Human Anatomy & Physiology (11th Edition)
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ISBN: 9780134580999
Author: Elaine N. Marieb, Katja N. Hoehn
Publisher: PEARSON
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Give an overview of the pathway and what it does, and explain the nature of the TNF ligand and the receptor for that ligand. Make sure to include an explanation of the proteolytic and phosphorylation cascades.
Transcribed Image Text:**TNF Receptor Signaling and Pathways**
**Overview:**
Figure 8.50 illustrates the role of the small protein tumor necrosis factor-α (TNF-α) in regulating both cell death (apoptosis) and cell survival. Upon binding to the trimeric TNF receptor, TNF-α can trigger programmed cell death while simultaneously activating a cell survival pathway. The balance between these pathways is influenced by downstream signaling proteins, which encompass both pro-apoptotic and anti-apoptotic proteins. Understanding this balance requires an examination of the TNF receptor adaptor proteins and their downstream targets.
**Diagram Explanation:**
- **Diagram Title:** Figure 8.50
- **Content:** The diagram portrays TNF receptor signaling involving cell death and survival pathways.
- **Left Side (Cell A):**
- Shows a high level of pro-apoptotic proteins leading to apoptosis.
- Pathway indicated by red arrows, labeled as the proteolytic cascade.
- **Right Side (Cell B):**
- Shows a low level of pro-apoptotic proteins and a high level of anti-apoptotic proteins that result in cell survival.
- Pathway indicated by blue arrows, labeled as the phosphorylation cascade.
**Detailed Explanation:**
- **Adaptor Proteins and Death Domains:**
Adaptor proteins interact with a domain in the TNF receptor’s cytoplasmic tail known as the death domain (DD), which is crucial for protein–protein interactions.
- **Cell Death Pathway:**
Triggered by cysteine–aspartate proteases (caspases), leading to a proteolytic cascade that degrades cellular proteins and induces cell death.
- **Cell Survival Pathway:**
Regulated by kinase-mediated phosphorylation, activating transcription factors that express genes encoding proteins inhibiting apoptosis.
**TNF Receptors and Cytosolic Adaptor Complexes:**
- **Human TNF-α:**
This protein is a 212-amino-acid molecule secreted by immune cells. Its proteolytic processing results in a 185-amino-acid signal that binds to TNF receptors to form a homotrimeric complex.
- **Activation Process:**
- TNF-α binding induces conformational changes in the TNF receptor’s cytoplasmic tails, modifying the DD region.
- This results in the dissociation of the inhibitory protein, silence of death domain (
Transcribed Image Text:**Figure 8.50 Explanation for Educational Website:**
The image illustrates the dual role of TNF receptor signaling in regulating cell death and survival pathways upon binding with the tumor necrosis factor-alpha (TNF-α). When TNF-α binds to the trimeric TNF receptor, it can initiate apoptosis (programmed cell death) or stimulate a survival pathway. The decision between these two outcomes depends on the relative abundance of downstream signaling proteins.
**Diagram Explanation:**
- **Left Side (Apoptosis Pathway):**
- TNF receptors on "Cell A" bind TNF-α.
- Death domains in the receptors activate adaptor proteins.
- High levels of pro-apoptotic proteins are present.
- This leads to a downstream proteolytic cascade, promoting cell death.
- **Right Side (Survival Pathway):**
- TNF receptors on "Cell B" bind TNF-α.
- Adaptor proteins are activated.
- High levels of anti-apoptotic proteins are present.
- This results in a kinase-mediated phosphorylation cascade, promoting cell survival.
**Text Explanation:**
Adaptor proteins bind to the death domain (DD) of TNF receptors, initiating either the cell death or survival pathway. In the apoptosis pathway, caspases degrade cellular proteins, leading to cell death. For cell survival, a kinase-mediated phosphorylation cascade activates transcription factors, promoting the expression of anti-apoptotic genes.
**Signal Transduction:**
TNF-α, a 185-amino-acid signaling protein, binds to TNF receptors. This binding induces conformational changes in the receptor that dissociate the silence of death domain (SODD) proteins, allowing DD regions to bind adaptor proteins. This forms a complex that promotes further downstream signaling, either leading to cell death or survival according to the context of the signaling proteins involved.
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