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)

The dorsoventral axis is established early in Xenopus development and may involve signaling by Wnts, a family of Wnt1-protooncogene-related proteins. The protein kinase shaggy functions in the wingless/Wnt signaling pathway, which operates during Drosophila development. To assess the role of a closely related kinase, glycogen synthase kinase 3 beta (GSK-3 beta), in vertebrate embryogenesis, we cloned a cDNA encoding a Xenopus homolog of GSK-3 beta (XGSK-3 beta). XGSK-3 beta-specific transcripts were detected by Northern analysis in Xenopus eggs and early embryos. Microinjection of the mRNA encoding a catalytically inactive form of rat GSK-3 beta into a ventrovegetal blastomere of eight-cell embryos caused ectopic formation of a secondary body axis containing a complete set of dorsal and anterior structures. Furthermore, in isolated ectodermal explants, the mutant GSK-3 beta mRNA activated the expression of neural tissue markers. Wild-type XGSK-3 beta mRNA suppressed the dorsalizing effects of both the mutated GSK-3 beta and Xenopus dishevelled, a proposed upstream signaling component of the same pathway. These results strongly suggest that XGSK-3 beta functions to inhibit dorsoventral axis formation in the embryo and provide evidence for conservation of the Wnt signaling pathway in Drosophila and vertebrates.
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PMID:Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos. 766 18

ILKAP, a protein serine/threonine (S/T) phosphatase of the PP2C family, was isolated in a yeast two-hybrid screen baited with integrin-linked kinase, ILK1. Association of ILK1 and ILKAP was independent of the catalytic activity of either partner, as assayed in co-precipitation and two-hybrid experiments. Condi tional expression of ILKAP in HEK 293 cells resulted in selective inhibition of ECM- and growth factor-stimulated ILK1 activity, but did not inhibit Raf-1 kinase activity. A catalytic mutant of ILKAP, H154D, did not inhibit ILK1 kinase activity. Two cellular targets of ILK1, glycogen synthase kinase 3 beta (GSK3beta) and protein kinase B (PKB)/AKT, were differentially affected by ILKAP-mediated inhibition of ILK1. Catalytically active, but not mutant ILKAP, strongly inhibited insulin-like growth factor-1-stimulated GSK3beta phosphorylation on Ser9, but did not affect phosphorylation of PKB on Ser473, suggesting that ILKAP selectively affects ILK-mediated GSK3beta signalling. Consistent with this, active, but not H154D mutant or the related PP2Calpha, selectively inhibited transactivation of a Tcf/Lef reporter gene, TOPFlash, in 293 cells. We propose that ILKAP regulates ILK1 activity, targeting ILK1 signalling of Wnt pathway components via modulation of GSK3beta phosphorylation.
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PMID:Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1. 1133 82

The specificity of 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), an ATP/GTP competitive inhibitor of protein kinase casein kinase-2 (CK2), has been examined against a panel of 33 protein kinases, either Ser/Thr- or Tyr-specific. In the presence of 10 microM TBB (and 100 microM ATP) only CK2 was drastically inhibited (>85%) whereas three kinases (phosphorylase kinase, glycogen synthase kinase 3 beta and cyclin-dependent kinase 2/cyclin A) underwent moderate inhibition, with IC(50) values one--two orders of magnitude higher than CK2 (IC(50)=0.9 microM). TBB also inhibits endogenous CK2 in cultured Jurkat cells. A CK2 mutant in which Val66 has been replaced by alanine is much less susceptible to inhibition by TBB as well as by another ATP competitive inhibitor, emodin. These data show that TBB is a quite selective inhibitor of CK2, that can be used in cell-based assays.
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PMID:Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 ('casein kinase-2'). 1134 4

In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into paired helical filaments. These Tau variants displayed specific epitopes that are immunoreactive with anti-phospho-Tau antibodies such as AT100. As shown in in vitro experiments, glycogen synthase kinase 3 beta (GSK3beta) and protein kinase A (PKA) may be key kinases in these phosphorylation events. In the present study, Tau was microinjected into Xenopus oocytes. Surprisingly, in this system, AT100 was generated without any GSK3beta and PKA contribution during the progesterone or insulin-induced maturation process. Our results demonstrate that a non-modified physiological process in a cell model can generate the most specific Alzheimer epitope of Tau pathology.
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PMID:Modelling Alzheimer-specific abnormal Tau phosphorylation independently of GSK3beta and PKA kinase activities. 1195 22

