Tumor Necrosis Factors (TNF) Signaling Pathways
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TNF ligands
TNF superfamily proteins consist of 19 members that signal through 29 receptors. TNF is a multifunctional proinflammatory cytokine, with effects on lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF family members play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis, modulation of immune responses, and induction of inflammation.
TNF
TNF-α, a pro-inflammatory cytokine, is produced by many cell types, including macrophages, lymphocytes, fibroblasts, and keratinocytes, in response to inflammation, infection, and other environmental stresses. TNF-Alpha induces a heterogeneous array of biological effects according to cell type.
TNF-β is produced by activated lymphocytes and can be cytotoxic to many tumors and other cells. In neutrophils, endothelial cells, and osteoclasts, TNF-Beta can lead to activation while in many other cell types it can lead to increased expression of MHC and adhesion molecules.
TRAFs are a major group of intracellular adaptors that bind directly or indirectly to many members of the TNF receptor superfamily. Six mammalian TRAFs, TRAF1 through TRAF6, have been identified. TRAFs can induce the activation of several kinase cascades that ultimately lead to the activation of signal transduction pathways such as NF-κB, JNK, ERK, p38, and PI3K, which can regulate cellular processes ranging from cell proliferation and differentiation to apoptosis.
TNF Receptors
The 19 ligands mediate their cellular response through 29 receptors, which belong to the TNF receptor (TNFR) superfamily. These ligands are characterized by the presence of a cysteine-rich domain (CRD) in the extracellular portion. Based on their cytoplasmic sequences and signaling properties, these TNF receptors can be classified into three major groups.
The first group, including Fas/ CD95/ Apo1/ APT1, TNFR1/ CD120a /p55-R /TNFAR/ TNFR60, DR3/TRAMP/WSL1/LARD/WSLLR/DDR3/TR3/Apo3, DR4/TRAILR1/Apo2, DR5/TRAILR2/KILLER/TRICK2A/TRICKB, and DR6/TR7, contains a DD (Death Domain) in the cytoplasmic tail. Fas, DR4, and DR5 interact with FADD while TNFR1 and DR3 interact with the adaptor TRADD. These molecules, in turn, cause the activation of the Caspase cascade and induction of apoptosis.
The second group includes TNFR2/p75/CD120b/TNFR80/TNFBR, CD40/p50/Bp50, CD30/Ki-1/D1S166E, CD27/Tp55/S152, TNFR2-RP/TNFCR/TNFRIII, LT-BetaR, OX40/ CD134/ACT35/TXGP1L, 4-1BB/CD137/ILA, BAFFR, BCMA/BCM, TACI/CAML interactor, RANK/TRANCE-R, p75NGFR, HVEM /HveA/ATAR/TR2/ LIGHTR, GITR/AITR/ TNFRSF18, TROY/TAJ, EDAR, XEDAR/EDA-A2R, RELT, and Fn14. These receptors contain one or more TIM (TRAF Interacting Motifs) in their cytoplasmic tails. Activation of TIM containing TNF receptors lead to recruitment of TRAF family members, and activation of multiple signal transduction pathways such as NF-κB, JNK, p38, ERK, and PI3K.
The third group of TNF receptor family members, including DcR1/TRID/TRAIL-R3, DcR2/ TRUNDD/TRAIL-R4, DcR3, and Opg, does not contain functional intracellular signaling domains or motifs. Although this group of receptors cannot provide intracellular signaling, they can effectively compete with the other two signaling groups of receptors for their corresponding ligands. These DcR, therefore, function by impeding the activation of signal transduction pathways by other TNF receptors.
TNF Signaling Pathway
The TNF superfamily of cytokines activate signaling pathways for cell survival, death, and differentiation. TNF signaling has been implicated in many other diseases, including multiple sclerosis, Alzheimer’s disease, and TRAPS (TNF-Receptor-Associated Periodic Syndrome).
Upon contacting with the ligand, TNF receptors also form trimers, fitting their tips into the grooves that formed between TNF monomers. This binding induces a change in the confirmation in the receptor, leading to the dissociation of the inhibitory protein SODD from the intracellular death domain. This dissociation enables the adaptor protein TRADD to bind to the death domain, serving as a platform for subsequent protein binding. Following TRADD binding, three pathways can be initiated.
- Activation of NF-κB: TRADD recruits TRAF2 and RIP. TRAF2, in turn, recruits the multicomponent protein kinase IKK, enabling the serine-threonine kinase RIP to activate it. An inhibitory protein, IκBα, normally binds to NF-κB and inhibits its translocation, is phosphorylated by IKK and subsequently degraded, releasing NF-κB. NF-κB is a heterodimeric transcription factor that translocates to the nucleus and mediates the transcription of a vast array of proteins involved in cell survival and proliferation, inflammatory response, and anti-apoptotic factors.
- Activation of the MAPK pathways: Of the three major MAPK cascades, TNF induces a strong activation of the stress-related JNK group, evokes the moderate response of the p38-MAPK, and is responsible for the minimal activation of the classical ERKs. TRAF2/Rac activates the JNK-inducing upstream kinases of MLK2/MLK3, TAK1, MEKK1, and ASK1. SRC- Vav- Rac axis activates MLK2/MLK3 and these kinases phosphorylate MKK7, which then activates JNK. JNK translocates to the nucleus and activates transcription factors such as c-Jun and ATF2. The JNK pathway is involved in cell differentiation, proliferation, and is generally pro-apoptotic.
- Induction of death signaling: Like all death-domain-containing members of the TNFR superfamily, TNFR1 is involved in death signaling. However, TNF-induced cell death only plays a minor role compared to its overwhelming functions in the inflammatory process. Its death-inducing capability is weak compared to other family members, such as Fas, and often masked by the anti-apoptotic effects of NF-κB. Nevertheless, TRADD binds FADD, which then recruits the cysteine protease caspase-8. A high concentration of caspase-8 induces its autoproteolytic activation and the subsequent cleaving of the effector caspases, leading to cell apoptosis.
