Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IkappaBalpha is a phosphoprotein that sequesters the NF-kappaB/Rel transcription factors in the cytoplasm by physical association. Following induction by a wide variety of agents, IkappaBalpha is further phosphorylated and degraded, allowing NF-kappaB/Rel proteins to translocate to the nucleus and induce transcription. We have previously reported that the constitutive phosphorylation site resides in the C-terminal PEST region of IkappaBalpha and is phosphorylated by casein kinase II (CKII). Here we show that serine 293 is the preferred CKII phosphorylation site. Additionally, we show compensatory phosphorylation by CKII at neighboring serine and threonine residues. Thus, only when all five of the serine and threonine residues in the C-terminal region of IkappaBalpha are converted to alanine (MutF), is constitutive phosphorylation abolished. Finally, we show that constitutive phosphorylation is required for efficient degradation of free IkappaBalpha, in that unassociated Mutf has a half-life two times longer than wild-type IkappaBalpha. A serine residue alone at position 293, as well as aspartic acid at this position, can revert the Mutf phenotype. Therefore, the constitutive CKII phosphorylation site is an integral part of the PEST region of IkappaBalpha, and this phosphorylation is required for rapid proteolysis of the unassociated protein.
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PMID:Constitutive phosphorylation of IkappaBalpha by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IkappaBalpha. 866 71

The product of the c-rel proto-oncogene (c-Rel) belongs to the NF-kappaB/Rel family of polypeptides and has been implicated in the transcriptional control of cell proliferation and immune function. In human T lymphocytes, c-Rel is sequestered in the cytoplasmic compartment by constitutively phosphorylated inhibitors, including I(kappa)B(alpha) and I(kappa)B(beta). Studies with bacterially expressed forms of these inhibitory proteins revealed that unphosphorylated I(kappa)B(alpha) but not I(kappa)B(beta) assembles with c-Rel and inhibits its DNA binding activity. Furthermore, latent I(kappa)B(beta)-c-Rel complexes derived from mammalian cells were sensitive to phosphatase treatment, whereas I(kappa)B(alpha)-c-Rel complexes were resistant. We have identified a constitutive protein kinase in unstimulated T cells that associates with and phosphorylates I(kappa)B(beta) in vitro. The substrate specificity, electrophoretic mobility, and antigenic properties of this I(kappa)B(beta)-associated kinase (BAK) suggest identity with casein kinase II (CKII), an enzyme known to mediate basal phosphorylation of I(kappa)B(alpha). Phosphorylation of recombinant I(kappa)B(beta) by either BAK or CKII restored the capacity of this inhibitor to antagonize the DNA binding activity of c-Rel. Peptide mapping and mutational analyses localized the bulk of the basal phosphorylation sites in I(kappa)B(beta) to the C-terminal PEST domain, which contains two potential acceptors for CKII-mediated phosphoryl group transfer (Ser-313 and Ser-315). Point mutations introduced into the full-length inhibitor at Ser-313 and Ser-315 led to a significant reduction in the phosphorylation of I(kappa)B(beta) and severely impaired its c-Rel inhibitory function in vivo. Taken together, these findings strongly suggest that basal phosphorylation of the PEST domain of I(kappa)B(beta) at consensus CKII sites is required for the efficient formation of latent I(kappa)B(beta)-c-Rel complexes.
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PMID:Basal phosphorylation of the PEST domain in the I(kappa)B(beta) regulates its functional interaction with the c-rel proto-oncogene product. 888 27

Cardiolipin- or protease-activated protein kinase, isolated from rat liver cytosol and originally named liver PAK-1, was found to be the natural form of protein kinase N (PKN) by comparing the sequences of 43 tryptic peptides of the purified liver enzyme and determining the corresponding liver cDNA sequence. These analyses also identified (i) Arg-546 as the major site of proteolytic activation, (ii) the protease resistance of the C-terminal extension beyond the catalytic domain, and (iii) in vivo stoichiometric phosphorylation of Thr-778 in the mature enzyme. Homology modeling of the catalytic domain indicated that phosphothreonine 778 functions as an anchoring site similar to Thr-197 in cAMP-dependent protein kinase, which stabilizes an active site compatible with preferred substrate sequences of PAK-1/PKN. Sigmoidal autophosphorylation kinetics and increased S6-(229-239) peptide kinase activity following preincubation with ATP suggested phosphorylation-dependent activation of PAK-1/PKN. The onset of activation corresponded with phosphorylation of the regulatory domain site Ser-377 (located within a spectrin homology region), followed by Thr-504 (within a limited protein kinase C homology region), and, to a lesser extent, Thr-64 (in the RhoA-binding region). Several additional sites in the hinge region adjacent to a PEST protein degradation signal were selectively autophosphorylated following cardiolipin activation. Overall, these observations suggest that the regulation of this class of protein kinase involves complex interactions among phosphorylation-, lipid-, and other ligand-dependent activation events.
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PMID:Phosphorylation events associated with different states of activation of a hepatic cardiolipin/protease-activated protein kinase. Structural identity to the protein kinase N-type protein kinases. 894 81

