What is the key activating signal in the TNF receptor signaling pathway that occurs downstream of TNF-alpha binding to the extracellular domain

TNF-alpha is expressed as a homotrimer that exerts its activities through binding to two types of receptors: TNFR1 and TNFR2, which are transmembrane glycoproteins characterized by having an extracellular domain with 4 cysteine-rich domains (CRD 1-4) , each with 3 cysteinecysteine disulfide bonds.

Explanation:

TNF-alpha (Tumor Necrosis Factor), which has the characteristic of being a paracrine signaling ligand, is a pleiotropic cytokine that functions as a mediator of immune regulation, the inflammatory response and apoptosis in some cell types. Receptors in this family are involved, with some exceptions, in juxtacrine signaling; that is, both the ligand and the receptor are membrane proteins with extracellular domains through which signaling is established. The cellular responses promoted by TNF are initiated by its interaction with two different types of cell receptors, the type I receptor (55 kDa) and the type II receptor (75 kDa). Both types of receptors are part of the TNF receptor family, members of which include Fas antigen (apoptosis inducer, also called Apo-1 or CD95), CD27 (T-cell activation antigen), CD30 (lymphoma marker Hodgkin) and CD40 (B-cell antigen), which share the characteristic of cysteine-rich sequences in their extracellular domains. This family of cytokines generate cellular responses that include differentiation, proliferation, activation of NFκB and cell death, promoting the aggregation of receptor monomers, that is, they have a transmembrane domain that participates in the solubilization of the receptor and a domain of intracellular death that is involved in signal transduction. The binding of TNF to TNF-R1 induces a signaling cascade through its intracellular death domain, which subsequently leads to the activation of complex I (or inflammatory) of NFkB and proceeds to the transcription of anti-apoptotic genes, pro- inflammatory diseases and apoptosis complex II (caspases).

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