Signal Transduction by Tumour Necrosis Factor and Tumour Necrosis Factor Related Ligands and Their Receptors
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I2 Ann Rheum Dis 1999;58:(Suppl I) I2–I13 Signal transduction by tumour necrosis factor and tumour necrosis factor related ligands and their receptors Bryant G Darnay, Bharat B Aggarwal Many biological functions are regulated a network of these and other cytokines through interactions of extracellular molecules produced by various types of cells and their with their cognate cell surface receptors. The aberrant regulation may result in inflamma- transduction of these signals by their receptors tory diseases. In this review, we would like to at the plasma membrane to the intracellular focus on the recent developments in the char- machinery results in such cellular activities as acterisation of the TNF signalling pathway gene activation, protein phosphorylation, cell learned from multiple approaches including proliferation, and cell destruction. Though the gene disruption in mice and on reports of kinetics of these activities may diVer, their recently discovered members of the TNF interactions are coordinated by selective inter- ligand and receptor superfamilies. It is likely play between the receptors’ intracellular do- that these novel cytokines also cooperate in mains and a select set of intracellular receptor regulating the immune system, and thus may binding proteins. One such family of extracel- be involved in inflammatory diseases. lular molecules and their cell-surface receptors are the tumour necrosis factor (TNF) family of related cytokines and receptors, which is the TNF signal transduction topic of this review. Although produced primarily by activated Rheumatoid arthritis, a disease of joint macrophages, small amounts of TNF are pro- inflammation and destruction, is the result of duced by several other cell types. TNF is inappropriate activation of resident and inflam- expressed as a 26 kDa transmembrane protein, matory cells within the synovial tissue. The which is processed to a soluble 17 kDa protein released via specific proteolytic cleavage. Some consequence of an initiating and as yet of the well known activities ascribed to TNF unknown stimulus, the cascade of inflamma- include septic shock, cytotoxicity, inflamma- tory processes are chronic and self perpetuat- tion, and viral replication. Clearly, TNF is a ing. The inflammation in the joints characteris- pleiotropic cytokine perhaps because virtually tic of arthritis is believed to be atrributable all cells express at least one of the two types of largely to misregulation of cytokine produc- TNF receptors. The signalling pathways initi- tion, abnormal expression of receptors, or the ated by TNF binding to its receptor have been absence of counter-regulatory pathways. Two extensively investigated, clarifying the signal- proinflammatory cytokines, TNF and inter- ling components linking receptor activation to leukin 1 (IL1), are believed to be the major biological activities.4 The advent of the yeast cytokines cooperating in the pathology of this 1 two hybrid system for identifying protein- disease. Therapeutic approaches that inhibit protein interactions and the availability of the interaction of these ligands with their expressed sequence tag (EST) databases have receptors has been a successful avenue in the assisted in the identification of a unique and 2 treatment of rheumatoid arthritis. novel set of signalling machinery used by TNF One characteristic common to both TNF and other related family members. These novel and IL1 is their ability to activate the adaptor proteins seem to be promiscuous and transcription factor nuclear factor-kappa B thus are used by more than one TNF receptor (NF-êB), which is responsible for regulation family member for signal transduction. Al- of a number of genes necessary for the inflam- though specific functions have been assigned to mation process.3 More recently, the elucida- these adaptors in relation to the cellular tion of the TNF and IL1 signalling pathways responses activated by TNF receptor engage- has provided novel candidate molecules from ment, the physiological relevance of each adap- which to develop therapeutic inhibitors that tor protein in the context of ligand stimulation would block NF-êB activation. Furthermore, must await its targeted disruption in mice. additional members of the TNF family have Where these experiments have been done, Cytokine Research been discovered and are also capable of however, some unexpected findings have Laboratory, activating NF-êB. To date, 21 members of the emerged. Department of Molecular Oncology, TNF receptor superfamily and 17 members of Signalling cascades initiated by various The University of the TNF ligand superfamily have been identi- members of the TNF receptor family include Texas M D Anderson fied. Most of these ligand/receptor pairs those that activate transcription factors (that is, Cancer Center, participate in modulating various physiologi- NF-êB and AP1),3 protein kinases (that is, Houston, Texas 77030, cal processes, including the immune response, MAPK, JNK, p38),5 and proteases.67Over the USA anti-tumour activity, cellular