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Tumor necrosis factor (TNF) signaling Explain in detail each step in figure 8.53.  Make sure to include an explanation of the proteolytic and phosphorylation cascades.

Tumor necrosis factor (TNF) signaling Explain in detail each step in figure 8.53.  Make sure to include an explanation of the proteolytic and phosphorylation cascades.

Human Anatomy & Physiology (11th Edition)
Human Anatomy & Physiology (11th Edition)
11th Edition
ISBN:9780134580999
Author:Elaine N. Marieb, Katja N. Hoehn
Publisher:Elaine N. Marieb, Katja N. Hoehn
Chapter1: The Human Body: An Orientation
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Tumor necrosis factor (TNF) signaling

Explain in detail each step in figure 8.53.  Make sure to include an explanation of the proteolytic and phosphorylation cascades.

Apoptotic pathway 1 TNF receptor-mediated assembly of DD and DED protein complexes Procaspase 8 Autocleavage of procaspase 8 3 CASP8 cleavage of procaspase 3 Procaspase 3 4 CASP3 cleavage of cellular proteins TNF receptors Death domains FADD CASP8 CASP3 TNF-α Cell death TRADD TRAF2 IKK Inactive NFkB NIK ATP RIP ADP 13 Cell survival Cell survival pathway ATP 1 NIK/RIP-mediated phosphorylation of IKK IKK -P ADP p50 IkBa p65 Plasma membrane 2 IKK phosphorylation of IkBa results in activation of p50/p65 Active NFkB +3 4 Increased expression of anti-apoptotic genes that inhibit CASP8 and CASP3 activation 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- 3 Active p50/p65 heterodimeric NFKB translocates to the nucleus Nuclear membrane 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 IkBa for degradation, which leads to activation of the transcription factor NFKB. Once the heterodimeric NFêB (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.
Transcribed Image Text:Apoptotic pathway 1 TNF receptor-mediated assembly of DD and DED protein complexes Procaspase 8 Autocleavage of procaspase 8 3 CASP8 cleavage of procaspase 3 Procaspase 3 4 CASP3 cleavage of cellular proteins TNF receptors Death domains FADD CASP8 CASP3 TNF-α Cell death TRADD TRAF2 IKK Inactive NFkB NIK ATP RIP ADP 13 Cell survival Cell survival pathway ATP 1 NIK/RIP-mediated phosphorylation of IKK IKK -P ADP p50 IkBa p65 Plasma membrane 2 IKK phosphorylation of IkBa results in activation of p50/p65 Active NFkB +3 4 Increased expression of anti-apoptotic genes that inhibit CASP8 and CASP3 activation 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- 3 Active p50/p65 heterodimeric NFKB translocates to the nucleus Nuclear membrane 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 IkBa for degradation, which leads to activation of the transcription factor NFKB. Once the heterodimeric NFêB (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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