scholarly journals GSK3-mediated raptor phosphorylation supports amino-acid-dependent mTORC1-directed signalling

2015 ◽  
Vol 470 (2) ◽  
pp. 207-221 ◽  
Author(s):  
Clare Stretton ◽  
Thorsten M. Hoffmann ◽  
Michael J. Munson ◽  
Alan Prescott ◽  
Peter M. Taylor ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Cell Growth ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Mechanistic Target Of Rapamycin ◽  
Amino Acid Availability ◽  
Cellular Autophagy ◽  
Mtor Complex 1

Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of raptor on Ser859, which crucially supports activation of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signalling in response to amino acid availability. GSK3 inhibition is associated with reduced mTORC1 signalling that impacts negatively on cell growth, protein synthesis and promotes cellular autophagy.

scholarly journals A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP

2015 ◽  
Vol 89 (18) ◽  
pp. 9232-9241 ◽  
Author(s):  
Crystal Woodard ◽  
Gangling Liao ◽  
C. Rory Goodwin ◽  
Jianfei Hu ◽  
Zhi Xie ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Glycogen Synthase ◽  
Primary Effusion Lymphoma ◽  
Protein Microarrays ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Parp Cleavage ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACTThe Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein is essential for the replication and maintenance of virus genomes in latently KSHV-infected cells. LANA also drives dysregulated cell growth through a multiplicity of mechanisms that include altering the activity of the cellular kinases extracellular signal-regulated kinase (ERK) and glycogen synthase kinase 3 (GSK-3). To investigate the potential impact of these changes in enzyme activity, we used protein microarrays to identify cell proteins that were phosphorylated by the combination of ERK and GSK-3. The assays identified 58 potential ERK-primed GSK-3 substrates, of which 23 had evidence forin vivophosphorylation in mass spectrometry databases. Two of these, SMAD4 and iASPP, were selected for further analysis and were confirmed as ERK-primed GSK-3 substrates. Cotransfection experiments revealed that iASPP, but not SMAD4, was targeted for degradation in the presence of GSK-3. iASPP interferes with apoptosis induced by p53 family members. To determine the importance of iASPP to KSHV-infected-cell growth, primary effusion lymphoma (PEL) cells were treated with an iASPP inhibitor in the presence or absence of the MDM2 inhibitor Nutlin-3. Drug inhibition of iASPP activity induced apoptosis in BC3 and BCBL1 PEL cells but did not induce poly(ADP-ribose) polymerase (PARP) cleavage in virus-negative BJAB cells. The effect of iASPP inhibition was additive with that of Nutlin-3. Interfering with iASPP function is therefore another mechanism that can sensitize KSHV-positive PEL cells to cell death.IMPORTANCEKSHV is associated with several malignancies, including primary effusion lymphoma (PEL). The KSHV-encoded LANA protein is multifunctional and promotes both cell growth and resistance to cell death. LANA is known to activate ERK and limit the activity of another kinase, GSK-3. To discover ways in which LANA manipulation of these two kinases might impact PEL cell survival, we screened a human protein microarray for ERK-primed GSK-3 substrates. One of the proteins identified, iASPP, showed reduced levels in the presence of GSK-3. Further, blocking iASPP activity increased cell death, particularly in p53 wild-type BC3 PEL cells.

scholarly journals The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bɛ at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase

2001 ◽  
Vol 355 (3) ◽  
pp. 609-615 ◽  
Author(s):  
Yvonne L. WOODS ◽  
Philip COHEN ◽  
Walter BECKER ◽  
Ross JAKES ◽  
Michel GOEDERT ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Initiation Factor ◽  
Glycogen Synthase Kinase 3 ◽  
General Role ◽  
Protein Tau ◽  
Microtubule Associated Protein Tau ◽  
Protein Synthesis Initiation

The substrate specificity of glycogen synthase kinase 3 (GSK3) is unusual in that efficient phosphorylation only occurs if another phosphoserine or phosphothreonine residue is already present four residues C-terminal to the site of GSK3 phosphorylation. One such substrate is the ε-subunit of rat eukaryotic protein-synthesis initiation factor 2B (eIF2Bε), which is inhibited by the GSK3-catalysed phosphorylation of Ser535. There is evidence that GSK3 is only able to phosphorylate eIF2Bε at Ser535 if Ser539 is already phosphorylated by another protein kinase. However, no protein kinases capable of phosphorylating Ser539 have so far been identified. Here we show that Ser539 of eIF2Bε, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other ‘proline-directed’ protein kinases tested. We also establish that phosphorylation of Ser539 permits GSK3 to phosphorylate Ser535in vitro and that eIF2Bε is highly phosphorylated at Ser539in vivo. The DYRK isoforms also phosphorylate human microtubule-associated protein tau at Thr212in vitro, a residue that is phosphorylated in foetal tau and hyperphosphorylated in filamentous tau from Alzheimer's-disease brain. Phosphorylation of Thr212 primes tau for phosphorylation by GSK3 at Ser208in vitro, suggesting a more general role for DYRK isoforms in priming phosphorylation of GSK3 substrates.