Cactus protein is a Drosophila homologue of the mammalian IkappaB family of cytoplasmic anchor proteins. In unstimulated cells they function to retain rel/NFkappaB transcription factors in the cytoplasm but are rapidly degraded in response to signalling. The destruction of cactus or IkappaBalpha allows the rel/NFkappaB transcription factor to relocalise to the nucleus. Cactus is a phosphoprotein and has in its C-terminus a PEST protein stability domain. In this paper we show that, like mammalian IkappaBalpha, the PEST domain of cactus is phosphorylated by casein kinase II. We have localised the site of modification to a single residue, Ser468, and find no evidence for additional phosphorylation sites. The conservation of these sites in mammalian and invertebrate cytoplasmic anchor proteins suggests that phosphorylation by casein kinase II may play a critical functional role, plausibly in the regulation of constitutive or inducible proteolysis.
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PMID:Casein kinase II phosphorylates Ser468 in the PEST domain of the Drosophila IkappaB homologue cactus. 900 May 11

A number of polyclonal mouse sera were raised against Drosophila proteins that bound to microtubules in vitro (Kellogg et al. (1989) J. Cell Biol. 109, 2977-2991). Some of these sera recognised centrosomes in vivo, and we have been using these to screen expression libraries to isolate cDNAs encoding these putative centrosomal microtubule-associated proteins. Here we report the cloning of one such cDNA that encodes a novel serine/threonine protein kinase called LK6. The protein appears to exist in two forms: an abundant 185 kDa form and a rarer approximately 220 kDa form that interacts with microtubules. At least some of the LK6 protein is located in centrosomes at all stages of the cell cycle in fly embryos. Interestingly, the protein contains a PEST-like sequence and is rapidly turned over in vivo. Constitutive overexpression of LK6 is deleterious to flies and causes defects in microtubule organisation in both eggs and early embryos, whereas constitutive overexpression of a mutant form containing a point mutation that severely impairs the kinase activity is without effect. These findings suggest that LK6 may play a role in regulating microtubule function.
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PMID:LK6, a short lived protein kinase in Drosophila that can associate with microtubules and centrosomes. 904 51

West-Western screening of a cDNA expression library using 32P-labeled, autophosphorylated protein kinase Cdelta (PKCdelta) as a probe, led us to identify cDNA clones encoding a PKCdelta-binding protein that contains a leucine zipper-like motif in its N-terminal region and two PEST sequences in its C-terminal region. This protein shows overall sequence similarity (43.3%) to the serum deprivation response (sdr) gene product, and we named it SRBC (sdr-related gene product that binds to c-kinase). PKCdelta binds to the C-terminal half of SRBC through the regulatory domain and phosphorylates it in vitro. In COS1 cells, the phosphorylation of over-expressed SRBC is stimulated by 12-O-tetradecanoylphorbol-13-acetate and further enhanced by the over-expression of PKCdelta. The mRNA for SRBC is detected in a wide variety of cultured cell lines and tissues and is strongly induced by serum starvation. Furthermore, SRBC mRNA is induced during retinoic acid-induced differentiation of P19 cells. These results suggest that SRBC serves as a substrate and/or receptor for PKC and might be involved in the control of cell growth mediated by PKC.
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PMID:A protein kinase Cdelta-binding protein SRBC whose expression is induced by serum starvation. 905 38

NF-kappa B/Rel transcription factors participate in the activation of numerous genes involved in immune regulation/inflammation including cytokines, cell surface receptors, adhesion molecules, and acute phase proteins. NF-kappa B activity is controlled by inhibitory proteins, I kappa Bs, that maintain the DNA-binding forms of NF-kappa B in an inactive state in the cytoplasm. Many viruses, including the human retroviruses HIV-1 and HTLV-1, also utilize the NF-kappa B/I kappa B pathway to their transcriptional advantage during viral infection. Our recent studies have focused on the I kappa B alpha inhibitor and have characterized several protein interactions that modulate the functional activity of I kappa B alpha during human retrovirus infection. In this article, we summarise recent studies demonstrating that (1) chronic HIV-1 infection of human myelomonoblastic PLB-985 cells leads to constitutive NF-kappa B activity, activated in part due to enhanced I kappa B alpha turnover and increased NF-kappa B/Rel production; (2) HTLV-1 Tax protein physically associates with the I kappa B alpha protein in vivo and in vitro and also mediates a 20- to 40-fold stimulation of NF-kappa B DNA binding activity mediated via an enhancement of NF-kappa B dimer formation; (3) casein kinase II phosphorylates I kappa B alpha at multiple sites in the C-terminal PEST domains and regulates I kappa B alpha function; (4) transdominant forms of I kappa B alpha, mutated in critical Ser or Thr residues required for inducer-mediated (S32A,S36A) and/or constitutive phosphorylation block HIV LTR trans-activation and also effectively inhibit HIV-1 multiplication in a single cycle infection model; and (5) the amino-terminal 55aa of I kappa B alpha (NIK) interacts with the human homologue of dynein light chain 1, a small 9-kDa human homologue of the dynein light chain protein involved in microtubule and cytoskeletal dynamics. Together, our results highlight a number of intriguing molecular interactions between I kappa B alpha and cellular or viral proteins that modulate transcription factor activity and nuclear-cytoplasmic flow of host proteins.
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PMID:Cellular and viral protein interactions regulating I kappa B alpha activity during human retrovirus infection. 922 98