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

Human tau-protein kinase I (TPK I; also known as glycogen synthase kinase 3 beta; GSK3 beta) is a serine/threonine protein kinase that participates in Alzheimer's disease. Here, binary complex structures of full-length TPK I/GSK3 beta with the ATP analogues ADP and AMPPNP solved by the X-ray diffraction method at 2.1 and 1.8 A resolution, respectively, are reported. TPK I/GSK3 beta is composed of three domains: an N-terminal domain consisting of a closed beta-barrel structure, a C-terminal domain containing a 'kinase fold' structure and a small extra-domain subsequent to the C-terminal domain. The catalytic site is between the two major domains and has an ATP-analogue molecule in its ATP-binding site. The adenine ring is buried in the hydrophobic pocket and interacts specifically with the main-chain atoms of the hinge loop. The overall structure and substrate-binding residues are similar to those observed in other Ser/Thr protein kinases, while Arg141 (which is not conserved among other Ser/Thr protein kinases) is one of the key residues for specific ATP/ADP recognition by TPK I/GSK3 beta. No residues are phosphorylated, while the orientation of the activation loop in TPK I/GSK3 beta is similar to that in phosphorylated CDK2 and ERK2, suggesting that TPK I/GSK3 beta falls into a conformation that enables it to be constitutively active.
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PMID:Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta. 1499 67

Lutheran (Lu) blood group and basal cell adhesion molecule (B-CAM) antigens reside on two glycoprotein (gp) isoforms Lu and Lu(v13) that belong to the Ig superfamily and differ only by the size of their cytoplasmic tail. Lu/B-CAM gps have been recognized as laminin alpha5 receptors on red blood cells and epithelial cells in multiple tissues. It has been shown that sickle red cells exhibit enhanced adhesion to laminin alpha5 when intracellular cAMP is up-regulated by physiological stimuli such as epinephrine and that this signaling pathway is protein kinase A- and Lu/B-CAM-dependent. In this study, we analyzed the relationship between the phosphorylation status of Lu/B-CAM gps and their adhesion function to laminin alpha5. We showed that Lu isoform was phosphorylated in sickle red cells as well as in erythroleukemic K562 and epithelial Madin-Darby canine kidney cells and that this phosphorylation is enhanced by different stimuli of the PKA pathway. Lu gp is phosphorylated by glycogen synthase kinase 3 beta, casein kinase II, and PKA at serines 596, 598, and 621, respectively. Alanine substitutions of serines 596 and 598 abolished phosphorylation by glycogen synthase kinase 3 beta and casein kinase II, respectively, but had no effect on adhesion of K562 cells to laminin under flow conditions. Conversely, mutation of serine 621 prevented phosphorylation by PKA and dramatically reduced cell adhesion. Furthermore, stimulation of K562 cells by epinephrine increased Lu gp phosphorylation by PKA and enhanced adhesion to laminin. It is postulated that modulation of the phosphorylation state of Lu gp might be a critical factor for the sickle red cells adhesiveness to laminin alpha5 in sickle cell disease.
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PMID:Protein kinase A-dependent phosphorylation of Lutheran/basal cell adhesion molecule glycoprotein regulates cell adhesion to laminin alpha5. 1597 31

Endocrine-disrupting compounds (EDCs) may interfere with neuronal development due to high levels of accumulation in biological tissue and potentially aberrant steroid signaling. Treatment of dissociated embryonic Xenopus spinal cord neurons with the EDC, nonylphenol (NP), did not alter cell survival or neurite outgrowth but inhibited neurotrophin-induced neurite outgrowth, effects that were recapitulated by treatment with comparable concentrations of 17 beta-estradiol (E2) and beta-estradiol 6-(O-carboxy-methyl)oxime: BSA (E2-BSA), but not a synthetic androgen. Effects of NP were not inhibited by the nuclear estrogen receptor antagonist, ICI 182,780, but were inhibited by the G protein antagonist, pertussis toxin. Nerve growth factor (NGF)-induced neurite outgrowth in Xenopus neurons was shown to require MAPK signaling. NP did not affect TrkA expression, MAPK signaling, or phosphatidylinositol 3' kinase-Akt-glycogen synthase kinase 3 beta (PI3K-Akt-GSK3 beta) signaling in Xenopus. The ability of NP to inhibit NGF-induced neurite outgrowth without altering survival was recapitulated in the rat pheochromocytoma (PC12) cell line. As with Xenopus neurons, the inhibitory actions of NP in PC12 cells were not antagonized by ICI 182,780 and did not involve alterations in signaling along either the MAPK or PI3K-Akt-GSK3 beta pathways. NP did significantly inhibit the ability of NGF to increase protein kinase A activity in this cell line. These data have important implications with respect to potentially deleterious effects of NP exposure during early neural development and highlight the fact that bioaccumulation of EDCs, such as NP, may elicit very disparate effects along divergent signaling pathways than those that arise from the actions of physiological levels of endogenous estrogens.
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PMID:The endocrine-disrupting compound, nonylphenol, inhibits neurotrophin-dependent neurite outgrowth. 1677 73

