Signaling mechanisms

The TNF receptors signal for both gene activation-dependent and -independent effects. Knowledge of the signaling mechanisms for both kinds of effects, though still fragmentary at present, is increasing rapidly. Several transcription factors involved in the gene activation-dependent effects of the receptors have been identified. The most extensively studied is NFkB, a transcription factor (or rather a family of related factors) which participates in the transcriptional regulation of many genes related to defense. Studies of the cytocidal effect, the best characterized of gene activation-independent TNF effects, revealed a critical role of several ICE/CED3 proteases in this death induction, resembling in that sense other programed cell death processes. Several protein kinases whose activities change rapidly after receptor triggering have been identified, including those comprising the three currently known main mitogen-ac-tivated protein (MAP) kinase cascades (the stress-activated protein kinase I (JUN N-terminal kinase, JNK), stress-activated protein kinase 2 (p38 kinase), and the extracellular signal-regulated kinase (ERK.) cascades). In addition, several lipases, including a phosphatidylcholine specific phospholipase C and the cellular phospholipase A2, are activated by the receptors. Signaling by the TNF receptors is initiated as a consequence of interaction of two or three receptor molecules, caused by their binding to the trimeric ligand molecules (or by cross-linking with TNF receptor-specific antibodies). Triggering results in recruitment of several adapter and signaling molecules.

The known receptor-associated adapter proteins and some of the signaling molecules that they activate are illustrated in Figure 2. They include a group of structurally related adapter proteins called the TRAFs (TRAF1, 2, 3 and 5), which bind through a shared C-terminal sequence motif (termed the TRAF domain) to distinct regions in CT)120b and I.T/3-R (though not to CD 120a). They also include three adapter proteins, TRADD, MORT1/FADD and RIP, which contain DDs and bind through them to the DDs in CD120a and in the structurally and functionally related receptor CD95 (Fas/Apol). These three proteins do not bind to CD 120b or to the LT/3-R. Both TRAF2 (which binds to CD 120a and to the IT^-R, as well as to some other members of the TNF/NGF family, such as CIM0) and TRAF5 i which binds to the LTjS-R) are involved in the activation of NFkB by these receptors. TRADD, a DD-containing adapter protein that binds to CD 120a, is involved in cell death induction, which most probably occurs through the binding of its DD to that of MORT1/FADD, a DD-containing adapter protein that binds directly to Fas/Apol. TRADD is also involved in the activation of NFkB by CD 120a, most likely through interaction of the region upstream of its DD with TRAF2.

Events further downstream in the death-inducing cascade include recruitment of a CED3/ICE protease called MACH (or FLICE or Mch.5 or caspase-8) to MORT1/FADD, and its consequent activation. They also include activation of several other ICF7CED3 proteases, including CPP32/Apopain/Yama icaspase-3) and Mch3/ICE-LAP3 (caspase-7), which is most probably a consequence of activation of MACH/FLICE. Activation of the acid sphingomyelinase, phospholipase A2 and JUN kinase by the TNF receptors may also participate in the death-induction process. The most crucial events further downstream in activation of NFkB by the receptors

MFkB activation

Figure 2 Signaling molecules that bind to the intracellular domains of the TNF receptors and some of their functions.

MFkB activation

Figure 2 Signaling molecules that bind to the intracellular domains of the TNF receptors and some of their functions.

are the induced phosphorylation and consequently the proteolytic degradation of IkB. The exact sequence of molecular events leading to this phosphorylation is not yet known, except that it appears to involve the participation of TRAF2 and a protein called TANK or I-TRAF, which binds to TRAF2. A MAP kinase kinase kinase called NIK. which binds to TRAF2 and apparently participates in NFkB activation, was recently identified.

A few TNF receptor-associated adapter proteins that signal for other TNF effects have also been identified. One of these is FAN, an adapter protein that is apparently involved in the TNF-induced activation of the neutral sphingomyelinase. FAN binds to a distinct region in the CD120a intracellular domain upstream of the DD.

Taken together, the emerging molecular picture reveals a rather wide diversity of receptor-activated signaling cascades, consistent with the wide range of activities that these receptors are able to trigger. Another interesting feature is an extensive interac tion among the molecules that participate in the signaling activities of the three TNF receptors, as well as between these molecules and those that participate in the signaling for effects of other receptors of the TNF/NGF family. Such interactions apparently account for the ability of these different receptors to induce many common effects.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment