Question

What is the key activating signal in the TNF receptor signaling pathway that occurs downstream of TNF-alpha binding to the extracellular domain? What are the analogous activating signals downstream of receptor activation in the GPCR and RTK pathways.

Answer 1

TNF alpha (Tumor necrosis factor) is a cytokine which is able to promote inflammation. It’s mainly produced by macrophages but also CD4 Lymphocytes, NK cells, neutrophils, mast cells, eosinophils and neurons can produce it as well. TNF is able to bind two receptors:TNFR1 and TNFR2. Once TNF alpha is in contact with TNFR will form trimers promoting a conformational change of the receptor, leading to the key activating signal, dissociation of several inhibitory proteins such as the silencer of death domains (SODD) from the intracellular death domain. After this, the adaptor Tumor necrosis factor receptor type 1-associated Death domain protein (TRADD) will bind to the death domain promoting three main pathways: Activation of NF-κB, MAPK pathways and death signaling. In the case of GPCR (G protein-coupled receptors) the analogous activating signals is the bind between GDP or GTP. GPCR activation is regulated by several factors that are able to control to bind or hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). If the protein is bound to GTP, the protein is activated. On the contrary, If the protein is bound to GDP is inactivated. Finally, RTKs (Receptor tyrosine kinases) are receptors with a high-affinity for its ligand. Once, the extracellular ligand binds to the receptor, It will lead stabilize receptor dimerization promoting that trans-phosphorylation of the tyrosine in the intracellular portion of RTK by its coupled receptor, activating the signal through the plasma membrane.