Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is characterized by benign tumors (hamartomas and hamartias) involving multiple organ systems, due to inactivating mutations in TSC1 or TSC2. Here, we review recent advances in our understanding of the growth and signaling functions of the TSC1 and TSC2 proteins. Led by seminal studies in Drosophila, the TSC1/TSC2 complex has been positioned in an ancestrally conserved signaling pathway that regulates cell growth. TSC1/TSC2 receives inputs from at least three major signaling pathways in the form of kinase-mediated phosphorylation events that regulate its function as a GTPase activating protein (GAP): the PI3K-Akt pathway, the ERK1/2-RSK1 pathway and the LKB1-AMPK pathway. TSC1/TSC2 functions as a GAP towards Rheb, which is a major regulator of the mammalian target of rapamycin (mTOR). In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth. As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas.
Hum Mol Genet 2005 Oct 15
PMID:Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. 1624 23

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.
Mol Cell Biol 2006 Jan
PMID:Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. 1635 80

Peroxisome proliferator-activated receptors gamma (PPARgamma) exert diverse effects on cancer cells. Recent studies showed that rosiglitazone, a synthetic ligand for PPARgamma, inhibits cell growth. However, the exact mechanisms underlying this effect are still being explored, and the relevance of these findings to lung cancer remains unclear. Here, we report that rosiglitazone reduced the phosphorylation of Akt and increased phosphatase and tensin homologue (PTEN) protein expression in non-small cell lung carcinoma (NSCLC) cells (H1792 and H1838), and this was associated with inhibition of NSCLC cell proliferation. These effects were blocked or diminished by GW9662, a specific PPARgamma antagonist. However, transfection with a CMX-PPARgamma2 overexpression vector restored the effects of rosiglitazone on Akt, PTEN, and cell growth in the presence of GW9662. In addition, rosiglitazone increased the phosphorylation of AMP-activated protein kinase alpha (AMPKalpha), a downstream kinase target for LKB1, whereas it decreased phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream target of mammalian target of rapamycin (mTOR). Of note, GW9662 did not affect the phosphorylation of AMPKalpha and p70S6K protein. The inhibitory effect of rosiglitazone on NSCLC cell growth was enhanced by the mTOR inhibitor rapamycin; however, it was blocked, in part, by the AMPKalpha small interfering RNA. Taken together, these findings show that rosiglitazone, via up-regulation of the PTEN/AMPK and down-regulation of the Akt/mTOR/p70S6K signal cascades, inhibits NSCLC cell proliferation through PPARgamma-dependent and PPARgamma-independent signals.
Mol Cancer Ther 2006 Feb
PMID:Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. 1650 18

Recently, fatty acid transport across the plasma membrane has been shown to be a key process that contributes to the regulation of fatty acid metabolism in the heart. Since AMP kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D: -ribofuranoside (AICAR) stimulates fatty acid oxidation, as well as the expression of selected proteins involved with energy provision, we examined (a) whether AICAR induced the expression of the fatty acid transporters FABPpm and FAT/CD36 in cardiac myocytes and in perfused hearts and (b) the signaling pathway involved. Incubation of cardiac myocytes with AICAR increased the protein expression of the fatty acid transporter FABPpm after 90 min (+27%, P < 0.05) and this protein remained stably overexpressed until 180 min. Similarly, FAT/CD36 protein expression was increased after 60 min (+38%, P < 0.05) and remained overexpressed thereafter. Protein overexpression, which occurred via transcriptional mechanisms, was dependent on the AICAR concentration, with optimal induction occurring at AICAR concentrations 1-5 mM for FABPpm and at 2-8 mM for FAT/CD36. The AICAR (2 h, 2 mM AICAR) effects on FABPpm and FAT/CD36 protein expression were similar in perfused hearts and in cardiac myocytes. AICAR also induced the plasmalemmal content of FAT/CD36 (+49%) and FABPpm (+42%) (P < 0.05). This was accompanied by a marked increase in the rate of palmitate transport (2.5 fold) into giant sarcolemmal vesicles, as well as by increased rates of palmitate oxidation in cardiac myocytes. When the AICAR-induced AMPK phosphorylation was blocked, neither FAT/CD36 nor FABPpm were overexpressed, nor were palmitate uptake and oxidation increased. This study has revealed that AMPK activation stimulates the protein expression of both fatty acid transporters, FAT/CD36 and FABPpm in (a) time- and (b) dose-dependent manner via (c) the AMPK signaling pathway. AICAR also (d) increased the plasmalemmal content of FAT/CD36 and FABPm, thereby (e) increasing the rates of fatty acid transport. Thus, activation of AMPK is a key mechanism regulating the expression as well as the plasmalemmal localization of fatty acid transporters.
Mol Cell Biochem 2006 Aug
PMID:Prolonged AMPK activation increases the expression of fatty acid transporters in cardiac myocytes and perfused hearts. 1671 Jul 44

