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Annu. Rev. Immunol. 1999. 17:331–67 c 1999 by Annual Reviews. All rights reserved Copyright °
TUMOR NECROSIS FACTOR RECEPTOR AND Fas SIGNALING MECHANISMS D. Wallach, E. E. Varfolomeev, N. L. Malinin, Yuri V. Goltsev, A. V. Kovalenko, and M. P. Boldin Department of Biological Chemistry, Weizmann Institute, Rehovot, 76100, Israel; e-mail:
[email protected] KEY WORDS:
apoptosis, caspase, MAP kinase, NF-κB, signaling
ABSTRACT Four members of the tumor necrosis factor (TNF) ligand family, TNF-α, LT-α, LT-β, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LTβR), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far—caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-κB activation cascade—mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.
INTRODUCTION The study of cell response to ligands of the tumor necrosis factor (TNF) family is one of the most dynamic research areas in the signaling field today. Vast 331 0732-0582/99/0410-0331$08.00
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amounts of phenomenological information have accumulated. Most of the available knowledge concerns the cell-killing activity of some of these ligands, a subject that has gained increased attention with the recent surge of interest in cell death mechanisms. The isolation and cloning of TNF-α and lymphotoxin (LT)-α in 1985 (196–199), and later of their receptors, the p55 and p75 TNF receptors (CD120a and CD120b) (200–204), confirmed that cell killing by these two ligands—a phenomenon then already known for almost 20 years (205–208)—is a receptor-induced effect. However, it was only after the discovery of Fas/Apo1 (CD95), a death-inducing receptor functionally related to CD120a (208–211), and its ligand (Fas-L) (212) that confidence in the biological significance of this death-inducing function prompted intense studies of the signaling mechanisms involved. The cloning of TNF-α and LT-α also confirmed indications that these cytokines have many other activities in addition to cell killing, mainly related to inflammation. The known range of activities has expanded with the recent discovery of two additional ligand molecules, LT-β (213) and LIGHT (11), which together with LT interact with two additional receptors, the lymphotoxin β receptor (LTβR) (214) and herpes virus entry mediator (HVEM) (10). The pattern of activities mediated by this group of ligands and receptors is outstanding in its complexity as well as in its diametric consequences, which range from destruction of tissues to orchestration of immune organogenesis. The nature of the mechanisms that control this complex response has gained wide interest even beyond the realm of basic science. Particular attention to TNF and its function has come from the fields of biomedicine and biotechnology because increasing evidence implicates dysregulation of the function of this cytokine in the pathology of many diseases. Molecular understanding in this field has lagged significantly behind the phenomenological knowledge. Today, however, the use of affinity purification and two-hybrid screening techniques, and the availability of data banks to identify proteins on the basis of sequence homology, allow rapid progress in elucidation of the signaling mechanisms of the TNF/Fas systems. Although still fragmentary, this knowledge has already yielded important lessons. Alongside principles of signaling shared with other pathways, features are emerging that are unique to the signaling for death of cells and to the functioning of the TNF receptor family in general. Space restrictions necessitate limitation of this review to aspects of the signaling mechanisms that currently seem most worthy of highlighting. The references cited are mostly the more recent and lesser-known studies, and readers are referred to other recent reviews for more detailed information and references. We apologize to the authors of many important relevant studies that could not be cited here.
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RECEPTORS AND LIGANDS OF THE TNF AND Fas/APO1 SYSTEMS1 The ligands and receptors whose signaling is the subject of this review belong to the large TNF-related ligand and TNF/nerve growth factor (NGF) receptor families. In addition to the receptor-ligand interaction motifs that define these families—a β-sheet receptor-binding structure arranged in β-jellyroll topology and a cysteine-rich repeat ligand-binding module (reviewed in 8, 215)—they share several other common structural and functional features. With the exception of LT-α, which is secreted by cells, all members of the ligand family are formed as type II transmembrane proteins and can therefore act in a juxtacrine manner. Some of them are subject to proteolytic processing, allowing them to act in a soluble form, either as ligands (as in the case of TNF-α) or as inhibitors of signaling (as in the case of Fas-L). It seems that all members of the TNF family act in the form of trimers, and most of them act as homotrimers. The only known exception is LT-β, which functions after forming heterotrimers with LT-α, apparently because of its inability to assemble properly on its own (9). The molecular structures recognized by the receptors reside in the groove between neighboring ligand monomers. Each of the receptors of the TNF system can bind to either one of two different structures. CD120a and CD120b bind both to TNF-α and to LT-α. The LTβR binds to LT-β and to LIGHT, and HVEM [initially identified by virtue of its binding to a Herpes simplex protein (10)], binds to LIGHT and (with low affinity) to LT-α (11). CD95, however, is known to bind only to Fas-L (Figure 1).
PHYSIOLOGICAL FUNCTIONS AND CELLULAR EFFECTS OF THE TNF AND Fas SYSTEMS The TNF and Fas (TNF/Fas) systems regulate immune defense. Their effects are characterized by a remarkable duality—induction of damage on the one hand accompanied by induction of repair and expansion on the other. Cell death is induced alongside cell growth and resistance to death; hematopoiesis is suppressed simultaneously with induction of hematopoietic growth factors; inflammation is promoted and then suppressed. Together, these contrasting effects result in an intense yet brief response, allowing adjustment to insult. Our knowledge of the relative contributions of the different components of these systems to their overall functioning is incomplete. Most of the current knowledge has to do with the functions of CD120a and CD95; least is known about the function of the recently identified HVEM and LIGHT. 1 For
other recent reviews, see (1 –7).
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Figure 1 Ligands and receptors of the TNF and Fas systems, their docking proteins, and their known structural modules.
In vivo assessment of the consequences of obliteration of individual receptor or ligand functions indicates that these proteins serve different yet overlapping physiological roles. The most salient in vivo consequences of obliteration of CD120a function are deficient defense against certain intracellular pathogens and restrained inflammatory response (12, 13). Restriction of the inflammatory response, although in a different manner, is also the most obvious change accompanying obliteration of CD120b function (14). Inhibition of LTβR function
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is most clearly reflected in deficient lymphoid organ development (15 and references therein). Inhibition of CD95 function is manifested mainly in excessive expansion of lymphoid organs, pointing to the critical role of CD95 in regulation of lymphocyte survival (16). However, more thorough examination revealed that the TNF receptors could also contribute to lymphoid organ development (15 and references therein) and to lymphocyte death (17), the LTβR to inflammatory disorders (JL Browning, submitted to Gastroenterology) and CD95 to inflammation (18). The individual cellular responses to CD120a appear to concern various aspects of innate immunity and also—although to a lesser extent—of adaptive immunity. This receptor controls defense on the level of the individual cell, for example, by inducing death of pathogen-afflicted cells. On the level of multicellular organs, CD120a controls defense by coordinating the inflammatory process, and on the level of the whole organism, by inducing changes such as fever, loss of appetite, or elevation of acute-phase serum proteins. CD120b, which is activated preferentially by the cell-bound form of TNF (19), is so far known to induce only a few effects. In most cases, the observed effect can also be induced by triggering CD120a. The known in vitro effects of the LTβR are growth stimulation of fibroblasts and a cytocidal effect on some tumor cell lines (20, 21), whereas HVEM induces enhancement of growth (and probably also of some other functions) of T lymphocytes (22). CD95 has been found to induce death of cells but may also stimulate cell growth and induce synthesis of the cytokines interleukin (IL)-6 and IL-8 (e.g. 23).
