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)

Microtubule dynamics is essential for many vital cellular processes such as morphogenesis and motility. Protein kinase CK2 is a ubiquitous protein kinase that is involved in diverse cellular functions. CK2 holoenzyme is composed of two catalytic alpha or alpha' subunits and two regulatory beta subunits. We show that the alpha subunit of CK2 binds directly to both microtubules and tubulin heterodimers. CK2 holoenzyme but neither of its individual subunits exhibited a potent effect of inducing microtubule assembly and bundling. Moreover, the polymerized microtubules were strongly stabilized by CK2 against cold-induced depolymerization. Interestingly, the kinase activity of CK2 is not required for its microtubule-assembling and stabilizing function because a kinase-inactive mutant of CK2 displayed the same microtubule-assembling activity as the wild-type protein. Knockdown of CK2alpha/alpha' in cultured cells by RNA interference dramatically destabilized their microtubule networks, and the destabilized microtubules were readily destructed by colchicine at a very low concentration. Further, over-expression of chicken CK2alpha or its kinaseinactive mutant in the endogenous CK2alpha/alpha'-depleted cells fully restored the microtubule resistance to the low dose of colchicine. Taken together, CK2 is a microtubule-associated protein that confers microtubule stability in a phosphorylation-independent manner.
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PMID:Direct regulation of microtubule dynamics by protein kinase CK2. 1463 6

In Alzheimer's disease (AD), neuronal thread protein (NTP) accumulates in cortical neurons and colocalizes with phospho- tau-immunoreactive cytoskeletal lesions that correlate with dementia. To generate additional information about the potential role of NTP in AD, we characterized its expression and regulation in human SH-Sy5y neuronal cells. Quantitative real-time reverse transcription-polymerase chain reactin and Western blot analysis demonstrated prominent insulin, moderate insulin-like growth factor, type 1 (IGF-1) and minimal nerve growth factor stimulation of NTP expression. In addition, NTP protein was more stable and it progressively accumulated in cells that were stimulated with insulin for 24 or 48 h. Metabolic labeling and phospho-amino acid analysis demonstrated phosphorylation of NTP on Serine residues, 30-60 min after insulin or IGF-1 stimulation, when glycogen synthase kinase 3beta (GSK-3beta) activity would no longer have been suppressed. Kinase inhibitor and in vitro phosphorylation studies demonstrated a role for GSK-3beta in the positive regulation of NTP expression and phosphorylation. Coimmunoprecipitation studies demonstrated physical interactions between NTP and tau or microtubule-associated protein 1b (MAP-1b), and ubiquitin immunoreactivity in NTP immunoprecipitates. In summary, these studies showed that (i) NTP expression is regulated at the level of transcription by insulin and IGF-1 stimulation; (ii) NTP is phosphorylated by GSK-3beta; (iii) NTP can physically interact with tau and MAP-1b and (iv) NTP-MAP complexes are ubiquitinated. The results suggest a functional role for NTP in relation to the turnover or processing of neuronal cytoskeletal proteins, attributes that may be modulated by insulin/IGF-1-mediated signaling.
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PMID:Neuronal thread protein regulation and interaction with microtubule-associated proteins in SH-Sy5y neuronal cells. 1468 91

We sought to elucidate the role of AKT in follicle-stimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Ras homolog enriched in brain) and subsequent mTOR (mammalian target of rapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-alpha, microtubule-associated protein 2D, and the PKA type IIbeta regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSH-stimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferase inhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated up-regulation of reporter activities for LHR, inhibin-alpha, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1alpha interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers.
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PMID:Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. 1498 27