proliferation and past few years, a number of novel adaptor pro- Correspondence to: diVerentiation, and apoptosis. Many of these teins have been identified that initiate these Dr B Darnay. physiological processes are controlled through signalling cascades. One family, the death- TNF related ligands and their receptors I3 domain proteins,8 link death receptors to seems that oligomerisation caused by ligand downstream proteases of the caspase family binding to the receptor initiates the signalling necessary for activation of apoptosis. The death cascades. domain is a protein-protein interaction motif, A second family of adaptor proteins identi- which is a conserved stretch of approximately fied as signalling components of the TNF 90 residues. The homophillic or heterophillic receptor family is the TNF receptor associated interaction between death domain containing factor (TRAFs) family, which appears to func- proteins is most probably through electrostatic tion primarily in the activation of transcription interactions, as revealed by the structure of the factors and protein kinases.10 The TRAF family death domain of Fas,9 which consists of a series consists of six distinct proteins, each containing of antiparallel amphipathic á-helices with a ring and zinc finger motif in their N-terminal many exposed charged residues. For example, and C-terminal domains that appear to be ligand binding to the cell surface receptor responsible for self association and protein causes a rearrangement of the intracellular interaction (fig 1). All, except for TRAF4, were domain to oligomerise with adaptors and in identified through yeast two-hybrid screening turn initiate signal transduction cascades. using a cytoplasmic domain of various mem- Consistent with this model, forced overexpres- bers of the TNF receptor family. To date, sion of death receptors in cultured cells causes TRAF4 has no known function. The interac- a ligand independent apoptotic eVect indistin- tion of TRAF1, TRAF2, and TRAF5 with vari- guishable from ligand stimulation. Thus, it ous cytoplasmic domains of TNF receptor Ring finger Zn finger TRAF-N TRAF-C TRAF2 TRAF1 TRAF3 TRAF4 TRAF5 TRAF6 Receptor TRAF1 TRAF2 TRAF3 TRAF5 TRAF6 TNFR2 ––– LTβ R ? CD40 CD30 ? CD27 ? – – HVEM – RANK LMP-1 –– IL1R –––– OX40 – – ? 4-1BB –– ? GITR –– Figure 1 The TRAF family of proteins. Top, each of the TRAF molecules is depicted with the indicated motifs. Bottom, members of the TNF receptor family are listed with the TRAF molecules that directly interact with the receptor. LMP-1 and IL1 receptors are not members of this family, but have been shown to bind to TRAF molecules. ¡¢ॗक़ख़ॏॐ॑ॖग़stu्ॎwx॒rv I4 Darnay, Aggarwal family members requires a specific motif in the these types of experiments.413 However, the receptor (that is, PXQXT). Unlike these TRAF physiological role of these adaptor molecules in molecules, TRAF6 uses a distinct motif (that is, TNF signalling and development has been QXPXE), which has been identified in CD40 recently revealed by targeted disruption of their and RANK.11 12 However, of the known TRAF genes in mice, most notably TRAF2, RIP, molecules, only TRAF2, TRAF5, and TRAF6 FADD, caspase 8, and FAN. have been demonstrated to mediate NF-êB and One of the first molecules to be identified JNK activation. and required for NF-êB and JNK activation by Over the past few years, the signalling TNF was TRAF2. Initially, when it was machinery linking the TNF receptor to three discovered, this protein was shown to activate downstream targets (that is, apoptosis, NF-êB, NF-êB, and was later found to activate JNK and JNK activation) has been elucidated (fig when overexpressed in cultured cells. Further- 2). To understand the complexity of the identi- more, a mutant version of TRAF2 could fication of the signalling components of a path- inhibit TNF induced NF-êB and JNK. Thus, way, one must first understand how they are from the early reports it appeared that TRAF2 identified. For example, after the adaptor is was essential for TNF dependent NF-êB acti- identified, it is examined for its ability to either vation. However, from the TRAF2 knockout activate or inhibit downstream signalling path- mouse model, TNF could surprisingly still ways by transfection of its cDNA into cultured activate NF-êB in embryonic fibroblasts, but cells. Furthermore, a mutant version of the not JNK.14 15 Furthermore, TRAF2 -/- mice potential adaptor molecule is introduced into appeared normal at birth but became progres- cells and examined for its ability to inhibit a sively runted and died prematurely. Defects in specific ligand dependent end point. If the B cell precursors and atrophy of the thymus mutant version blocks this pathway, then one were also observed. Moreover, these mice concludes this adaptor molecule participates in exhibited increased serum concentrations of signalling by the tested ligand. Although this is TNF, and thymocytes and haematopoietic cells not a foolproof scheme, it has become a very were highly sensitive to TNF induced apopto- powerful tool in the study of the signalling sis. These observations suggest that TRAF2 is events aVected by TNF and other members of required for TNF induced JNK activation and this family.