THE SIGNALING MECHANISMS General Considerations: Reliability of Interpretation The flood of new molecular data concerning the functions of the TNF/Fas systems raises a need to define measures of quality control to evaluate their significance. Two issues are of particular concern in this connection: primary versus secondary targets of signaling and the exact role of the signaling molecules themselves. TARGETS FOR SIGNALING: WHICH ARE DIRECT AND WHICH ARE SECONDARY?
Sorting out the primary targets of signaling among the profusion of molecular events has proved particularly difficult in the case of the TNF/Fas systems. The degree of uncertainty can be appreciated from the fact that, as opposed to the common practice in the signaling field, in most cases targets have been identified by elucidation of their corresponding signaling mechanisms, rather than the other way around. Several features unique to the TNF/Fas systems have contributed to this high degree of uncertainty.
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1. Cell death induction. The cell death process is notorious for its multiplicity of molecular events and the difficulties involved in distinguishing the primary ones. Over the years of study of death induction by the TNF/Fas systems, several different mechanisms have been proposed as the initiators of these processes. It was only through sequential analysis of the death-inducing signaling cascades, however, that a direct target for their action, activation of specific caspases, was discovered. 2. Lipid-derived mediators. The identity of the initial targets in the induction of lipid-derived mediators by the TNF/Fas systems is particularly uncertain, for several reasons: (a) In cells where these systems trigger cytocidal effects, lipases are activated at a late stage of the response as part of the death process itself; (b) the inflammatory function of the TNF system also involves induction of lipid-derived mediators as part of the cellular response, rather than as the signaling mechanism itself; (c) lack of familiarity with the techniques involved has prevented all but a few laboratories from contributing materially to the knowledge of the formation of lipid mediators. The lipase activation pathways described below are therefore supported only by a limited amount of data, and only parts of them are clear enough to allow full identification of the lipase involved. 3. Transcription factors. As with the mechanism of death induction by the TNF/Fas systems, the most solid information about the targets of the signaling mechanisms that control gene expression has come from the study of the mechanisms themselves. Analysis of these signaling cascades has confirmed that NF-κB and AP1, two groups of transcription factors with central roles in inflammation and immune response regulation, are direct targets of these signaling systems (see below). Several other transcription factors, including IRF1, NF-IL6, and others, are known to be affected. However, owing to the complexity of the gene-activation effects of the TNF system and the multiplicity of interactions among different transcription factors, there is still only partial knowledge of the identity of the factors affected directly by these systems. No information is available on the molecular targets in posttranscriptional modulation of gene expression by these systems, such as that thought to be mediated by the JNK and p38 MAPK cascades (see below). SIGNALING MOLECULES: THE TEST SYSTEMS APPLIED AND THEIR PHYSIOLOGICAL RELEVANCE In many cases (several of which are cited in this review),
initial notions about particular events activated by the TNF/Fas systems have later turned out to be erroneous. As in any other experimental endeavor, all techniques applied in this field involve varying degrees of distortion of the natural situation. Knowledge of the interactions of signaling proteins gained
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by their artificial expression either in mammalian cells or in transfected yeast (two-hybrid tests) has proved less reliable than that gained by monitoring the interaction of the proteins expressed endogenously in cells. Similarly, knowledge of protein function gained by assessing the effects of high-level expression of the proteins or their mutants in transfected cells has often proved to be less reliable that the knowledge gained by elimination of the endogenous expression of the proteins in cells through mutation or targeted disruption of their genes. Much of our current knowledge of the molecular interactions in the TNF/Fas systems is still based on the less reliable method of enforced expression testing.
INITIATION OF SIGNALING Triggering As in many other receptor-induced processes, the signaling activity of the TNF family of receptors is triggered upon juxtaposition of the intracellular domains of the receptor molecules following binding of the ligand molecules to their extracellular domains. The trimeric structure of the ligands probably contributes to this juxtaposition, although formation of dimeric receptor molecules also seems to suffice for triggering. Signaling by the receptors can be triggered merely by imposing aggregation of the receptor molecules, for example, with antireceptor antibodies (e.g. 216, 217). It seems likely, however, that this process involves not only translocation of the receptor molecules on the cell surface but also an induced conformational change that may account for the reported ability of certain fragments of TNF-α to initiate signaling (e.g. 24, 25). That the receptors play an active role in their induced triggering is indicated by the finding that both the death domain (DD) motif in the intracellular domain of CD120a (see below) and the receptor’s extracellular domain undergo self-association. It was suggested that the self-association of the DD might contribute to initiation and amplification of signaling, whereas dimerization of the extracellular domain may prevent spontaneous initiation of signaling by keeping their intercellular domains apart (26, 27). As with other receptors that have intrinsic protein kinase activity, in the initiation of signaling by the receptors of the TNF/Fas systems the activation step seems to occur by cross-modification of enzymes found in the signaling complexes (see the description below of the way in which caspase-8 is activated). In this case, however, the enzymatic activity is mediated not by the receptor itself but by other, recruited proteins.
Role of Docking Proteins The recruitment of signaling molecules to the receptors of the TNF/Fas systems occurs through an intermediate phase of adapter proteins, most of which
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have no enzymatic activity of their own. These adapter (docking) proteins, like the ligands and receptors, are modular in structure. Several of the docking proteins can bind to each other through specific modules distinct from those involved in their binding to signaling molecules. The result is the formation of a network of proteins that dictate signaling for different effects through binding to different enzymes. This network is composed of two main parts, each involving a distinct major protein-binding motif that prompts homophilic protein interactions. One part involves several docking proteins, including MORT1/FADD, TRADD, RIP, and RAIDD/CRADD, which bind to each other as well as to CD120a and CD95 through a DD motif found both in the docking proteins and in the receptors. The other part is centered around a group of adapter molecules that share a protein-binding motif called the TRAF domain (Figure 2). The two parts of the network are linked through association of the TRAF domain in the adapter protein TRAF2 with the regions upstream of the DD in the adapter proteins TRADD and RIP (28–30). The functions of these two parts of the docking protein network are not entirely distinct. As described below, the DD-containing adapter proteins are involved mainly in death induction, yet the DD-containing protein MORT1/FADD seems to be involved in induction of lymphocyte growth as well (31). Conversely, the TRAF domain complex, which is involved mainly in gene regulation, also seems to affect the induction of death (32–34).
STRUCTURES INVOLVED Motifs in the Extracellular Domains of the Receptors and the Ligands Apart from the receptor-ligand interacting motifs shared by the ligands and receptors of the TNF-related families, the extracellular domains of TNF-α and its receptors (and probably of other ligands and receptors of these families) contain membrane-proximal regions whose structural features, which have yet to be identified, render these molecules susceptible to shedding. The enzyme responsible for the shedding of TNF-α (and perhaps also of its receptors), TACE, is a transmembrane protease of the adamylisin family. The crystal structure of its catalytic domain was recently defined (35).