A-kinase anchoring proteins (AKAPs) function to target protein kinase A (PKA) to specific locations within the cell. AKAPs are functionally identified by their ability to bind the type II regulatory subunits (RII) of PKA in an in vitro overlay assay. We previously showed that follicle-stimulating hormone (FSH) induces the expression of an 80-kDa AKAP (AKAP 80) in ovarian granulosa cells as they mature from a preantral to a preovulatory phenotype. In this report, we identify AKAP 80 as microtubule-associated protein 2D (MAP2D), a low molecular weight splice variant of the neuronal MAP2 protein. MAP2D is induced in granulosa cells by dexamethasone and by FSH in a time-dependent manner that mimics that of AKAP 80, and immunoprecipitation of MAP2D depletes extracts of AKAP 80. MAP2D is the only MAP2 protein present in ovaries and is localized to granulosa cells of preovulatory follicles and to luteal cells. MAP2D is concentrated at the Golgi apparatus along with RI and RII and, based on coimmunoprecipitation results, appears to bind both RI and RII in granulosa cells. Reduced expression of MAP2D resulting from treatment of granulosa cells with antisense oligonucleotides to MAP2 inhibited the phosphorylation of cAMP-response element-binding protein. These results suggest that this classic neuronal RII AKAP is a dual RI/RII AKAP that performs unique functions in ovarian granulosa cells that contribute to the preovulatory phenotype.
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PMID:Neuronal microtubule-associated protein 2D is a dual a-kinase anchoring protein expressed in rat ovarian granulosa cells. 1505 65

The microtubule-associated protein, tau, is involved in numerous neuronal processes such as vesicle transport, microtubule-plasma membrane interaction and the intracellular localization of proteins. Tau is known to be phosphorylated by several kinases such as mitogen activated protein kinase, microtubule affinity regulating kinase, and protein kinase A. We found a putative serum- and glucocorticoid-induced protein kinase 1 (SGK1) phosphorylation site within the 207GSRSRTPSLP216 tau amino acid sequence. We report here that SGK1 phosphorylates Ser214 of Tau. Using a pull-down assay, we found that 14-3-3q interacts with SGK1 and tau to form a ternary protein complex that leads to phosphorylation of tau. 14-3-3 and phosphorylated tau were mainly co-localized in the nucleus of COS-1 cells. These results demonstrate that 14-3-3 scaffolds tau with SGK1 to facilitate the phosphorylation of tau at Ser214 and to regulate its subcellular localization.
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PMID:14-3-3 Protein mediates phosphorylation of microtubule-associated protein tau by serum- and glucocorticoid-induced protein kinase 1. 1565 Mar 34

Recent studies demonstrate that lithium and valproic acid (VPA), two commonly used mood-stabilizing drugs, have neuroprotective effects against a variety of insults. Inhibition of the proapoptotic enzyme, glycogen synthase kinase-3 (GSK-3), has been suggested to be the mechanism of action of neuroprotection for both drugs. In this study, we tested if lithium and VPA could protect cultured cerebellar granule neurons (CGNs) from GSK-3-mediated apoptosis induced by trophic factor withdrawal (serum/potassium deprivation). Both lithium and indirubin, a specific GSK-3 inhibitor, protected CGNs in a dose-dependent manner. In contrast, VPA did not provide any neuroprotection and even potentiated cell death. Immunoblot analysis revealed that lithium inhibited the trophic factor deprivation-induced activation of GSK-3 as well as the in vivo phosphorylation of the microtubule-associated protein Tau on Ser199, a specific target site for GSK-3. Under these same experimental conditions, however, VPA neither inhibited GSK-3 activation nor hindered GSK-3 mediated Tau phosphorylation. Furthermore, in accordance with their effects on neuronal survival, lithium prevented the induction of c-Jun expression in trophic factor-deprived CGNs, whereas VPA potentiated it. Collectively, these results show that VPA is not a universal inhibitor of neuronal GSK-3, and that instead of being neuroprotective, VPA can even exacerbate neuronal death under some conditions.
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PMID:Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death. 1575 85

Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3beta (GSK3beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3beta (pGSK3beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3beta remained low 4 h after HI. Administration of IGF-I (50 microg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.
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PMID:IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta? 1584 77

