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
6th Edition
ISBN:9781305577206
Author:Reginald H. Garrett, Charles M. Grisham
Publisher:Reginald H. Garrett, Charles M. Grisham
Chapter32: The Reception And Transmission Of Extracellular Information
Section: Chapter Questions
Problem 3P
Related questions
Question
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?
![Apoptotic pathway
TNF receptor-mediated
assembly of DD and DED
protein complexes
Procaspase 8
Autocleavage of
procaspase 8
CASP8 cleavage of
procaspase 3
Procaspase 3
O CASP3 cleavage of
cellular proteins
TNF
receptors.
Death
domains
FADD
CASP8
CASP3
Cell
death
TNF-α
TRADD
TRAF2
IKK
Inactive
NFkB
NIK
ATP
RIP
ADP
13
Cell
survival
Cell survival pathway
IKK
ATP
NIK/RIP-mediated
phosphorylation of IKK
P
ADP
p50
+9
Increased expression
of anti-apoptotic genes
that inhibit CASP8 and
CASP3 activation
IkBa
p65
Plasma
membrane.
2 IKK phosphorylation
of IkBa results in
activation of p50/p65
Active
NFkB
Active p50/p65
heterodimeric
NFKB translocates.
to the nucleus
Nuclear
membrane.
Figure 8.53 TNF-a activation of the TNF receptor
stimulates both a protease cascade, leading to cell death,
and a phosphorylation cascade, resulting in cell survival
The two signaling pathways diverge at the level of the
TRADD protein, which contains both a DD and an N-
terminal domain that binds TNF receptor-associated
factor 2 (TRAF2). In the apoptosis pathway, TNF
receptor activation leads to assembly of a TRADD-
FADD complex that results in autocleavage of procaspas
8 through its interaction with the death effector domain
(DED) of FADD. Once caspase 8 (CASP8) is activated,
proteolytic cascade is initiated by the cleavage and
activation of caspase 3 (CASP3), the "executioner"
protease. TNF receptor signaling can also induce a cell
survival pathway through an adaptor complex consisting
of TRADD, TRAF2, and receptor interacting protein
(RIP) kinase, which leads to the phosphorylation and
activation of IkBa kinase (IKK). Phosphorylation of IKB
by IKK targets IKBα for degradation, which leads to
activation of the transcription factor NFKB. Once the
heterodimeric NFkB (p50/p65) transcription factor is
activated, it enters the nucleus and induces the expressio
of anti-apoptotic genes that inhibit caspase 8 and caspas
3 activation.](/v2/_next/image?url=https%3A%2F%2Fcontent.bartleby.com%2Fqna-images%2Fquestion%2Ff123c09d-ccbd-492d-9b0f-c8892232526f%2F05576bec-f76c-4405-8ee3-f92ce5b0c377%2Fv384os_processed.png&w=3840&q=75)
Transcribed Image Text:Apoptotic pathway
TNF receptor-mediated
assembly of DD and DED
protein complexes
Procaspase 8
Autocleavage of
procaspase 8
CASP8 cleavage of
procaspase 3
Procaspase 3
O CASP3 cleavage of
cellular proteins
TNF
receptors.
Death
domains
FADD
CASP8
CASP3
Cell
death
TNF-α
TRADD
TRAF2
IKK
Inactive
NFkB
NIK
ATP
RIP
ADP
13
Cell
survival
Cell survival pathway
IKK
ATP
NIK/RIP-mediated
phosphorylation of IKK
P
ADP
p50
+9
Increased expression
of anti-apoptotic genes
that inhibit CASP8 and
CASP3 activation
IkBa
p65
Plasma
membrane.
2 IKK phosphorylation
of IkBa results in
activation of p50/p65
Active
NFkB
Active p50/p65
heterodimeric
NFKB translocates.
to the nucleus
Nuclear
membrane.
Figure 8.53 TNF-a activation of the TNF receptor
stimulates both a protease cascade, leading to cell death,
and a phosphorylation cascade, resulting in cell survival
The two signaling pathways diverge at the level of the
TRADD protein, which contains both a DD and an N-
terminal domain that binds TNF receptor-associated
factor 2 (TRAF2). In the apoptosis pathway, TNF
receptor activation leads to assembly of a TRADD-
FADD complex that results in autocleavage of procaspas
8 through its interaction with the death effector domain
(DED) of FADD. Once caspase 8 (CASP8) is activated,
proteolytic cascade is initiated by the cleavage and
activation of caspase 3 (CASP3), the "executioner"
protease. TNF receptor signaling can also induce a cell
survival pathway through an adaptor complex consisting
of TRADD, TRAF2, and receptor interacting protein
(RIP) kinase, which leads to the phosphorylation and
activation of IkBa kinase (IKK). Phosphorylation of IKB
by IKK targets IKBα for degradation, which leads to
activation of the transcription factor NFKB. Once the
heterodimeric NFkB (p50/p65) transcription factor is
activated, it enters the nucleus and induces the expressio
of anti-apoptotic genes that inhibit caspase 8 and caspas
3 activation.
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