Motifs Identified in the Intracellular Domains of the Receptors and the Proteins That Bind to Them 1. The death domains. A shared sequence motif in the intracellular domains of CD120a and CD95 was dubbed the death domain in view of its critical
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Figure 2 Regulation of the direct caspase activation and the NF-κB activating cascades by the TNF receptors and CD95.
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role in the cytocidal effect of these receptors. Its presence was later detected in many other proteins, only some of which participate in death induction [reviewed in (36, 37)]. Structural modeling of the DDs in various proteins, as well as NMR studies of the DD in CD95 (38, 39) and the low-affinity NGF (40), indicated that this motif is composed of six amphipatic α-helical regions arranged antiparallel to one another. The DD serves as a proteindocking site and apparently also as a transducer of conformational changes. It participates mainly in homotypic interactions. Four adapter proteins that take part in the signaling by CD120a and CD95—MORT1/FADD (41, 42), TRADD (43), RIP (44), and RAIDD (45, 46)—contain DDs. The proteins bind to the receptors, to each other, or both and, with the exception of MORT1/FADD, also self-associate through homotypic DD interactions. An exception is the adapter protein DAXX, which binds to the DD of CD95, but is itself devoid of a DD (47). A protein called MADD/Rab3-GAP, containing a region with a low degree of homology to the DD, was shown in one study to bind through this region to the DD of CD120a (48). Enforced expression of this protein or of its putative DD homology region was found to affect the activation of JNK, ERK, and cPLA2 by TNF-α. The same protein also serves as a GDP/GTP exchange protein for certain members of the Rab family of small G proteins that associate with synaptic vesicles and regulate neurotransmitter release. A short splice variant of the protein, called DENN, is phosphorylated by the brain-specific JNK isoform (JNK3) and translocated with it in neurons to the nucleoli in response to hypoxia (49, 50). 2. Regions upstream of the DDs. The membrane-proximal region in CD120a, upstream of the DD, participates in signaling both independently and in cooperation with the DD (51–53). Three proteins are known to bind to it. A protein called FAN, which is required for neutral sphingomyelinase activation by this receptor, binds through a WD-repeat region to a stretch of nine residues (residues 309–319) upstream of the DD (52). A regulatory component of the 26 proteasomes, called 55.11, p97 or TRAP2, binds to a region just upstream of the FAN-binding site (residues 234–308), possibly allowing direct regulation of proteasomal function by the receptor (54, 55). A protein of unknown function, called TRAP1, closely related to hsp90, binds to recognition sites diffusely spread upstream of the DD (56). 3. Regions downstream of the DDs. As in some other DD-containing proteins (36), the regions downstream of the DDs in CD120a and CD95 have a high content of serine, threonine, and proline residues, whose functional significance is still unknown. In the human CD95, though apparently not
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in the mouse receptor, the three most C-terminal residues (SVL) serve as a binding motif for a protein tyrosine phosphatase, FAP1, which can downregulate death induction by the receptor (57, 58). 4. The TRAFs and their binding regions in the receptors. The TRAFs are adapter proteins that share a sequence homology C-terminal motif (the TRAF domain), N-terminal ring finger and zinc finger motifs, and a central coiledcoil region. They participate in the signaling activity of several receptors of the TNF/NGF family, including the three receptors of the TNF system that do not contain DDs; they bind to these latter receptors through their TRAF domains. CD120b binds to TRAF 2 and (indirectly, through binding to TRAF2) also to TRAF1 (59, 60). LTβR binds to TRAF2, 3 and 5 (61), and HVEM binds to TRAF1, 2, 3, and 5 (62, 63). With other receptors, the TRAFs could be shown to bind to distinct intracellular domain sequence motifs (e.g. 64). Both the TRAF domain region and the N-terminal part of the TRAF protein are required for the signaling function. Yet, while several signaling and regulatory proteins are known to bind to the TRAF homology region (TRAF-C) and to the region immediately upstream of it (TRAF-N) (see 65 for review), no protein that binds to the N-terminal part of the TRAFs has yet been identified. Preliminary evidence suggests that this region can act independently as a transcription regulator, after being transported by an unknown mechanism to the nucleus (66). 5. Conserved phosphorylation sites. A conserved tyrosine in the CD120a DD (Tyr 331 in the human receptor) can be phosphorylated by pp60src, apparently affecting the function of a serine/threonine kinase associated with this domain (67). A conserved tyrosine is present at a similar site in CD95. A cluster of serines at the TRAF2-binding site in CD120b contains a casein kinase I phosphorylation motif, whose phosphorylation was suggested to down-regulate signaling by the receptor (68–70).
Motifs in the Intracellular Domains of the Ligands and Reversed Signaling The intracellular domain of TNF is phosphorylated in cells (71). A substrate site for phosphorylation by casein kinase I is found in this domain, as well as in the intracellular domains of most other members of the TNF ligand family, including Fas-L, and apparently participates in signaling by these domains upon ligand binding to their receptors (reversed signaling; A Watts, submitted to EMBO J.). It was suggested that an additional conserved site in the Fas-L intracellular domain, an SH3 binding motif, allows anchoring of the ligand molecules to the cytoskeleton (72).
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SPECIFIC SIGNALING PATHWAYS The known enzymes through which the receptors of the TNF/Fas systems initiate signaling include proteases of the caspase family, phospholipases, and protein kinases. Some of the multiple functional changes regulated by these enzymes reflect altered gene activity, resulting from direct activation of transcription factors (e.g. NF-κB), increased synthesis of such factors (e.g. IRF1), or modulation of translation rate or message stability. Other effects, like the induction of cell death, occur independently of gene activation. Although this review is concerned with intracellular signaling, it should be noted that the TNF/Fas systems also control the formation of molecules that transmit signals among cells. The formation of these extracellular mediators and of the intracellular signaling mediators are closely linked. The activation of caspases within cells results in processing of the precursors for extracellular polypeptide mediators such as IL-1β and IL-18, whereas the activation of phospholipases yields compounds that can be metabolized to lipid extracellular mediators such as prostaglandins and PAF. These polypeptide and lipid extracellular mediators, together with mediators like IL-8 whose genes are activated by the kinase cascades stimulated by the TNF/Fas systems, act outside of their producing cells to perpetuate the signals initiated within them, and coordinate the multicellular inflammatory processes that these systems induce.