Proteins that in cells specifically bind to growing microtubule plus ends (+TIPs) are thought to play important roles in polarization of the cytoskeleton. However, most +TIPs do not show a bias of their microtubule-binding behavior toward different subcellular regions. Here, we examine the dynamics of the +TIP CLASP in migrating PtK1 epithelial cells. We find that, although CLASPs track microtubule plus ends in the cell body, they dynamically decorate the entire microtubule lattice in the leading edge lamella and lamellipodium. Microtubule lattice binding is mediated by the COOH-terminal region of the CLASP microtubule-binding domain and is regulated downstream of Rac1. Phosphorylation of sites in the NH2-terminal part of the microtubule-binding domain by glycogen synthase kinase 3beta likely regulates the affinity of CLASPs for microtubule lattices. These results demonstrate the striking difference of the microtubule cytoskeleton in the lamella as compared with the cell body and provide the first direct observation of subcellular regulation of a microtubule-associated protein in migrating cells.
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PMID:Spatial regulation of CLASP affinity for microtubules by Rac1 and GSK3beta in migrating epithelial cells. 1595 47

Tau is a neuronal microtubule-associated protein whose function is regulated by site-specific phosphorylation. One protein kinase that is likely to play an important role in regulating the phosphorylation state of tau in vivo is glycogen synthase kinase (GSK) 3beta. The activity of GSK3beta is regulated by specific protein-protein interactions and 14-3-3zeta, a member of a protein family that can act as scaffolds, was recently reported to co-purify with GSK3beta in a large protein complex that was isolated from bovine brain [A. Agarwal-Mawal, H.Y. Qureshi, P.W. Cafferty, Z. Yuan, D. Han, R. Lin, H.K. Paudel, 14-3-3 connects glycogen synthase kinase-3 beta to tau within a brain microtubule-associated tau phosphorylation complex, J. Biol. Chem. 278 (2003) 12722-12728]. The purpose of this study was to determine if 14-3-3zeta could act as a scaffolding protein to promote the interaction of GSK3beta with tau and subsequently, enhance GSK3beta-mediated tau hyperphosphorylation. We used cell culture models, immunoprecipitation, and Western blotting to examine the interaction of GSK3beta and 14-3-3zeta with both exogenously and endogenously expressed proteins. We found that GSK3beta, 14-3-3zeta and tau do not interact in these cellular models under our experimental conditions and that GSK3beta-mediated tau phosphorylation is not effected by the presence of 14-3-3zeta. These data indicate that 14-3-3zeta may not be directly interacting with GSK3beta and tau in the brain, but may indirectly facilitate the interactions by binding to other proteins.
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PMID:14-3-3Zeta does not increase GSK3beta-mediated tau phosphorylation in cell culture models. 1596 40

Activation of the Akt/protein kinase B (PKB) kinase pathway can be neuroprotective after stroke. Akt is activated by growth factors via a phosphorylation-dependent pathway involving the kinases phosphoinositide 3 (PI3) kinase and phosphoinositide-dependent protein kinase-1 (PDK1) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Akt kinase blocks apoptosis by phosphorylating the substrates forkhead transcription factor (FKHR) and glycogen synthase kinase 3beta (GSK3beta). We found that intra-ischemic hypothermia (30 degrees C) reduced infarct size and improved functional outcomes up to 2 months. Changes in phosphorylation levels of Akt, as measured by Western blots and immunostaining, differed from levels of Akt activity measured in an in vitro assay in normothermic animals. Hypothermia blocked most of these changes and maintained Akt activity. Inhibition of PI3/Akt enlarged infarct size in hypothermic animals. Hypothermia improved phosphorylation of PDK1, PTEN, and FKHR. Hypothermia did not improve GSK3beta (Ser9) phosphorylation but blocked the nuclear translocation of phosphorylated beta-catenin (Ser33/37/Thr41) downstream of GSK3beta. Phosphorylation levels of PTEN, Akt, and Akt substrate decreased before apoptotic cytochrome c release and degradation of microtubule-associated protein-2, a marker of neuronal survival. Hypothermia may protect from ischemic damage in part by preserving Akt activity and attenuating the apoptotic effects of PTEN, PDK1, and FKHR.
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PMID:Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. 1623 83


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