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)

Activated Wnt signaling pathways have been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. As a result, beta-catenin is accumulated and becomes transcriptionally active for proliferative genes and oncogenes. Wnt pathway mutations result in biochemical mechanisms yielding inefficient phosphorylation of beta-catenin by GSK3beta due to APC, beta-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/beta-catenin/Lef/Tcf signals. Exisulind and analogues are inhibitors of cyclic GMP phosphodiesterases (PDE) that have been shown to activate and induce protein kinase G. The data show PKG regulation of beta-catenin in wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or beta-catenin mutations. Exisulind and analogs reduce beta-catenin via a novel, GSK3beta independent processing mechanism. Activated PKG directly phosphorylate beta-catenin at its C-terminal domain and causes proteasome dependent degradation of the protein. Since this pathway is independent of APC and GSK3beta, exisulind and analogs provide a superior approach to circumvent the molecular defects of wnt signaling pathway and to treat cancers with such defects.
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PMID:beta-Catenin signaling: therapeutic strategies in oncology. 1264 83

RGS proteins comprise a large family of proteins named for their ability to negatively regulate heterotrimeric G protein signaling. RGS6 is a member of the R7 subfamily of RGS proteins possessing DEP (disheveled/Egl-10/pleckstrin) homology and GGL (G protein gamma-subunit-like) domains in addition to the semiconserved RGS domain. Our previous study documented unusual complexity in splicing of the human RGS6 gene, and we demonstrated localization of various RGS6 splice forms at sites other than the plasma membrane, including the cytoplasm and nucleus, where G proteins are not localized (Chatterjee, T. K., Liu, Z., and Fisher, R. A. (2003) J. Biol. Chem. 278, 30261-30271). Here we provide new evidence that mild heat stress, proteasome-mediated proteotoxic stress, and HSF1 expression induces dramatic relocalization of RGS6 proteins from such sites to nucleoli. This response was observed in COS-7 cells expressing various splice forms of RGS6, was not elicited by other forms of cellular stress and was observed in cells treated with various protein kinase inhibitors or co-expressing a dominant-negative kinase inactive SAPK. The RGS domain of RGS6 was identified as a primary structural module providing support for its stress-induced nucleolar trafficking and various other RGS proteins or their isolated RGS domains similarly undergo nucleolar migration in response to heat or proteotoxic stress or during co-expression of HSF1. The atypical RGS domains of axin and AKAP10 also underwent stress-induced nucleolar trafficking while structural domains outside of the RGS domain of some RGS proteins can override nucleolar trafficking in response to stress. Inhibition of rDNA transcription also promoted nucleolar migration of RGS6, a response previously observed in a subset of nucleolar proteins. The DEP domain of RGS6, but not its RGS domain, conferred structural support for its transcription-linked nucleolar migration. RGS6 exhibited trafficking from subnuclear dots to nucleoli in response to heat-, proteotoxic- or transcription-linked stress. These results provide new evidence that mammalian RGS proteins undergo unique subcellular trafficking in response to specific forms of cellular stress and implicate the RGS family of proteins in cellular stress signaling pathways.
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PMID:Mild heat and proteotoxic stress promote unique subcellular trafficking and nucleolar accumulation of RGS6 and other RGS proteins. Role of the RGS domain in stress-induced trafficking of RGS proteins. 1276 Dec 20

Wnt signaling causes changes in gene transcription that are pivotal for normal and malignant development. A key effector of the canonical Wnt pathway is beta-catenin, or Drosophila Armadillo. In the absence of Wnt ligand, beta-catenin is phosphorylated by the Axin complex, which earmarks it for rapid degradation by the ubiquitin system. Axin acts as a scaffold in this complex, to assemble beta-catenin substrate and kinases (casein kinase I [CKI] and glycogen synthase kinase 3 beta [GSK3]). The Adenomatous polyposis coli (APC) tumor suppressor also binds to the Axin complex, thereby promoting the degradation of beta-catenin. In Wnt signaling, this complex is inhibited; as a consequence, beta-catenin accumulates and binds to TCF proteins to stimulate the transcription of Wnt target genes. Wnt-induced inhibition of the Axin complex depends on Dishevelled (Dsh), a cytoplasmic protein that can bind to Axin, but the mechanism of this inhibition is not understood. Here, we show that Wingless signaling causes a striking relocation of Drosophila Axin from the cytoplasm to the plasma membrane. This relocation depends on Dsh. It may permit the subsequent inactivation of the Axin complex by Wingless signaling.
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PMID:A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling. 1278 Nov 35