Direct Caspase Activation Cascades The caspases, a family of evolutionarily conserved cysteine proteases that cleave proteins at specific substrate sites downstream of aspartate residues, play crucial roles in apoptotic processes and in the formation of several proinflammatory mediators (reviewed in 73). These proteases normally exist in cells as inactive precursors, yet upon death induction become activated by processing at internal caspase substrate sites, allowing a cascade-like caspase activation process. The precursors of some of the caspases bind through the region upstream of their protease moiety to regulatory proteins that control their processing. Three caspases have been found to associate through motifs in these prodomains to homologous motifs found in adapter proteins of the CD120a and CD95 signaling complexes. Caspase-8 (MACH/FLICE/Mch5) (74–76) and caspase-10 (FLICE2/Mch4) (76, 77) bind through duplicated N-terminal death effector domains (DEDs) to an N-terminal DED in MORT1/FADD, and caspase-2 binds through an N-terminal motif called CARD to a CARD domain in RAIDD (45, 46). Duplicated N-terminal DED also occurs in a protein with multiple names, including FLIP, Casper, and CASH (reviewed in 78), which displays sequence homology to the caspases, yet lacks several residues critical for
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protease activity. The DED and CARD motifs display some sequence and structural similarities to the DD, raising the possibility that the conformational changes underlying their homotypic associations are similar to those in the DD (79, 80). Apparently, all three caspases mentioned above participate in the induction of death, while CASH serves as a regulator (an inhibitor, or—according to several studies—a stimulator) of the death process. At the moment, however, the only one of these proteins for which there is direct evidence of involvement in death induction beyond that gained in enforced expression studies is caspase-8. There is conclusive evidence for recruitment of this caspase to the Fas signaling complex (75). Moreover, targeted disruption of the caspase-8 gene was found to ablate death induction by TNF or by CD95 ligation (81). The processing of caspase-8 upon ligation of CD95 or CD120a seems to result from juxtaposition of the caspase-8 molecules recruited to the receptors, apparently through the mild proteolytic activity of the unprocessed caspase-8 molecules themselves (82, 83). Knowledge of the events after caspase-8 activation is fragmentary. In vitro, caspase-8 is capable of processing and activating almost all other caspases (84). Within cells, however, it seems to act in a much more restricted manner, resulting in the sequential activation, first of caspase-9 (85), then of caspase-3 and caspase-7, and later of caspase-6 (86). Even the processing of caspase-9 may not be directly mediated by caspase-8 but rather may occur as a consequence of the cleavage of other proteins. Recent findings indicate that BID, a mammalian homolog of the nematode death inhibitory CED9 protein, and plectin, a major cytoskeletal protein, serve as direct substrates of caspase-8 (87, 88, 218). The COOH-terminal fragment of BID formed in its processing by caspase-8 translocates from the cytosol to the mitochondria, causes their clustering, and initiates mitochondrial changes characteristic of apoptotic events, such as permeability transition and leakage of cytochrome c. This last event may well trigger self-processing of caspase-9, catalyzed by Apaf1, a mammalian homolog of the nematode major regulatory protein CED4, which is subject to allosteric activation by cytochrome c (89). 2 In cells in which CD95 ligation causes relatively weak caspase-8 processing, death induction by this receptor indeed involves a crucial amplification role of mitochondrial functions (90, 91). In such cells, Bcl-2 or Bcl-xL, two death-inhibitory proteins related to CED9, can block CD95-mediated death induction by inhibiting death-related events occurring consequently to caspase-8 activation. In most types of cells, 2 BID is apparently not the only cytosolic protein that mediates caspase-8-induced mitochondrial apoptotic changes. BID depleted cytosol preparations can also induce, after their treatment with caspase-8, cytochrome c release from mitochondria and loss of mitochondrial membrane potential [M Steemans et al 1998. Caspase-8 induced mitochondrial permeability transition through a nonprotease intermediate. J. Interferon Cytokine Res. 18:A-79 (Abstr.), and M Steemans, personal communication].
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however, caspase-8 signals for death in a way that appears to be independent of mitochondrial involvement. In these cells, Bcl-2 and Bcl-xL, which block the death-related mitochondrial events as well as the caspase-8-induced cleavage of plectin after CD95 ligation (though not the processing of caspase-8 itself ), are incapable of providing effective protection from death induction by CD95 or TNF (91–94). The mechanism of caspase-9 activation in these cells remains to be clarified. There is no evidence for any mechanistic link between initiating events in death induction by the TNF/Fas systems and by other apoptotic triggers such as growth factor withdrawal. However, the TNF/Fas systems seem to use the same downstream mechanisms, subsequent to caspase-9 activation, as those activated by other apoptotic processes.
Death Induction Independent of Direct Caspase Activation The available knowledge of the molecular changes underlying death processes induced by the TNF/Fas systems suggests that these processes depend on the cooperative functioning of several different mechanisms. The relative contribution of these mechanisms may vary from one cell type to another. Among these contributing factors are the mitochondria-associated death processes. As described above, inhibition of these processes can cause arrest of the TNF/Fasinduced death in some cells, but not in others. This is also the case with some enzymatic activities that appear to be critical for inducing the death processes; yet they exert their effects in a cell-specific manner. Such enzymes include chymotrypsin-like proteases (95), cellular phospholipase A2 (96 and references therein), lysosomal enzymes such as cathepsin D and the acid sphingomyelinase, and protein kinases like JNK [e.g. (97, 98) and references therein]. As discussed below, several of these death-related activities are stimulated by CD120a or CD95 through signaling pathways independent of the direct activation of caspase-8. CD120a may have the ability directly to affect even the mitochondria in a way that might contribute to death induction (kinesinmediated translocation to a perinuclear site) via a region distinct from that involved in caspase-8 activation [upstream of the DD and the FAN-binding motif (53)]. Whether the contribution of these activities to death induction can allow initiation of the death process independently of the direct caspase activation process is a matter of debate. Two very recent findings are of relevance here: 1. Targeted disruption of either MORT1/FADD or caspase-8 in mice was found to result in complete unresponsiveness of fibroblasts derived from the mutated mice (and in the case of the MORT1/FADD null mice, also of lymphocytes) to death induction by TNF or by CD95 ligation. Thus, at least in
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fibroblasts, the direct caspase-8 activation pathway plays an indispensable role in apoptosis induction (31, 81, 99). 2. Although induction of apoptosis by the TNF/Fas systems has not been observed in the absence of caspase action, very recent studies clearly show that both CD120a and CD95 have the ability to induce in some cells, though not in others, a caspase-independent necrotic process. Which, if any, of the cell line-specific, death-related mechanisms listed above contribute to this effect is not yet known. There are some indications that the necrotic process involves a critical role of mitochondria-produced oxygen radicals. Notably, in cells exhibiting this effect, caspase blockage actually results in augmentation of death, suggesting that the caspases act to suppress mechanisms of necrosis (100–102).
Phospholipase Activation Cascades Effects of the TNF system on the formation of lipid mediators reflect, to some extent, enhanced expression of the enzymes involved. The signaling by both CD120a and CD95, however, also seems to have a direct effect on certain enzymes that produce such mediators. Knowledge of these signaling mechanisms is still rather limited (see above, section on Reliability of Interpretation). SPHINGOMYELINASE ACTIVATION3
Increased sphingomyelinase (SMase) activity in response to TNF-α application or CD95 ligation has been observed in various cells, either shortly after stimulation or as a late event that occurs secondarily to other signaling events or as part of the apoptotic process. Ceramide, the product of SMase action on membrane sphingomyelin, is thought to act as a secondary mediator that, through modulation of the activity of certain enzymes, enhances the response to stress. Initial speculation that ceramide also affects NF-κB activation by TNFα could not be confirmed (105). There is some evidence that, however, ceramide effects contribute to JNK activation and death induction by the TNF/Fas systems. It was suggested that the latter activity is mediated only by the lysosome-bound acid SMase (see below) and involves activation of the lysosomal protease cathepsin D, to which ceramide seems to bind specifically (106). Although some mammalian proteins with SMase activity have been cloned, it is not clear whether these or other enzymes are involved in the TNF/Fas effects. Nor is there any information on the nature of the structural changes in SMases that underlie their activation by CD120a or CD95. At least two distinct target enzymes appear to be involved. Neutral sphingomyelinase (nSMase) Both CD120a and CD95 activate this cell membrane-associated enzymatic function (107, 108). Although the 3 (See
98, 103–104 for reviews.)