The biological activity of the transcription factor NF-kappaB is controlled mainly by the IkappaB alpha and IkappaB beta proteins, which restrict NF-kappaB to the cytoplasm and inhibit its DNA binding activity. Here, we carried out experiments to determine and compare the mechanisms by which IkappaB alpha and IkappaB beta inhibit NF-kappaB-dependent transcriptional activation. First, we found that in vivo IkappaB alpha is a stronger inhibitor of NF-kappaB than is IkappaB beta. This difference is directly correlated with their abilities to inhibit NF-kappaB binding to DNA in vitro and in vivo. Moreover, IkappaB alpha, but not IkappaB beta, can remove NF-kappaB from functional preinitiation complexes in in vitro transcription experiments. Second, we showed that both IkappaBs function in vivo not only in the cytoplasm but also in the nucleus, where they inhibit NF-kappaB binding to DNA. Third, the inhibitory activity of IkappaB beta, but not that of IkappaB alpha, is facilitated by phosphorylation of the C-terminal PEST sequence by casein kinase II and/or by the interaction of NF-kappaB with high-mobility group protein I (HMG I) on selected promoters. The unphosphorylated form of IkappaB beta forms stable ternary complexes with NF-kappaB on the DNA either in vitro or in vivo. These experiments suggest that IkappaB alpha works as a postinduction repressor of NF-kappaB independently of HMG I, whereas IkappaB beta functions preferentially in promoters regulated by the NF-kappaB/HMG I complexes.
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PMID:Distinct functional properties of IkappaB alpha and IkappaB beta. 927 16

The ume3-1 allele was identified as a mutation that allowed the aberrant expression of several meiotic genes (e.g. SPO11, SPO13) during mitotic cell division in Saccharomyces cerevisiae. Here we report that UME3 is also required for the full repression of the HSP70 family member SSA1. UME3 encodes a non-essential C-type cyclin (Ume3p) whose levels do not vary through the mitotic cell cycle. However, Ume3p is destroyed during meiosis or when cultures are subjected to heat shock. Ume3p mutants resistant to degradation resulted in a 2-fold reduction in SPO13 mRNA levels during meiosis, indicating that the down-regulation of this cyclin is important for normal meiotic gene expression. Mutational analysis identified two regions (PEST-rich and RXXL) that mediate Ume3p degradation. A third destruction signal lies within the highly conserved cyclin box, a region that mediates cyclin-cyclin-dependent kinase (Cdk) interactions. However, the Cdk activated by Ume3p (Ume5p) is not required for the rapid destruction of this cyclin. Finally, Ume3p destruction was not affected in mutants defective for ubiquitin-dependent proteolysis. These results support a model in which Ume3p, when exposed to heat shock or sporulation conditions, is targeted for destruction to allow the expression of genes necessary for the cell to respond correctly to these environmental cues.
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PMID:Stress and developmental regulation of the yeast C-type cyclin Ume3p (Srb11p/Ssn8p). 930 11

A170 is an oxidative stress-inducible protein having a Zinc finger domain, two PEST sequences, and many potential phosphorylation sites for serine/threonine kinases. These structural features suggest that the phosphorylation of A170 affects its function and degradation. We have found that A170 is phosphorylated in cultured murine peritoneal macrophages. In addition, using recombinant A170 proteins, we found two proteins of 40 and 44 kDa with kinase activity in cell extracts using an in-gel kinase assay. We compared the properties of the intrinsic A170 kinases with those of mitogen-activated protein kinase (ERK 2), protein kinase A (PKA), casein kinase II (CK II), and protein kinase C, since their catalytic subunits have molecular masses similar to A170 kinases. ERK 2, CK II, and PKA phosphorylated recombinant A170 as a substrate. The 40 and 44 kDa kinases present in the macrophage extract were similar to alpha and alpha' subunits of CK II in respect to substrate specificity, pharmacological properties, immuno-reactivities, and ubiquitous expression in tissues.
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PMID:Phosphorylation of A170 stress protein by casein kinase II-like activity in macrophages. 940 50


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