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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?

Biology 2e
Biology 2e
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Author:Matthew Douglas, Jung Choi, Mary Ann Clark
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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?

 

 

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.
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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