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mechanism of the CD95 effect is still unknown, CD120a activation has been shown to involve the receptor-associated adapter protein FAN (52). Cells from mice with targeted disruption of FAN fail to show nSMase activation by TNF-α. The mice also lack natural killer cell development (109). Acid sphingomyelinase (aSMase) and phosphatyidylcholine–specific phospolipase C (PC-PLC) As with the nSMase, the activity of aSMases, which reside in the lysosomes, is enhanced by both CD120a and CD95, but the receptor region involved in the aSMase effect is the DD (107, 108). Both receptors also activate PC-PLC, an effect involving TRADD and the DD regions in the receptors. D609, an inhibitor of PC-PLC, blocks aSMase activation by TNF, suggesting that the PC-PLC products play a role in this activation (110). The TNF-induced activation of phospholipase A2 (PLA2) has attracted considerable attention in view of the role of secondary mediators produced by the enzyme in the proinflammatory and pyrogenic activity of this cytokine. PLA2 provides arachidonic acid, the precursor for the eicosanoids (cytoplasmic PLA2 preferentially acts on sn-2-arachidonoyl phospholipids), and the precursor for PAF, when the sn-1 position of the phospholipid is an alkyl ether linkage. As in SMase activity, PLA2 can be activated by the TNF/Fas systems in different ways and at different times after receptor ligation. At least four different mechanisms are known to participate in these effects: (a) induced expression of the gene encoding the secreted PLA2, which acts remotely from its producing cells (see, e.g. 111); (b) induced expression of the cytoplasmic PLA2 (cPLA2) gene, observed several hours after TNF-α application (112); (c) early activation of cPLA2 (within minutes of ligand application) and its translocation from the cytoplasm to the plasma membrane, which seems to involve cPLA2 phosphorylation by any of the three MAP kinase cascades (113–115). Though this activation is modest, it strongly synergizes with that of Ca2+ ions (112); (d) Late increase in activity of a cellular PLA2 as part of the apoptotic program. This increase appears to be secondary to caspase activation (116). It is unlikely to involve the cPLA2 that is inactivated by the caspases. Rather, it seems to reflect activation of a type VI Ca2+-independent PLA2 (iPLA2) (96, 116). Apart from PLA2, phospholipase D (117) and—as mentioned above at least in some cells—sphingomyelinases (118) are activated at a late stage of the process of death induction. PHOSPHOLIPASE A2 (PLA2)
Protein Kinase and Protein Phosphatase Activation Changes in cellular protein phosphorylation patterns, reflecting alterations in the activity of a variety of protein kinases and phosphatases, are observed in cells shortly after TNF treatment (e.g. 119, 120). These phosphorylation and
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dephosphorylation events seem to be the exclusive mode of gene modulation by the TNF/Fas systems. They also appear to contribute to the regulation of all of their other effects. Most of the current knowledge on the identity of the enzymes involved in these phosphorylation events concerns the MAP kinases, an evolutionarily conserved group of protein kinase cascades whose basic module comprises three consecutively active enzymes: a proline-directed serine/threonine kinase (MAPK), a dual-specificity kinase (MAP2K) that activates the MAPK by phosphorylating both a serine and a tyrosine residue, and a serine/threonine kinase (MAP3K), which activates the MAP2K. The way in which the MAP3Ks become activated is not well understood. In several systems, the activation involves small G proteins. These proteins apparently prompt phosphorylation of the MAP3Ks by other, heterogeneous kinases (MAP4Ks). The substrates affected by these cascades are highly heterogeneous, some themselves being protein kinases (dubbed MAPKAPKs). Mammalian cells contain three known MAPK cascades (reviewed in 121–124); all are activated by both the TNF and the Fas systems, though the components of the activated cascades, as well as their targets, may vary from one cell type to another, in keeping with the cell type-specific patterns of responses to the TNF/Fas systems. The three cascades have different functions but cross-react on several levels. A related cascade, which is involved in NF-κB activation by these systems, was recently elucidated (reviewed 125, 126). STRESS-ACTIVATED PROTEIN KINASE 1 (SAPK1)/C-JUN N-TERMINAL KINASE (JNK) MAP KINASE CASCADE Contribution to the function of the TNF/Fas systems
As implied by their name, the SAPK cascades induce adaptive responses to a variety of stress signals. They do so mainly through induced changes in gene expression. The SAPK1/JNK pathway participates in the regulation of gene expression by the TNF/Fas systems both by enhancing the function of transcription factors, of which the most thoroughly studied is AP1 (123), and by affecting the stability of certain messages (127). It affects transcription through the phosphorylation of various transcription factors, including c-Jun, ATF2, Elk-1, and CREB. Among the genes it affects are those of collagenase IL-1α and c-Jun. Prolonged JNK activation results in death of some cells by an unknown mechanism, suggesting that this enzyme might be involved in the TNF/Fas-induced signaling for death. As with various other activities of the TNF and Fas systems, their activating effect on the SAPK cascades is restricted by antagonizing mechanisms and is therefore mostly transient, followed by a rather long period of lethargy. TNF-induced activation of phosphatase(s) may contribute to the transient character of SAPK1/JNK activation (128).
