PubMed Journals: Annu Rev Immunol

  Source:		PMID: 10837071
  Download:	https://www.annualreviews.org/doi/pdf/10.1146/annurev.immunol.18.1.621

    		Annu Rev Immunol. 2000;18:621-63.
			Phosphorylation meets ubiquitination: the
			control of NF-[kappa]B activity.

			Karin M(1), Ben-Neriah Y.

			Author Information
			(1) Department of Pharmacology, Laboratory
			of Gene Regulation and Signal Transduction
			University of California, San Diego,
			La Jolla, California 92093-0636, USA.

			NF-kappaB (nuclear factor-kappaB) is a collective
			name for inducible dimeric transcription
			factors composed of members of the Rel family
			of DNA-binding proteins that recognize a
			common sequence motif. NF-kappaB is found
			in essentially all cell types and is involved
			in activation of an exceptionally large
			number of genes in response to infections,
			inflammation, and other stressful situations
			requiring rapid reprogramming of gene expression.
			NF-kappaB is normally sequestered in the
			cytoplasm of nonstimulated cells and consequently
			must be translocated into the nucleus to
			function. The subcellular location of NF-kappaB
			is controlled by a family of inhibitory
			proteins, IkappaBs, which bind NF-kappaB
			and mask its nuclear localization signal,
			thereby preventing nuclear uptake. Exposure
			of cells to a variety of extracellular stimuli
			leads to the rapid phosphorylation, ubiquitination,
			and ultimately proteolytic degradation of
			IkappaB, which frees NF-kappaB to translocate
			to the nucleus where it regulates gene
			transcription. NF-kappaB activation represents
			a paradigm for controlling the function
			of a regulatory protein via ubiquitination-dependent
			proteolysis, as an integral part of a
			phosphorylationbased signaling cascade.
			Recently, considerable progress has been
			made in understanding the details of the
			signaling pathways that regulate NF-kappaB
			activity, particularly those responding
			to the proinflammatory cytokines
			tumor necrosis factor-alpha and interleukin-1.
			The multisubunit IkappaB kinase (IKK) responsible
			for inducible IkappaB phosphorylation is
			the point of convergence for most
			NF-kappaB-activating stimuli. IKK contains
			two catalytic subunits, IKKalpha and IKKbeta,
			both of which are able to correctly phosphorylate
			IkappaB. Gene knockout studies have shed
			light on the very different physiological functions
			of IKKalpha and IKKbeta. After phosphorylation,
			the IKK phosphoacceptor sites on IkappaB
			serve as an essential part of a specific
			recognition site for E3RS(IkappaB/beta-TrCP),
			an SCF-type E3 ubiquitin ligase, thereby
			explaining how IKK controls IkappaB ubiquitination
			and degradation. A variety of other signaling
			events, including phosphorylation of NF-kappaB,
			hyperphosphorylation of IKK, induction of
			IkappaB synthesis, and the processing of
			NF-kappaB precursors, provide additional
			mechanisms that modulate the level and duration
			of NF-kappaB activity.

			DOI: 10.1146/annurev.immunol.18.1.621
			PMID: 10837071 [Indexed for MEDLINE]

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