Pathway: TNF alpha/NF-kB

TNF alpha is a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily.It signals through two distinct cell surface receptors, TNFR1 and TNFR2. NFKB is a transcription regulator that is activated by various intra and extra cellular stimuli including cytokines like TNF alpha. The TNF alpha induced NFKB activity involves the five mammalian NF-kappaB/Rel proteins that have been cloned and characterized, so far that is : c-Rel, NF-kappaB1 (p50/p105), NF-kappaB2 (p52/p100), RelA/p65, RelB. In the absence of TNF alpha stimulation, NF-kappaB is associated with the inhibitor IkappaB in the cytoplasm.TNF-induced activation of NF-kB largely relies on phosphorylation dependent ubiquitination and degradation of inhibitor of kappa B (IkB) proteins. The inhibitor of kappa B kinase (IKK) complex, a multiprotein kinase complex is responsible for the TNF alpha induced phosphorylation of IkB. The free NF-kappaB translocates to the nucleus and induces expression of certain genes. TRADD adaptor molecule interacts with TNFR1 and recruits the additional adaptor proteins like RIP, TRAF2, and FADD, which in turn recruit additional key components to TNFR1 responsible for initiating downstream events and mediating programmed cell death signaling and NF-kappaB activation. This pathway is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. more...