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Mode of activation and the kinases involved All five receptors of the TNF/Fas systems can activate the SAPK1/JNK cascade (62, 129, 130). The effect of the TNF receptors involves TRAF2 (131), and according to limited evidence also MADD (48), as well as effects of the ceramide formed upon aSMase stimulation (reviewed in 98, yet see 132). The effect of CD95 involves the DD-associated adaptor protein DAXX (47, 219). In addition, the SAPK1/JNK pathway can be activated late in the process of death induction through caspase-mediated processing and activation of kinases that act in this pathway, for example PAK2 (133), PAK65 (134) and MEKK1 (135, 136). At least in macrophages, TNF affects the p46 isoform of JNK1 (MAPK) much more strongly than the p54 isoform (137). The main MAP2K mediating JNK activation by the TNF/Fas systems is MKK7 (138, 139). Recent studies point to two caspase-independent pathways through which this activation can occur. One of these pathways involves ASK1, a MAP3K whose carboxy-terminal kinase-flanking region has the ability to bind to TRAF2, 5 and 6, and its aminoterminal region to DAXX. Binding of ASK1 to either of the two adapter proteins results in displacement of an inhibitory intermolecular interaction between the two kinase-flanking regions, allowing activation of the kinase by both the TNF receptors and CD95 (141, 219, 220). The other pathway involves the MAP4K GCK. Similarly to ASK1, GCK binds to TRAF2. It also binds to the MAP3K MEKK1 and apparently activates it in a stimulus-dependent manner (221). GCKR/GLK, a kinase related to GCK, also seems to contribute in a similar way, to JNK activation by TNF (140, 222). Limited evidence suggests that JNK activation by TNF may also be mediated by the MAP3Ks TAK1 (perhaps through an effect of ceramide) (223) and MLK2 (142). SAPK2/P38 CASCADE Contribution to the function of the TNF/Fas systems Among the known target proteins of the SAPK2/p38 cascade are several transcription factors, some of which (such as ATF2) are identical to those affected by the JNKs, and also cytosolic proteins such as cPLA2 and hsp27. In many cells, the phosphorylation of hsp27—which is mediated by MAPKAP2, a kinase phosphorylated by p38 (the MAPK in this cascade)—is the most prominent TNF-α-induced serine/threonine phosphorylation event. Most of the information on the physiological significance of activation of this cascade is based on assessment of the effects of certain bicyclic imidazole inhibitors, which at least at low concentrations, appear to affect the function of the p38 kinase in a specific manner (143). These data suggest involvement of the kinase in the up-regulation of various inflammation-related genes, like TNFα itself, prostaglandin H synthase 2, collagenase-1, IL-6, and IL-8,
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through effects on transcription of the genes, translation of the transcripts or their stability (144, and references therein). The functional significance of hsp27 phosphorylation in response to TNF is not known. Mode of activation and the kinases involved In all in vivo studies reported so far, induction of the p38 and JNK pathways has occurred simultaneously. In certain in vivo situations, however, it is possible to observe differential responses of the two pathways to some stimuli, suggesting that they share both common and distinct activation mechanisms. The MAP2Ks activating the p38 kinases were reported to be MKK2 and MKK3 (in response to TNF; 147) and MKK6 (in response to CD95 ligation) (139). As in the case of the JNK pathway, these kinases are activated by the TNF/Fas systems in both a caspase-dependent and a caspase-independent manner (139, 145). Of the two caspase-independent JNK-activation pathways (described above), the one involving GCK (or GCKR) and MEKK1 seems to lead rather specifically to JNK activation (221 and references within). The other, mediated by ASK1, can activate p38 as well (146). Occurrence of a signaling pathway that can mediate specific activation of p38 by TNF was suggested in a recent report describing association of a “p38 specific” MAP3K activity with the intermediate region of RIP (the region linking its death domain to the kinase domain in RIP). The identity of the RIP-associated enzyme mediating this p38-specific function is still unknown (221). Contribution to the function of the TNF and Fas systems Phosphorylation of the p42 and p44 ERKs (the MAPKs in this cascade) is the most prominent tyrosine phosphorylation event observed in certain cells in response to TNF (148, 149). There are also cells in which these kinases become activated upon Fas ligation (108). In many cells, however, activation of this cascade by the TNF/Fas systems is milder than that of SAPK cascades. The ERKs seem to contribute to the growth-stimulatory effects of TNF and Fas as well as to their effects on cell differentiation and inflammation. Their substrates include transcription factors such as Elk-1 and cytosolic proteins such as cPLA2.
ERK/MAP KINASE CASCADE
Mode of activation and the kinases involved Both the p42 and the p44 ERKs are activated by TNF. In murine macrophages, CD120a ligation was found preferentially to trigger activation of the p42 isoform through phosphorylation of the MAP2K MEK1, which in turn is activated by the MAP3K MEK kinase (150). In some other cells the MAP3K seems to be cRaf1 (151, 152). In studies of the involvement of cRaf1 in the activation of this cascade by the TNF/Fas systems, it was suggested that this kinase is activated through phosphorylation, either by a ceramide-regulated kinase activated by the FANnSMase pathway (151) or by protein kinase C zeta (153). The mechanism of the
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reported stimulatory effect of the CD120a-associated adapter protein MADD on the ERK/MAP kinase pathway is unknown (48). NF-κB ACTIVATION KINASE CASCADE Contribution to the function of the TNF/ Fas systems The group of transcription factors collectively called NF-κB contributes to the control of expression of many of the genes that participate in inflammation and immune response. In most cells, these factors normally occur in a latent form imposed by their association with inhibitory proteins collectively termed I-κB, which dictate the cytoplasmic location of the proteins. They can, however, become activated in response to a wide range of inducers, including all receptors of the TNF system, and in some cells also CD95. The proteins controlled by NF-κB include many that contribute to the proinflammatory functions of TNF-α. Cells deficient in NF-κB function display increased sensitivity to the cytocidal effect of TNF and much lower dependence on treatment with protein-synthesis inhibitors for exhibiting such an effect, suggesting that some proteins regulated by NF-κB serve to protect cells against undue killing by TNF (reviewed in 154).
Kinases involved As with various other inducing agents, activation of NFκB by the two TNF receptors, and probably also the activation mediated by the two other receptors of the TNF system and by CD95, occur by triggering the phosphorylation of I-κBα at serines 32 and 36. Such phosphorylation targets this inhibitor for proteasomal degradation. Two structurally homologous serine/threonine kinases, IKK1 and IKK2, which mediate the phosphorylation of I-κB in response to these and various other inducers, were recently identified (155–159). These two enzymes associate within a macromolecular complex of ∼700,000 Daltons (the signalosome) that apparently contains several other regulatory enzymes and structural proteins. Two protein kinases homologous to MAP3Ks, NIK and MEKK1 (the latter also functions as a MAP3K in the JNK cascade), can activate the signalosome. NIK activates it mainly through phosphorylation of IKK1, and MEKK1 mainly through phosphorylation of IKK2 (160–163). Of these two MAP3K homologs, NIK is differentially involved in mediating the NF-κB-stimulating effects of receptors of the TNF family and IL1, while MEKK1 plays a central role in NF-κB activation by the HTLV-I Tax protein (161, 164). Although NIK does not activate JNK or the p38 kinase (146, 165), its enforced expression leads by unknown mechanisms to AP1 activation (166). Mode of activation Studies of enforced expression in cultured cells indicated involvement of the adapter proteins TRADD, RIP, and TRAF2 in NF-κB activation by CD120a, as well as involvement of TRAF2 in NF-κB activation by CD120b and by CD95. Specific binding of NIK to TRAF2 also indicates
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involvement of this adapter protein in NF-κB activation (161). Yet, although targeted disruption or mutation of RIP indeed results in ablation of TNF-induced NF-kB activation (167, 168), fibroblasts deficient in TRAF2 can still display such activation, suggesting that the role of this adapter protein in the process is dispensable (131). A number of other protein kinases, for example, certain protein kinase C species (153), are reportedly involved in the TNF-induced NF-κB activation. Whether these kinases operate by activating the NIK-IKK pathway or in other ways remains to be clarified. Several studies suggest that TNF also controls NFκB function at some post-I-κB phosphorylation step(s), through involvement of additional signaling pathways such as the SAPK2/p38 cascade (169). OTHER KINASES INVOLVED IN THE FUNCTION OF THE TNF/Fas SYSTEMS Fragmentary evidence points to the involvement of a number of additional protein kinases in the signaling activities of the TNF/Fas systems. Protein kinase C, most prominently the epsilon isoform but also other isoforms like zeta, display increased activity shortly after TNF application, probably partly in response to the diacyl glycerol formed by the PC–PLC activated by CD120a. These kinase isoforms might contribute to the activation of the NF-κB and the ERK/MAP kinase cascades as well as to the TNF-mediated induction of resistance to its own cytotoxicity. They may also contribute to the TNF-induced down-regulation and shedding of its own receptors (153, 170, 171). A poorly defined enzyme with beta casein kinase activity and apparently tyrosine kinase activity is stimulated rather specifically by TNF, IL-1, and IL-18. Its activation mechanism is unknown, except that it appears not to involve phosphorylation of the enzyme (172). Limited evidence indicates that Jak1, Jak2, and Tyk2, tyrosine kinases that are centrally involved in signaling for the effects of the interferons and of various receptors of the hematopoietin family, can also bind to the intracellular domain of CD120a and mediate activation of the transcriptional factors STAT1, 3, 5, and 6 (173). There is some evidence for the association of undefined serine/threonine kinase(s) with the intracellular domains of CD120a, CD120b (reviewed in 4; also see 68), LTβR (174), and CD95 (175) and phosphorylation of these receptors by them. Phosphorylation of CD120b by its associated kinase(s) (which displays casein kinase I activity) results in decreased signaling activity (68). The serine/threonine kinase(s) associated with the membrane-proximal region in CD95 are also capable of phosphorylating the CD95-associated adapter protein MORT1/FADD (175). RIP, a DD-containing adapter protein that participates in the activation of JNK and NF-κB, has serine/threonine kinase activity and can self-phosphorylate,
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but its substrate proteins and the functional significance of this kinase activity are not yet known (29, 44).