We have sought to determine the roles of beta-catenin and the Wnt signaling pathway in neurite outgrowth using a model cell system, the Neuro-2a neuroblastoma cell line. Activation of the Wnt signaling pathway disrupts a multiprotein complex that includes beta-catenin, Axin, and glycogen synthase kinase-3 (GSK-3), which would otherwise promote the phosphorylation and degradation of beta-catenin. Stabilized beta-catenin accumulates in the cytosol and in the nucleus; in the nucleus it binds to TCF family transcription factors, forming a bipartite transcriptional activator of Wnt target genes. These events can be mimicked by lithium (Li(+)), which inhibits GSK-3 activity. Both Li(+) and the GSK-3 inhibitor SB415286 induced neurite outgrowth of Neuro-2a cells. Li(+)-induced neurite outgrowth did not require beta-catenin-/TCF-dependent transcription, and increasing levels of beta-catenin either by transfection or using Wnt-3A was not sufficient to induce neurite outgrowth. Interestingly, Axin, which is also a substrate for GSK-3, was destabilized by Li(+) and ectopic expression of Axin inhibited Li(+)-induced neurite outgrowth. Deletion analysis of Axin indicated that this inhibition required the GSK-3 binding site, but not the beta-catenin binding site. Our results suggest that a signaling pathway involving Axin and GSK-3, but not beta-catenin, regulates Li(+)-induced neurite outgrowth in Neuro-2a cells.
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PMID:Glycogen synthase kinase-3 and Axin function in a beta-catenin-independent pathway that regulates neurite outgrowth in neuroblastoma cells. 1466 17

Adenomatous polyposis coli (APC) tumor suppressor protein, together with Axin and glycogen synthase kinase 3beta (GSK-3beta), forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of cytoplasmic beta-catenin by ubiquitin-dependent proteolysis. Degradation of phosphorylated beta-catenin is initiated by interaction through the WD40-repeat of a F-box protein beta-TrCP, a component of SCF ubiquitin ligase complex. Mutations in APC, Axin, and beta-catenin that prevent down-regulation of cytoplasmic beta-catenin are found in various types of cancers. In the search for efficient treatment and prevention of malignancies associated with increased levels of cytoplasmic beta-catenin, we created chimeric F-box fusion proteins by replacing the WD40-repeat of beta-TrCP with the beta-catenin-binding domains of Tcf4 and E-cadherin. Expression of chimeric F-box fusion proteins successfully promotes degradation of beta-catenin independently of GSK-3beta-mediated phosphorylation. More importantly, this degradation does not require intact APC protein (pAPC).
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PMID:Targeted degradation of beta-catenin by chimeric F-box fusion proteins. 1470 45

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3beta (GSK-3beta). In the canonical WNT pathway, the negative regulator Axin forms a complex with beta-catenin and GSK-3beta, resulting in beta-catenin degradation. Inhibition of GSK-3beta by DVL increases beta-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3beta through a transcription- and beta-catenin-independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3beta-mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3beta, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.
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PMID:A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules. 1473 35

Axin, a negative regulator of Wnt, forms a complex with glycogen synthase kinase 3beta, beta-catenin, and adenomatous polyposis coli and promotes GSK3beta-dependent phosphorylation of beta-catenin, thereby stimulating degradation of the beta-catenin. An essential step in that process is the phosphorylation of Axin. Examination of Axin's amino acid sequence revealed it to contain six arginine-X-leucine (RXL) sequences, the cyclin-dependent kinase 2 (CDK2) binding motif, and 10 CDK2 consensus phosphorylation sequences. We also found that cyclin A/CDK2 phosphorylates Axin, thereby enhancing its association with beta-catenin. This suggests that cyclin A/CDK2 is a negative regulator of beta-catenin-mediated signal transduction, which exerts its effects through phosphorylation of Axin.
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PMID:Cyclin-dependent kinase 2 regulates the interaction of Axin with beta-catenin. 1506 82

