BIOMAT Database Logo BIOMAT Database Logo

Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B. 1995

Y C Lin, and K Brown, and U Siebenlist
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1876.

The transcription factor NF-kappa B is retained in the cytoplasm by its inhibitor I kappa B-alpha. Upon cellular stimulation with a variety of pathogen- or stress-related agents, I kappa B-alpha is functionally inactivated and NF-kappa B translocates to the nucleus to trigger transcription of a large array of genes, many of which encode proteins critical for immune or stress responses. Here, we demonstrate that signal-induced proteolysis of I kappa B-alpha is an obligatory step for activation of NF-kappa B: calpain inhibitors I and II, which inhibit cysteine proteases, block activation of NF-kappa B by blocking degradation of I kappa B-alpha without affecting signal-induced phosphorylation of this inhibitor. This contrasts with previous models in which phosphorylation of I kappa B-alpha was postulated to be sufficient for activation. We demonstrate further that signal-induced phosphorylation of I kappa B-alpha does not by itself lead to dissociation of the inhibitor from NF-kappa B, providing a rationale for and confirmation of the need to proteolyze I kappa B-alpha in order to activate NF-kappa B. Signal-controlled, target-specific proteolysis is an unexpected, yet likely more general, mechanism for regulating transcription factors.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002154 Calpain Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including NEUROPEPTIDES; CYTOSKELETAL PROTEINS; proteins from SMOOTH MUSCLE; CARDIAC MUSCLE; liver; platelets; and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. This enzyme was formerly listed as EC 3.4.22.4. Calcium-Activated Neutral Protease,Calcium-Dependent Neutral Proteinase,Ca2+-Activated Protease,Calcium-Activated Neutral Proteinase,Calcium-Activated Protease,Calcium-Dependent Neutral Protease,Calpain I,Calpain II,Desminase,Ca2+ Activated Protease,Calcium Activated Neutral Protease,Calcium Activated Neutral Proteinase,Calcium Activated Protease,Calcium Dependent Neutral Protease,Calcium Dependent Neutral Proteinase,Neutral Protease, Calcium-Activated,Neutral Protease, Calcium-Dependent,Neutral Proteinase, Calcium-Activated,Neutral Proteinase, Calcium-Dependent,Protease, Ca2+-Activated,Protease, Calcium-Activated,Protease, Calcium-Activated Neutral,Protease, Calcium-Dependent Neutral,Proteinase, Calcium-Activated Neutral,Proteinase, Calcium-Dependent Neutral
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D003546 Cysteine Endopeptidases ENDOPEPTIDASES which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by CYSTEINE PROTEINASE INHIBITORS such as CYSTATINS and SULFHYDRYL REAGENTS.
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D006023 Glycoproteins Conjugated protein-carbohydrate compounds including MUCINS; mucoid, and AMYLOID glycoproteins. C-Glycosylated Proteins,Glycosylated Protein,Glycosylated Proteins,N-Glycosylated Proteins,O-Glycosylated Proteins,Glycoprotein,Neoglycoproteins,Protein, Glycosylated,Proteins, C-Glycosylated,Proteins, Glycosylated,Proteins, N-Glycosylated,Proteins, O-Glycosylated
D000072000 NF-KappaB Inhibitor alpha An I-kappa B protein that inhibits the activity of dimeric NF-KAPPA B P50-REL complexes, sequesters transcription factor NF-kappaB as an inactive complex in the cytoplasm; and prevents NF-kappaB nuclear translocation and DNA binding. I Kappa B-alpha Protein,IKappaB-alpha,IKappaBalpha,Major Histocompatibility Complex Enhancer-Binding Protein MAD3,p40 Protein (IKappaB-alpha),I Kappa B alpha Protein,IKappaB alpha,Inhibitor alpha, NF-KappaB,Major Histocompatibility Complex Enhancer Binding Protein MAD3,NF KappaB Inhibitor alpha,alpha, NF-KappaB Inhibitor
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015853 Cysteine Proteinase Inhibitors Exogenous and endogenous compounds which inhibit CYSTEINE ENDOPEPTIDASES. Acid Cysteine Proteinase Inhibitor,Cysteine Protease Inhibitor,Cysteine Protease Inhibitors,Cysteine Proteinase Antagonist,Cysteine Proteinase Antagonists,Cysteine Proteinase Inhibitor,Cysteine Proteinase Inhibitors, Endogenous,Cysteine Proteinase Inhibitors, Exogenous,alpha-Cysteine Protease Inhibitor,Acid Cysteine Proteinase Inhibitors,alpha-Cysteine Protease Inhibitors,Antagonist, Cysteine Proteinase,Antagonists, Cysteine Proteinase,Inhibitor, Cysteine Protease,Inhibitor, Cysteine Proteinase,Inhibitor, alpha-Cysteine Protease,Inhibitors, Cysteine Protease,Inhibitors, Cysteine Proteinase,Inhibitors, alpha-Cysteine Protease,Protease Inhibitor, Cysteine,Protease Inhibitor, alpha-Cysteine,Protease Inhibitors, Cysteine,Protease Inhibitors, alpha-Cysteine,Proteinase Antagonist, Cysteine,Proteinase Antagonists, Cysteine,Proteinase Inhibitor, Cysteine,Proteinase Inhibitors, Cysteine,alpha Cysteine Protease Inhibitor,alpha Cysteine Protease Inhibitors

Related Publications

Y C Lin, and K Brown, and U Siebenlist
Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha.
September 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences,
Y C Lin, and K Brown, and U Siebenlist
Cupric ion blocks NF kappa B activation through inhibiting the signal-induced phosphorylation of I kappa B alpha.
November 1995, Biochemical and biophysical research communications,
Y C Lin, and K Brown, and U Siebenlist
Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation.
March 1995, Science (New York, N.Y.),
Y C Lin, and K Brown, and U Siebenlist
Vitamin C suppresses TNF alpha-induced NF kappa B activation by inhibiting I kappa B alpha phosphorylation.
October 2002, Biochemistry,
Y C Lin, and K Brown, and U Siebenlist
Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli.
June 1995, The EMBO journal,
Y C Lin, and K Brown, and U Siebenlist
Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B.
December 1994, Proceedings of the National Academy of Sciences of the United States of America,
Y C Lin, and K Brown, and U Siebenlist
Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B.
April 1990, Nature,
Y C Lin, and K Brown, and U Siebenlist
Inactivation of NF-kappa B inhibitor I kappa B alpha: ubiquitin-dependent proteolysis and its degradation product.
October 1995, Biochemical and biophysical research communications,
Y C Lin, and K Brown, and U Siebenlist
Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B.
September 1993, Nature,
Y C Lin, and K Brown, and U Siebenlist
Mechanism of inactivation of NF-kappa B by a viral homologue of I kappa b alpha. Signal-induced release of i kappa b alpha results in binding of the viral homologue to NF-kappa B.
November 2000, The Journal of biological chemistry,
Copied contents to your clipboard!