamycin resistance; in mammalian cells, it is called mTOR, which exists in cells in two functionally distinct multiprotein complexes. mTOR complex 1 contains the protein raptor; this complex is sensitive to rapamycin, and it stimulates cell growth—both by promoting ribosome production and protein synthesis and by inhibiting protein degradation. Complex 1 also promotes both cell growth and cell survival by stimulating nutrient uptake and metabolism. mTOR complex 2 contains the protein rictor and is insensitive to rapamycin; it helps to activate Akt (see Figure 15–53), and it regulates the actin cytoskeleton via Rho family GTPases.
The mTOR in complex 1 integrates inputs from various sources, including extracellular signal proteins referred to as growth factors and nutrients such as amino acids, both of which help activate mTOR and promote cell growth. The growth factors activate mTOR mainly via the PI-3-kinase–Akt pathway. Akt activates mTOR in complex 1 indirectly by phosphorylating, and thereby inhibiting, a GAP called Tsc2. Tsc2 acts on a monomeric Ras-related GTPase called Rheb (see Table 15–5). Rheb in its active form (Rheb-GTP) activates mTOR in complex 1. The net result is that Akt activates mTOR and thereby promotes cell growth (Figure 15–54). We discuss how mTOR stimulates ribosome production and protein synthesis in Chapter 17 (see Figure 17–64).
As mentioned earlier, RTKs and GPCRs activate some of the same intracellular signaling pathways. Both, for example, can activate the inositol phospholipid pathway triggered by phospholipase C. Moreover, even when they activate different pathways, the different pathways can converge on the same target proteins. Figure 15–55 illustrates both of these types of signaling overlaps: it summarizes five parallel intracellular signaling pathways that we have discussed so far—one triggered by GPCRs, two triggered by RTKs, and two triggered by both kinds of receptors. Interactions among these pathways allow different extracellular signal molecules to modulate and coordinate each other’s effects.
Figure 15–54 Activation of mTOR by the PI-3-kinase–Akt signaling pathway.
(A) In the absence of extracellular growth factors, Tsc2 (a Rheb-GAP) keeps Rheb inactive; mTOR in complex 1 is inactive, and there is no cell growth. (B) In the presence of growth factors, activated Akt phosphorylates and inhibits Tsc2, thereby promoting the activation of Rheb. Activated Rheb (Rheb-GTP) helps activate mTOR in complex 1, which in turn stimulates cell growth. Figure 15–53 shows how growth factors (or survival signals) activate Akt. The Erk MAP kinase (see Figure 15–49) can also phosphorylate and inhibit Tsc2 and thereby activate mTOR. Thus, both the PI-3-kinase–Akt and Ras–MAP-kinase signaling pathways converge on mTOR in complex 1 to stimulate cell growth.
Tsc2 is short for tuberous sclerosis protein 2, and it is one component of a heterodimer composed of Tsc1 and Tsc2 (not shown); these proteins are so called because mutations in either gene encoding them cause the genetic disease tuberous sclerosis, which is associated with benign tumors that contain abnormally large cells.
PI(3,4,5)P3