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Tumor necrosis factor (TNF) signaling Discuss the nature of the TNF ligand and the receptor for that ligand, and explain the general steps in the pathway (use figure 8.53 and explain in your own words). Make sure to include an explanation of the proteolytic and phosphorylation cascades. What advantage is there in having a cascade part of these pathways? What purpose does it serve?

Tumor necrosis factor (TNF) signaling Discuss the nature of the TNF ligand and the receptor for that ligand, and explain the general steps in the pathway (use figure 8.53 and explain in your own words). Make sure to include an explanation of the proteolytic and phosphorylation cascades. What advantage is there in having a cascade part of these pathways? What purpose does it serve?

Biochemistry
Biochemistry
9th Edition
ISBN:9781319114671
Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Publisher:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Chapter1: Biochemistry: An Evolving Science
Section: Chapter Questions
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Tumor necrosis factor (TNF) signaling

Discuss the nature of the TNF ligand and the receptor for that ligand, and explain the general steps in the pathway (use figure 8.53 and explain in your own words). Make sure to include an explanation of the proteolytic and phosphorylation cascades. What advantage is there in having a cascade part of these pathways? What purpose does it serve?

 

 

**Figure 8.53: TNF-α Activation of TNF Receptor Signaling Pathways** This figure illustrates how the activation of the TNF receptor by TNF-α can stimulate two distinct signaling pathways: a protease cascade leading to cell death, and a phosphorylation cascade resulting in cell survival. ### Apoptotic Pathway (Left Side of the Diagram) 1. **TNF Receptor-Mediated Assembly:** - Upon TNF-α binding, TNF receptors are activated, initiating the assembly of death domain (DD) and death effector domain (DED) protein complexes. This involves TRADD and FADD. 2. **Autocleavage of Procaspase 8:** - The TRADD–FADD complex activates caspase 8 (CASP8) through autocleavage, crucial for the apoptotic process. 3. **Caspase Cascade:** - Activated CASP8 cleaves and activates procaspase 3 (CASP3), known as the "executioner" protease, which further cleaves cellular proteins leading to cell death. ### Cell Survival Pathway (Right Side of the Diagram) 1. **NIK/RIP-Mediated Phosphorylation:** - Signaling through TRADD, TRAF2, and RIP kinases activates NIK and IKK complexes. IKK phosphorylation is a critical step resulting in IκBα degradation. 2. **Activation of NFκB:** - IKK phosphorylation targets IκBα for degradation, subsequently activating NFκB (p50/p65). Once activated, NFκB translocates to the nucleus. 3. **Gene Expression:** - In the nucleus, NFκB promotes the expression of anti-apoptotic genes, inhibiting CASP8 and CASP3 and favoring cell survival. This bifurcated signaling process is crucial in maintaining cellular balance between survival and death, dependent on the cellular context and external stimuli.
Transcribed Image Text:**Figure 8.53: TNF-α Activation of TNF Receptor Signaling Pathways** This figure illustrates how the activation of the TNF receptor by TNF-α can stimulate two distinct signaling pathways: a protease cascade leading to cell death, and a phosphorylation cascade resulting in cell survival. ### Apoptotic Pathway (Left Side of the Diagram) 1. **TNF Receptor-Mediated Assembly:** - Upon TNF-α binding, TNF receptors are activated, initiating the assembly of death domain (DD) and death effector domain (DED) protein complexes. This involves TRADD and FADD. 2. **Autocleavage of Procaspase 8:** - The TRADD–FADD complex activates caspase 8 (CASP8) through autocleavage, crucial for the apoptotic process. 3. **Caspase Cascade:** - Activated CASP8 cleaves and activates procaspase 3 (CASP3), known as the "executioner" protease, which further cleaves cellular proteins leading to cell death. ### Cell Survival Pathway (Right Side of the Diagram) 1. **NIK/RIP-Mediated Phosphorylation:** - Signaling through TRADD, TRAF2, and RIP kinases activates NIK and IKK complexes. IKK phosphorylation is a critical step resulting in IκBα degradation. 2. **Activation of NFκB:** - IKK phosphorylation targets IκBα for degradation, subsequently activating NFκB (p50/p65). Once activated, NFκB translocates to the nucleus. 3. **Gene Expression:** - In the nucleus, NFκB promotes the expression of anti-apoptotic genes, inhibiting CASP8 and CASP3 and favoring cell survival. This bifurcated signaling process is crucial in maintaining cellular balance between survival and death, dependent on the cellular context and external stimuli.
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