Activation of the beta-adrenergic (beta-AR) signaling pathway enhances cardiac function through protein kinase A (PKA)-mediated phosphorylation of target proteins involved in the process of excitation-contraction (EC) coupling. Experimental studies of the effects of beta-AR stimulation on EC coupling have yielded complex results, including increased, decreased, or unchanged EC coupling gain. In this study, we extend a previously developed model of the canine ventricular myocyte describing local control of sarcoplasmic reticulum (SR) calcium (Ca(2+)) release to include the effects of beta-AR stimulation. Incorporation of phosphorylation-dependent effects on model membrane currents and Ca(2+)-cycling proteins yields changes of action potential (AP) and Ca(2+) transients in agreement with those measured experimentally in response to the nonspecific beta-AR agonist isoproterenol (ISO). The model reproduces experimentally observed alterations in EC coupling gain in response to beta-AR agonists and predicts the specific roles of L-type Ca(2+) channel (LCC) and SR Ca(2+) release channel phosphorylation in altering the amplitude and shape of the EC coupling gain function. The model also indicates that factors that promote mode 2 gating of LCCs, such as beta-AR stimulation or activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), may increase the probability of occurrence of early after-depolarizations (EADs), due to the random, long-duration opening of LCC gating in mode 2.
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PMID:Modeling the actions of beta-adrenergic signaling on excitation--contraction coupling processes. 1520 Nov 46

Beta-catenin is a potent oncogenic protein whose cytoplasmic accumulation is a frequent event in cancer cells. The level of beta-catenin is regulated by two mechanisms: the adenomatous polyposis coli/Axin/glycogen synthase kinase 3beta-dependent degradation pathway and the Siah-1/Siah interacting protein/Ebi-mediated degradation pathway. In this study, we have investigated the functional significance of p53-inducible human Siah-family protein expression in the regulation of beta-catenin activity. We show here by reverse-transcriptase polymerase chain reaction that two mRNA transcripts, designated human Siah-1 and Siah-1L, are generated from the human Siah-1 locus. Interestingly, the expression of Siah-1L was upregulated by p53, whereas human Siah-1 expression was constant. Furthermore, introduction of exogenous Siah-1L protein downregulated beta-catenin protein and promoted apoptosis induced by anticancer drugs in cancer cells that lack endogenous p53. Thus, Siah-1L represents a new member of the human Siah family that is induced in response to p53 and plays an important role in the regulation of beta-catenin activity in tumor cells. These findings also suggest new strategies for restoring tumor suppressive pathways lost in cancer cells that have suffered p53 inactivation.
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PMID:Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates beta-catenin activity in a p53-dependent manner. 1532 81

The transcriptional coactivator beta-catenin mediates Wnt growth factor signaling. In the absence of a Wnt signal, casein kinase 1 (CK1) and glycogen synthase kinase-3beta (GSK-3beta) phosphorylate cytosolic beta-catenin, thereby flagging it for recognition and destruction by the ubiquitin/proteosome machinery. Phosphorylation occurs in a multiprotein complex that includes the kinases, beta-catenin, axin, and the Adenomatous Polyposis Coli (APC) protein. The role of APC in this process is poorly understood. CK1epsilon and GSK-3beta phosphorylate APC, which increases its affinity for beta-catenin. Crystal structures of phosphorylated and nonphosphorylated APC bound to beta-catenin reveal a phosphorylation-dependent binding motif generated by mutual priming of CK1 and GSK-3beta substrate sequences. Axin is shown to act as a scaffold for substrate phosphorylation by these kinases. Phosphorylated APC and axin bind to the same surface of, and compete directly for, beta-catenin. The structural and biochemical data suggest a novel model for how APC functions in beta-catenin degradation.
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PMID:Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation. 1532 68


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