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.
Mol Hum Reprod 2006 Aug
PMID:The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. 1680 78

LKB1 is a tumor suppressor that may also be fundamental to cell metabolism, since LKB1 phosphorylates and activates the energy sensing enzyme AMPK. We generated muscle-specific LKB1 knockout (MLKB1KO) mice, and surprisingly, found that a lack of LKB1 in skeletal muscle enhanced insulin sensitivity, as evidenced by decreased fasting glucose and insulin concentrations, improved glucose tolerance, increased muscle glucose uptake in vivo, and increased glucose utilization during a hyperinsulinemic-euglycemic clamp. MLKB1KO mice had increased insulin-stimulated Akt phosphorylation and a > 80% decrease in muscle expression of TRB3, a recently identified Akt inhibitor. Akt/TRB3 binding was present in skeletal muscle, and overexpression of TRB3 in C2C12 myoblasts significantly reduced Akt phosphorylation. These results demonstrate that skeletal muscle LKB1 is a negative regulator of insulin sensitivity and glucose homeostasis. LKB1-mediated TRB3 expression provides a novel link between LKB1 and Akt, critical kinases involved in both tumor genesis and cell metabolism.
Mol Cell Biol 2006 Nov
PMID:Skeletal muscle-selective knockout of LKB1 increases insulin sensitivity, improves glucose homeostasis, and decreases TRB3. 1696 78

By a differential cDNA screening technique, we have isolated a dehydration-inducible gene (designated OSRK1) that encodes a 41.8 kD protein kinase of SnRK2 family from Oryza sativa. The OSRK1 transcript level was undetectable in vegetative tissues, but significantly increased by hyperosmotic stress and Abscisic acid (ABA). To determine its biochemical properties, we expressed and isolated OSRK1 and its mutants as glutathione S-transferase fusion proteins in Escherichia coli. In vitro kinase assay showed that OSRK1 can phosphorylate itself and generic substrates as well. Interestingly, OSRK1 showed strong substrate preference for rice bZIP transcription factors and uncommon cofactor requirement for Mn(2+) over Mg(2+). By deletion of C-terminus 73 amino acids or mutations of Ser-158 and Thr-159 to aspartic acids (Asp) in the activation loop, the activity of OSRK1 was dramatically decreased. OSRK1 can transphosphorylate the inactive deletion protein. A rice family of abscisic acid-responsive element (ABRE) binding factor, OREB1 was phosphorylated in vitro by OSRK1 at multiple sites of different functional domains. MALDI-TOF analysis identified a phosphorylation site at Ser44 of OREB1 and mutation of the residue greatly decreased the substrate specificity for OSRK1. The recognition motif for OSRK1, RQSS is highly similar to the consensus substrate sequence of AMPK/SNF1 kinase family. We further showed that OSRK1 interacts with OREB1 in a yeast two-hybrid system and co-localized to nuclei by transient expression analysis of GFP-fused protein in onion epidermis. Finally, ectopic expression of OSRK1 in transgenic tobacco resulted in a reduced sensitivity to ABA in seed germination and root elongation. These findings suggest that OSRK1 is associated with ABA signaling, possibly through the phosphorylation of ABF family in vivo. The interaction between SnRK2 family kinases and ABF transcription factors may constitute an important part of cross-talk mechanism in the stress signaling networks in plants.
Plant Mol Biol 2007 Jan
PMID:A rice dehydration-inducible SNF1-related protein kinase 2 phosphorylates an abscisic acid responsive element-binding factor and associates with ABA signaling. 1697 24