scholarly journals Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth

2014 ◽  
Vol 15 (5) ◽  
pp. 510-515 ◽  
Author(s):  
Yvette M Carter ◽  
Selvi Kunnimalaiyaan ◽  
Herbert Chen ◽  
T Clark Gamblin ◽  
Muthusamy Kunnimalaiyaan
Keyword(s):  
Cell Growth ◽  
Glycogen Synthase ◽  
Neuroblastoma Cell ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Neuroendocrine Markers

Glycogen synthase kinase-3 inhibitors suppress the AR-V7-mediated transcription and selectively inhibit cell growth in AR-V7-positive prostate cancer cells

The Prostate ◽  
2017 ◽  
Vol 77 (9) ◽  
pp. 955-961 ◽  
Author(s):  
Daisuke Nakata ◽  
Ryokichi Koyama ◽  
Kazuhide Nakayama ◽  
Satoshi Kitazawa ◽  
Tatsuya Watanabe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Prostate Cancer Cells ◽  
Inhibit Cell Growth

Inhibition of T-antigen expression promoting glycogen synthase kinase 3 impairs merkel cell carcinoma cell growth

2022 ◽  
Vol 524 ◽  
pp. 259-267
Author(s):  
Roland Houben ◽  
Sonja Hesbacher ◽  
Bhavishya Sarma ◽  
Carolin Schulte ◽  
Eva-Maria Sarosi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Carcinoma Cell ◽  
Glycogen Synthase ◽  
Antigen Expression ◽  
T Antigen ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Merkel Cell

scholarly journals Glycogen Synthase Kinase-3 regulates multiple myeloma cell growth and bortezomib-induced cell death

BMC Cancer ◽  
2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesco Piazza ◽  
Sabrina Manni ◽  
Laura Quotti Tubi ◽  
Barbara Montini ◽  
Laura Pavan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Growth ◽  
Glycogen Synthase ◽  
Myeloma Cell ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Multiple Myeloma Cell

scholarly journals Bioinformatic analysis of glycogen synthase kinase 3: human versus parasite kinases

Parasitology ◽  
2011 ◽  
Vol 138 (6) ◽  
pp. 725-735 ◽  
Author(s):  
DMITRY I. OSOLODKIN ◽  
NATALIA V. ZAKHAREVICH ◽  
VLADIMIR A. PALYULIN ◽  
VALERY N. DANILENKO ◽  
NIKOLAY S. ZEFIROV
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Leishmania Donovani ◽  
Glycogen Synthase ◽  
Pathogenic Fungi ◽  
Bioinformatic Analysis ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Atp Binding Site ◽  
Human Kinase

SUMMARYObjective. Glycogen synthase kinase 3 (GSK-3) is a promising target for the treatment of various human diseases such as type 2 diabetes, Alzheimer's disease and inflammation. Successful inhibition of the homologues of this kinase in Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani makes the kinase an attractive target for the treatment of malaria, trypanosomiasis and leishmaniasis, respectively. The aim of this work was to compare the binding sites of the GSK-3 kinases of different parasites and to analyse them as possible targets for therapeutic compounds. Methods. Both a sequence alignment and homology models of the structure of 21 different GSK-3 homologues belonging to mammals, insects, pathogenic fungi, nematodes, trematodes and protozoa have been analysed, 17 of them being studied for the first time. Results. The structure of the kinases and, in particular, their binding sites, were found to be rather conserved, possessing small insertions or deletions and conserved amino acid substitutions. Nevertheless, the kinases of most species of parasite did have some amino acid differences from the human kinase, which could be exploited for the design of selective drugs. Conclusion. Comparison of the human and parasite GSK-3 ATP binding site models has shown that the development of selective drugs affecting parasite GSK-3 is possible. Known inhibitors of human GSK-3 can also be used as starting scaffolds for the search for drugs acting against parasitic diseases.

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