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Unformatted text preview: th neuronal survival and differentiation by activating a receptor protein-tyrosine kinase. Other types of cells are similarly dependent upon growth factors or cell contacts that activate nonreceptor protein-tyrosine kinases associated with integrins. Indeed, most cells in higher animals are programmed to undergo apoptosis unless cell death is actively suppressed by survival signals from other cells. One of the major intracellular signaling pathways responsible for promoting cell survival is initiated by the enzyme PI 3-kinase, which is activated by either protein-tyrosine kinases or G protein-coupled receptors. PI 3-kinase phosphorylates the membrane phospholipid PIP2 to form PIP3, which activates the protein-serine/threonine kinase Akt (see Figures 15.30 and 15.31). Akt then phosphorylates a number of proteins that regulate apoptosis (Figure 17.11). One key substrate for Akt is the proapoptotic BH3only Bcl-2 family member called Bad. Phosphorylation of Bad by Akt creates a binding site for 14-3-3 chaperone proteins that sequester Bad in an inactive form, so phosphorylation of Bad by Akt inhibits apoptosis and promotes cell survival. Bad is similarly phosphorylated by protein kinases of other growth factor-induced signaling pathways, including the Ras/Raf/MEK/ERK pathway, so it serves as a convergent regulator of growth factor signaling in mediating cell survival. Other targets of Akt, including the FOXO transcription factors, also play key roles in cell survival. Phosphorylation of FOXO by Akt creates a binding site for 14-3-3 proteins, which sequester FOXO in an inactive form in the cytoplasm (see Figure 15.32). In the absence of growth factor signaling and Akt activity, FOXO is released from 14-3-3 and translocates to the nucleus, stimulating transcription of proapoptotic genes, including the gene encoding the BH3-only protein, Bim. Akt and its downstream target GSK-3 also regulate other transcription factors with roles in cell survival, including p53 and NF-kB, which control the expression of additional Bcl-2 family members. In addition, the level of the antiapoptotic Bcl-2 family member Mcl-1 may be modulated via translational regulation by both GSK-3 and the mTOR pathway (see Figure 15.33). These multiple effects on members of the Bcl-2 family converge to regulate the intrinsic pathway of apoptosis, PUMA Noxa Apoptosis FIGURE 17.10 Role of p53 in DNA damage-induced apoptosis DNA damage leads to activation of the ATM and Chk2 protein kinases, which phosphorylate and stabilize p53 resulting in rapid increases in p53 levels. The protein p53 then activates transcription of genes encoding the proapoptotic BH3-only proteins PUMA and Noxa, leading to cell death.
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CELL DEATH AND CELL RENEWAL 11 Survival factor Receptor tyrosine kinase Plasma membrane PIP2 P P PI 3-kinase mTOR mTORC2 Active Akt P Bad FOXO p53 NF-kB Translational regulation P GSK-3 mTORC1 PIP3 Akt P P PDK1 Bim FIGURE 17.11 The PI 3-kinase pathway and cell survival Many growth factors that signal cell survival activate receptor protein-tyrosine kinases, leading to activation of PI 3-kinase, formation of PIP3, and activation of the protein kinase, Akt. Akt then phosphorylates a number of proteins that contribute to cell survival. Phosphorylation of the BH3-only protein Bad maintains it in an inactive state, as does phosphorylation of the FOXO transcription factors. In the absence of Akt signaling, activation of Bad promotes apoptosis and activation of FOXO stimulates transcription of another BH3-only protein, Bim. Additional targets of Akt that have been implicated in regulation of apoptosis include the protein kinase GSK-3 and additional transcription factors, such as p53 and NF-kB, both of which are regulated by Akt and GSK-3 phosphorylation. Translational regulation by GSK-3 and by the mTOR pathway (see Figure 15.33) may also affect cell survival. controlling the activation of caspase-9 and cell survival in response to growth factor stimulation. In contrast to the cell stress and growth factor signaling pathways that regulate the intrinsic pathway of apoptosis, some secreted polypeptides activate receptors that induce cell death via the extrinsic pathway of apoptosis. These receptors directly activate a distinct initiator caspase, caspase-8 ( Figure 17.12). The polypeptides that signal cell death by this pathway belong to the tumor necrosis factor (TNF) family. They bind to members of the TNF receptor family, which can induce apoptosis in a variety of cell types. One of the best characterized members of this family is the cell surface receptor called Fas, which plays important roles in controlling cell death in the immune system. For example, apoptosis induced by activation of Fas is responsible for killing target cells of the immune system, such as cancer cells or virus-infected cells, as well as for eliminating excess lymphocytes at the end of an immune response. TNF and related family members consist of three identical polypeptide chains, and their binding induces receptor trime...
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