Intercellular signals regulate most activities of animal cells, including apoptosis. These extracellular signals are part of the normal “social” controls that ensure that individual cells behave for the good of the organism as a whole—in this case, by surviving when they are needed and killing themselves when they are not. Some extracellular signal molecules stimulate apoptosis, whereas others inhibit it. We have discussed signal proteins such as Fas ligand that activate death receptors and thereby trigger the extrinsic pathway of apoptosis. Other extracellular signal molecules that stimulate apoptosis are especially important during vertebrate development: a surge of thyroid hormone in the bloodstream, for example, signals cells in the tadpole tail to undergo apoptosis at metamorphosis. In mice, locally produced signal proteins stimulate cells between developing fingers and toes to kill themselves (see Figure 18–2). Here, however, we focus on extracellular signal molecules that inhibit apoptosis, which are collectively called survival factors.
Most animal cells require continuous signaling from other cells to avoid apoptosis. This surprising arrangement apparently helps ensure that cells survive only when and where they are needed. Nerve cells, for example, are produced in excess in the developing nervous system and then compete for limited amounts of survival factors that are secreted by the target cells that they normally connect to (see Figure 21–81). Nerve cells that receive enough survival signals live, while the others die. In this way, the number of surviving neurons is automatically adjusted so that it is appropriate for the number of target cells they connect with (Figure 18–11). A similar competition for limited amounts of survival factors produced by neighboring cells is thought to control cell numbers in other tissues, both during development and in adulthood.
Survival factors usually bind to cell-surface receptors, which activate intracellular signaling pathways that suppress the apoptotic program, often by regulating members of the Bcl2 family of proteins. Some survival factors, for example, stimulate the synthesis of anti-apoptotic Bcl2 family proteins such as Bcl2 itself or BclXL (Figure 18–12A). Others act by inhibiting the function of pro-apoptotic BH3-only proteins such as Bad (Figure M18–12B). In Drosophila, some survival factors act by phosphorylating and inactivating anti-IAP proteins such as Hid, thereby enabling IAP proteins to suppress apoptosis (Figure 18–12C). Some developing neurons, like those illustrated in Figure 18–11, use an ingenious alternative approach: survival-factor receptors stimulate apoptosis—by an unknown mechanism—when they are not occupied, and then stop promoting death when survival factor binds. The end result in all these cases is the same: cell survival depends on survival factor binding.
phagocytes remove the Apoptotic Cell
Apoptotic cell death is a remarkably tidy process: the apoptotic cell and its fragments do not break open and release their contents, but instead remain intact as they are efficiently eaten—or phagocytosed—by neighboring cells, leaving no trace and therefore triggering no inflammatory response (see Figure 18–1B and Movie 13.5). This engulfment process depends on chemical changes on the surface of the apoptotic cell, which displays signals that recruit phagocytic cells. An especially important change occurs in the distribution of the negatively charged phospholipid phosphatidylserine on the cell surface. This phospholipid is normally located exclusively in the inner leaflet of the lipid bilayer of the plasma membrane (see Figure 10–15), but it flips to the outer leaflet in apoptotic cells. The
Figure 18–11 The role of survival factors and cell death in adjusting the number of developing nerve cells to the amount of target tissue. More nerve cells are produced than can be supported by the limited amount of survival factors released by the target cells. therefore, some nerve cells receive an insufficient amount of survival factors to avoid apoptosis. this strategy of overproduction followed by culling helps ensure that all target cells are contacted by nerve cells and that the extra nerve cells are automatically eliminated.