WNTs (Wingless-type MMTV integration site family member) are involved in critical developmental and growth processes in animals. These studies investigated WNT pathways in the ovine uterus and conceptus during the periimplantation period of pregnancy. WNT2 and WNT2B mRNAs were detected in endometrial stroma. WNT5A and WNT5B mRNAs were most abundant in the stroma and less so in the luminal epithelium, whereas WNT11 mRNA was detected primarily in the glands. WNT7A mRNA was present in the luminal epithelium on d 10, absent on d 12 and 14, and increased between d 16 and 20. Only WNT2, WNT2B, and WNT4 were detected in conceptus trophectoderm. FZD6/8 (frizzled receptor) and GSK3B (glycogen synthase kinase 3beta) mRNAs were detected primarily in endometrial epithelia and conceptus trophectoderm, whereas the LRP5/6 (low-density lipoprotein receptor-related proteins 5 and 6) coreceptor was present in all endometrial cells and the trophectoderm. DKK1 (Dickkopf), a WNT signaling inhibitor, increased in the endometrium from d 16-20. CTNNB1 [catenin (cadherin associated protein) beta1] and CDH1 (E-cadherin) mRNAs were most abundant in the endometrial epithelia and trophectoderm. LEF1 (lymphoid enhancer-binding factor 1) mRNA was expressed primarily in uterine epithelia, whereas TCF7L2 [(transcription factor 7-like 2 (T-cell specific, HMG-box)] was primarily in the conceptus. CTNNB1 and TCF7L2 proteins were both abundant in the nuclei of trophoblast giant binucleate cells. WNT7A stimulated a TCF/LEF-luciferase reporter activity in ovine trophectoderm cells that was inhibited by dominant-negative TCF and Sfrp2 (secreted FZD-related protein 2). WNT7A increased trophectoderm cell proliferation as well as MSX2 (msh homeobox 2) and MYC (myelocytomatosis oncogene) mRNA levels. Wnt5a increased trophectoderm cell migration in a Rho kinase-dependent manner. These results support the hypotheses that canonical and noncanonical WNT signaling pathways are conserved regulators of conceptus-endometrial interactions in mammals and regulate periimplantation ovine conceptus development.
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PMID:WNTs in the ovine uterus: potential regulation of periimplantation ovine conceptus development. 1743 Oct 4

Continuous exposure of follicles/oocytes to elevated levels of insulin compromises embryonic developmental competence, although the underlying cellular mechanisms are unknown. The objectives of the present study were to determine whether mouse oocytes have insulin receptors and a functional insulin signaling cascade, and whether insulin exposure during oocyte growth or maturation influences meiotic progression and chromatin remodeling. Immunoblot and immunocytochemical analyses of germinal vesicle-intact (GVI) oocytes demonstrated the presence of insulin receptor-beta. Insulin receptor expression in oocytes was increased by gonadotropin stimulation, and remained elevated throughout meiotic maturation. Fully grown GVI oocytes contained 3-phosphoinositide-dependent protein kinase-1 (PDPK1), thymoma viral proto-oncogene 1 (AKT1), and glycogen synthase kinase 3 (GSK3). In vitro maturation of GVI oocytes in 5 microg/ml insulin had no influence on meiotic progression or the incidence of normal metaphase II (MII) chromosome condensation. Treatment of oocytes during maturation had no effect on GSK3A/B protein expression or phosphorylation of S21/9. However, the culturing of preantral follicles for 10 days with 5 microg/ml insulin increased the phosphorylation of oocyte GSK3B, indicating GSK3 inactivation. The rates of development to metaphase I (MI) were similar for oocytes obtained from insulin-treated follicles and controls, whereas the incidence of abnormal MI chromatin condensation was significantly higher in oocytes obtained from follicles cultured with insulin compared to those cultured without insulin. These results demonstrate that oocytes contain a functional insulin signaling pathway, and that insulin exposure during oocyte growth results in chromatin remodeling aberrations. These findings begin to elucidate the mechanisms by which chronic elevated insulin influences oocyte meiosis, chromatin remodeling, and embryonic developmental competence.
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PMID:Insulin signaling in mouse oocytes. 1762 12


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