Communication between mammalian oocytes and their surrounding granulosa cells through the Kit-Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL-Kit-PI3 kinase (PI3K)-Akt-Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3alpha and GSK-3beta, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3alpha and GSK-3beta in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3alpha and GSK-3beta. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit-PI3K-Akt-GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.
J Mol Endocrinol 2007 Feb
PMID:Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development. 1724 76

The purpose of this study was to examine the effects of an activator of AMPK (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)) on bovine oocyte nuclear maturation in vitro. After 7 hr of culture, AICAR (1 mM) significantly increased the percentages of cumulus-enclosed oocytes (CEO) and denuded oocytes (DO) remaining at the germinal vesicle stage. After 22 hr of culture, AICAR significantly reduced the percentage of CEO reaching metaphase II (MII). AICAR at 1.0 mM also increased the inhibitory effect of the adenylate cyclase activator forskolin in CEO; however, at 0.05 mM, AICAR increased the percentage of oocytes at MII after 22 hr of culture compared to forskolin alone. The adenosine kinase inhibitor 5'-aminodeoxyadenosine reversed the effect of AICAR in CEO and DO showing that phosphorylation of AICAR by adenosine kinase is required for its inhibitory activity. GMP, but not AMP, inhibited meiosis in CEO and DO; however, inhibition of guanyl and adenyl nucleotides synthesis did not reverse the effect of AICAR suggesting that the inhibitory effect of AICAR is not due to increased synthesis of these nucleotides. Metformin, another activator of AMPK, also inhibited GVBD in CEO and DO. The alpha-1 isoform of the catalytic subunit of AMPK was detected in oocytes and cumulus cells, and reverse transcription-polymerase chain reaction experiments showed the presence of transcripts for alpha-1, alpha-2, beta-1, and gamma-3 isoforms of the regulatory subunits in cumulus cells and oocytes. These data show that the AMPK activator AICAR is inhibitory to nuclear maturation in bovine oocytes due to activation of AMPK.
Mol Reprod Dev 2007 Aug
PMID:Effects of adenosine monophosphate-activated kinase activators on bovine oocyte nuclear maturation in vitro. 1729 Apr 17

Genetic and biochemical studies have shown that Ser(20) phosphorylation in the transactivation domain of p53 mediates p300-catalyzed DNA-dependent p53 acetylation and B-cell tumor suppression. However, the protein kinases that mediate this modification are not well defined. A cell-free Ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including CHK2, CHK1, DAPK-1, DAPK-3, DRAK-1, and AMPK, as Ser(20) kinases. Phosphorylation of a p53 transactivation domain fragment at Ser(20) by these enzymes in vitro can be mediated in trans by a docking site peptide derived from the BOX-V domain of p53, which also harbors the ubiquitin signal for MDM2. Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53. Using CHK1 as a prototypical in vivo Ser(20) kinase, we demonstrate that (i) CHK1 protein depletion using small interfering RNA can attenuate p53 phosphorylation at Ser(20), (ii) an enhanced green fluorescent protein (EGFP)-BOX-V fusion peptide can attenuate Ser(20) phosphorylation of p53 in vivo, (iii) the EGFP-BOX-V fusion peptide can selectively bind to CHK1 in vivo, and (iv) the Deltap53 spliced variant lacking the BOX-V motif is refractory to Ser(20) phosphorylation by CHK1. These data indicate that the BOX-V motif of p53 has evolved the capacity to bind to enzymes that mediate either p53 phosphorylation or ubiquitination, thus controlling the specific activity of p53 as a transcription factor.
Mol Cell Biol 2007 May
PMID:The MDM2 ubiquitination signal in the DNA-binding domain of p53 forms a docking site for calcium calmodulin kinase superfamily members. 1733 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>