REGULATION OF THE RESPONSE General Considerations The multiple and contrasting activities of the receptors of the TNF/Fas systems could not result in any meaningful functional consequence were they not adjusted and coordinated by regulatory mechanisms. The ability of these systems to elicit antagonistic effects that can counterbalance each other probably contributes to this adjustment. Molecules that contribute to the restriction of the response can be identified in these signaling systems on almost all mechanistic levels—the availability of ligands and receptors, interaction of the receptors with docking proteins and of docking proteins with signaling enzymes, the function of the signaling enzymes and of amplification processes, and the function of proteins participating in the eventual phenotypic changes (reviewed in 176). One important feature of the process of decision taking in this regulation is that, once taken, the decision is perpetuated by the suppression of alternative options. In cells where death is induced, NF-κB action is prevented by inhibition of TRADD recruitment (177), and activation of the ERKs—although not of JNK or p38 kinase—is prevented through the action of some caspases (178). Conversely, once NF-κB is activated, it elicits the transcription of proteins with anti-apoptotic function (reviewed in 154). Another major mode of regulation affecting both the quality and the quantity of the response is the control of expression of the various receptors and ligands. This regulation occurs on the levels of transcription, translation, intracellular transport, and shedding. There are marked differences in the cellular expression patterns of the individual receptors and ligands, and for most (with the exception of CD120a, which is constitutively expressed by almost all types of cells) the expression is largely dependent on extracellular stimuli (reviewed in 7).
Localization of the Signaling Events As discussed above, (see Reliability of Interpretation), enforced expression studies in transfected cells could lead to erroneous impression of the function of signaling proteins. This might be the result of abnormal placing of transfected proteins in the cell, in a way that is inconsistent with the compartmentalization necessary for maintaining specificity in their function. Evidence has indeed been presented for restricted localization of various components of the TNF/Fas signaling cascades, as well as for strictly defined induced changes in these localizations as part of the signaling process. Some examples are given below.
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SIGNALING INITIATION AND OTHER PROTEIN TRANSLOCATION EVENTS None of the signaling proteins known to participate in signaling induction by CD120a, CD120b, or CD95 was found to associate with the receptors before triggering. For some of these molecules, receptor recruitment upon triggering may simply reflect their increased affinity for the receptors, to which they may well have bound loosely a priori. This was clearly shown, however, not to be the case with TRADD. At least in endothelial cells, this protein is largely located in the Golgi region before stimulation (179). Translocation of signaling molecules from the cell interior to the cell membrane is followed by the translocation of signal-mediating proteins in the reverse orientation, to target sites within the cell. The TNF/Fas systems use all three known modes of targeting of gene-activating signals to the nucleus: phosphorylation of nucleus-resident factors by activated kinases following their translocation to the nucleus (for example, the phosphorylation of cJun by JNK), direct phosphorylation of transcription factors by receptor-associated kinases (for example, phosphorylation of the STATs by the JAKs), and phosphorylation of a protein that holds back a transcription factor in the cytoplasm, thus allowing its translocation to the nucleus (for example, phosphorylation of I-κB by the IKKs). The fragmentary information of the death processes induced by these systems indicates that targeting of the death signals is defined just as carefully. As with the control of the transcription factor NF-κB, activation of CAD (an enzyme participating in the cleavage of DNA as part of the apoptotic process) occurs by inactivation of an inhibitory protein that holds it back in the cytoplasm, thus allowing its transport into the nucleus. In this case, however, the enzyme responsible for inactivation of the inhibitor is not a kinase, but a caspase (180). The location of the caspases themselves within the cell also seems to be restricted by specific molecular interactions. In some cells caspase-8, before being recruited by the activated receptors, is mainly associated with the mitochondria [as are caspase-7 (181) and to some extent caspase-3 (182)]. After processing, however, it is associated specifically with the cytoskeleton (87). Caspase-8 can also associate with a specific endoplasmic reticulum protein (183). LOCALIZATION OF THE EVENTS RELATED TO SIGNALING THROUGH THE MAP KINASE AND NIK-IKK CASCADES In addition to interacting through the actual
substrate recognition sites, kinases of the MAP kinase cascades can interact with each other, as well as with their substrates, through distinct docking sites. These interactions may not, however, fully account for the specificity of action of these kinases within the cell, which greatly exceeds their specificity observed in vitro. In yeast cells, colocalization of the different components of the pheromone-responsive MAPK cascade is dictated by their binding to a common scaffolding protein, STE5. Putative MAPK scaffolding proteins, one specific to the ERK and the other to the JNK MAP kinase cascades, have recently been
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identified (224, 225). TRAF2 also seems to act as scaffolding protein to which numerous proteins participating in the signaling for MAPK activation can bind. In this case, however, the majority of these proteins are not the kinases themselves but other adapters such as RIP and TRADD and regulatory molecules such as cIAP2, TRAF1, TRIP, A20, and I-TRAF/TANK (reviewed in 65). Two additional macromolecular complexes specifically involved in the pathway that leads to NF-κB activation are the signalosome (157, 160) and the proteasome (184). The exact locations of these complexes in the cell, the extent to which they are distinct, and the way in which proteins such as NIK and the NF-κB complex are translocated between them remain to be further clarified.
