scholarly journals Glycogen Synthase Kinase 3β Is a Negative Regulator of Growth Factor-induced Activation of the c-Jun N-terminal Kinase

2004 ◽  
Vol 279 (49) ◽  
pp. 51075-51081 ◽  
Author(s):  
Shuying Liu ◽  
Shuangxing Yu ◽  
Yutaka Hasegawa ◽  
Ruth LaPushin ◽  
Hong-Ji Xu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glycogen Synthase ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Glycogen Synthase Kinase-3β is Involved in the Process of Myocardial Hypertrophy Stimulated by Insulin-Like Growth Factor-1

2004 ◽  
Vol 68 (3) ◽  
pp. 247-253 ◽  
Author(s):  
Satomi-Kobayashi Seimi ◽  
Kawashima Seinosuke ◽  
Sakoda Tsuyoshi ◽  
Ueyama Tomomi ◽  
Hirase Tetsuaki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Myocardial Hypertrophy ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Insulin Like Growth Factor ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Functional Effects of PTPN11 (SHP2) Mutations Causing LEOPARD Syndrome on Epidermal Growth Factor-Induced Phosphoinositide 3-Kinase/AKT/Glycogen Synthase Kinase 3β Signaling

2010 ◽  
Vol 30 (10) ◽  
pp. 2498-2507 ◽  
Author(s):  
Thomas Edouard ◽  
Jean-Philippe Combier ◽  
Audrey Nédélec ◽  
Sophie Bel-Vialar ◽  
Mélanie Métrich ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Hek293 Cells ◽  
Glycogen Synthase Kinase 3Β ◽  
Leopard Syndrome ◽  
Epidermal Growth ◽  
Gsk 3Β ◽  
Phosphoinositide 3 Kinase

ABSTRACT LEOPARD syndrome (LS), a disorder with multiple developmental abnormalities, is mainly due to mutations that impair the activity of the tyrosine phosphatase SHP2 (PTPN11). How these alterations cause the disease remains unknown. We report here that fibroblasts isolated from LS patients displayed stronger epidermal growth factor (EGF)-induced phosphorylation of both AKT and glycogen synthase kinase 3β (GSK-3β) than fibroblasts from control patients. Similar results were obtained in HEK293 cells expressing LS mutants of SHP2. We found that the GAB1/phosphoinositide 3-kinase (PI3K) complex was more abundant in fibroblasts from LS than control subjects and that both AKT and GSK-3β hyperphosphorylation were prevented by reducing GAB1 expression or by overexpressing a GAB1 mutant unable to bind to PI3K. Consistently, purified recombinant LS mutants failed to dephosphorylate GAB1 PI3K-binding sites. These mutants induced PI3K-dependent increase in cell size in a model of chicken embryo cardiac explants and in transcriptional activity of the atrial natriuretic factor (ANF) gene in neonate rat cardiomyocytes. In conclusion, SHP2 mutations causing LS facilitate EGF-induced PI3K/AKT/GSK-3β stimulation through impaired GAB1 dephosphorylation, resulting in deregulation of a novel signaling pathway that could be involved in LS pathology.

scholarly journals Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice

2018 ◽  
Vol 315 (5) ◽  
pp. H1127-H1136 ◽  
Author(s):  
Qing Qin ◽  
Hemal Mehta ◽  
Kelvin Yen ◽  
Gerardo Navarrete ◽  
Sebastian Brandhorst ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factor ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Biological Process ◽  
Glycogen Synthase ◽  
Myocardial Dysfunction ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Aged Mice

Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5′-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-β1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/glycogen synthase kinase -3β pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3β pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice.

scholarly journals Glycogen Synthase Kinase-3β Is a Negative Regulator of Cardiomyocyte Hypertrophy

2000 ◽  
Vol 151 (1) ◽  
pp. 117-130 ◽  
Author(s):  
Syed Haq ◽  
Gabriel Choukroun ◽  
Zhao Bin Kang ◽  
Hardeep Ranu ◽  
Takashi Matsui ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Cellular Response ◽  
Glycogen Synthase ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Activated T Cells ◽  
Gsk 3Β

Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

scholarly journals Axil, a Member of the Axin Family, Interacts with Both Glycogen Synthase Kinase 3β and β-Catenin and Inhibits Axis Formation ofXenopus Embryos

1998 ◽  
Vol 18 (5) ◽  
pp. 2867-2875 ◽  
Author(s):  
Hideki Yamamoto ◽  
Shosei Kishida ◽  
Takaaki Uochi ◽  
Satoshi Ikeda ◽  
Shinya Koyama ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Binding Site ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Amino Acid Identity ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Axis Formation ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

ABSTRACT Using a yeast two-hybrid method, we identified a novel protein which interacts with glycogen synthase kinase 3β (GSK-3β). This protein had 44% amino acid identity with Axin, a negative regulator of the Wnt signaling pathway.We designated this protein Axil for Axin like. Like Axin, Axil ventralized Xenopus embryos and inhibited Xwnt8-induced Xenopus axis duplication. Axil was phosphorylated by GSK-3β. Axil bound not only to GSK-3β but also to β-catenin, and the GSK-3β-binding site of Axil was distinct from the β-catenin-binding site. Furthermore, Axil enhanced GSK-3β-dependent phosphorylation of β-catenin. These results indicate that Axil negatively regulates the Wnt signaling pathway by mediating GSK-3β-dependent phosphorylation of β-catenin, thereby inhibiting axis formation.

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