Interactions of Different Signaling Systems In addition to the ability of each of the individual receptors of the TNF/Fas systems to induce multiple effects, the pleiotropicity of these systems reflects cross talk between the receptors. It also involves various kinds of interactions with other receptors, most notably with the receptors for cytokines such as the interferons, IL-1, various growth factors, and insulin, whose physiological roles are intimately related to those of these systems. INTERACTIONS OF THE DIFFERENT RECEPTORS OF THE TNF/Fas SYSTEMS Both similarities and differences between the death processes induced by CD120a and CD95 have been noted. It now seems that the similarities reflect activation of a shared death-inducing signaling pathway (31, 81, 99). The differences may well be a function of the different ways by which the receptors activate this shared caspase-8 pathway (for example, the inability of MORT1/FADD to bind directly to CD120a). They may also reflect superimposed effects of other signaling pathways, activated differentially by the two receptors. Shared signaling pathways may well account for the close functional relationship between CD120a and CD120b. The following three mechanisms have been suggested to contribute to these similarities: (a) cross talk between signaling molecules. The two receptors indeed use the same proximal molecules both in activating NF-κB [NIK (161)] and in inducing cell death (MORT1/FADD; W Declercq, personal communication). Several points of evidence indicate involvement of TRAF2 in the pro-apoptotic CD120b effect, perhaps by mediating the deviation of anti-apoptotic molecules such as cIAP1 and 2 or CASH (which bind to TRAF2) (185, 186) from CD120a (33, 34); (b) induced synthesis of cell-bound TNF-α and autocrine activation of CD120a by it (M Grell, personal communication); (c) enhancement of TNF-α binding to the CD120a by the CD120b at low TNF-α concentration (a ligand passing mechanism) (187). As in CD120b, the functions shared between the LTβR and CD120a seem to be mediated by TRAF molecules; however, the TRAF species involved in
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death induction by this receptor (TRAF3) is distinct from those responsible for NF-αB activation (TRAF2 and TRAF5) (32). With the exception of the LTβ2/LTα1 heterotrimer, each of the ligands in the TNF system can bind more than one kind of receptor species. It thus seems possible that signaling initiation by these ligands involves not only imposed juxtaposition of the same receptor molecules but also heteroassociation of different receptors that bind to the same ligand. Some evidence indicates that CD120a and CD120b can indeed bind simultaneously to the same TNF-α molecule (188). INTERACTIONS WITH THE IL-1S There is almost no known effect of TNF that cannot be induced in some cells by IL-1, and for many of these effects, there is pronounced synergism in the function of the two cytokines. This relationship at least partly reflects shared early postreceptor events activated by these ligands. Like the TNF receptors, the IL-1 receptor uses a member of the TRAF family, TRAF6, in its signaling activity, and TRAF6 shares various functional features with the TNF-activated TRAF2. It binds common signaling molecules like NIK (161, 165). It also hetero-associates with TRAF2, a mechanism that may contribute to the synergism of the signaling pathways activated by IL-1 and TNF. INTERACTIONS WITH THE IFNS TNF-α has various antiviral effects, like those of the IFNs. Conversely, the IFNs, like TNF-α, have cytotoxic effects that can preferentially affect virus-infected cells (although, unlike with TNF-α, this effect—like all others of the IFNs—is dependent on gene activation). The ability of CD120a to activate the Jak kinases and Tyk, which play a principal role in signaling by the IFN receptors (173), might contribute to this close similarity of function. INTERACTIONS WITH THE EGF RECEPTOR FAMILY The cytocidal effects of both TNF-α and CD95 ligation are antagonized by certain growth-inducing ligands. There is particular interest in the mediation of such effects by receptors of the EGF family, as it appears that these receptors interact with those of TNF-α on several mechanistic levels. TNF-α induces increased expression both of the EGF receptor (EGF-R) and of its ligand TGF-α, although it suppresses the synthesis of the EGF-R homolog HER2/ERBB2 (189). Triggering or overexpression of HER2/ERBB2 or other members of the EGF-R family, with consequent activation of their tyrosine kinase function, endows cells with resistance to TNF-α cytotoxicity although they maintain expression of the TNF receptors (e.g. 190). Moreover, triggering of the TNF receptors induces serine or threonine phosphorylation of the EGF-R, apparently mediated by the ERK and JNK MAPKs (191), and in some cells, it induces tyrosine phosphorylation of the EGF-R. The latter, which results in increased in vitro kinase activity of
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the receptor and signaling for c-fos gene expression (192), probably contributes to the resistance of the cells to TNF-α cytotoxicity (193). INTERACTIONS WITH THE INSULIN SIGNALING PATHWAY TNF-α inhibits signaling by the insulin receptor, an effect that—because TNF-α is constitutively formed by adipocytes—is believed to contribute to obesity-linked insulin resistance. The inhibitory effect, which is triggered by CD120a, is manifested in decreased association of the adapter protein IRS1 with the insulin receptor. It is also manifested by an inhibitory effect of IRS1 on the tyrosine proteinkinase activity of the insulin receptor, which is required for signaling by this receptor. These effects reflect increased serine phosphorylation of IRS1. It was suggested that the kinase mediating this phosphorylation is activated by ceramide, formed as a consequence of sphingomyelinase activation by TNF-α. Its identity is not known, however, and there is no knowledge of its substrate site(s) in IRS1 (194, 195).
CONCLUDING REMARKS “The world is embodied in a drop of dew,” said Goethe. To paraphrase this poetic insight, tracking the chains of interactions of even a single molecule may reward us with a view of the whole world. The vista obtained, however, depends on the starting point. The odyssey begun by tracking the molecules linked to the receptors of the TNF and Fas systems has already given us a unique outlook on the world of biological regulation. It has made a significant contribution to knowledge of the regulation of cell death, an aspect of biology that until recently was largely neglected, and is likely to contribute further to our understanding of how death of the individual cell and damage on the level of the whole tissue occur. There are additional functions that are unique to the TNF and Fas systems, for example, the function of lymph node organogenesis. Their exploration may well also make a novel contribution to the study of signaling. Perhaps the most intriguing next frontier in this odyssey, however, is one that concerns not so much the features unique to one particular signaling system as much as the features shared between the various members of the TNF/NGF family. The last few years have seen rapid growth in the numbers of known members of this family and of the family of TNF-related ligands. The ability to induce both death and growth of cells is rather common in these families, but, at the same time, they are also in charge of regulating almost any other biological function that comes to mind. Despite their large sizes and the wide range of activities they mediate, these families display a rather conserved pattern of molecular structures and mechanisms. Further studies of the TNF and Fas systems and of the various other receptors of the TNF/NGF family should provide
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a better understanding of the unique mechanistic features of the combination of molecular structures that characterize this family. They will also increasingly reveal the advantages of this particular combination, used so abundantly and in so many ways by nature for the control of immune defense. ACKNOWLEDGMENTS The authors thank Jeffery Browning, Wim Declercq, Marja Jaattela, Stefan Leu, Peter Krammer, Martin Kroenke, Marcus Peter, Jordan Pober, and Peter Vandenabeele for advice and for providing unpublished results for inclusion in the manuscript and Shirley Smith for editorial assistance. Work cited from the authors’ laboratory was supported by grants from Inter-Lab Ltd., Ness Ziona, Israel, from Ares Trading SA, Switzerland, and from the Israeli Ministry of Arts and Sciences. Visit the Annual Reviews home page at http://www.AnnualReviews.org
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