Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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PMID:Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. 852 13

Coactivators, such as steroid receptor coactivator 1 (SRC-1A) and CREB (cAMP response element binding protein)-binding protein (CBP), are required for efficient steroid receptor transactivation. Using an in vitro transcription assay, we found that progesterone receptor (PR)-driven transcription is inhibited by a dominant negative PR ligand-binding domain-interacting region of SRC-1A, indicating that SRC-1A is required for actual transcriptional processes. In addition, these coactivators also possess intrinsic histone acetyltransferase (HAT) activity and bind to each other and another HAT, p300/CBP-associated factor. Here we show that the human PR also interacts with p300/CBP-associated factor in vitro. Recruitment of multiple HATs to target promoters suggests an important role for chromatin remodeling in transcriptional activation of genes by steroid receptors. In transient transfection assays, we found that addition of a histone deacetylase inhibitor, trichostatin A, strongly potentiated PR-driven transcription. In contrast, directing histone deacetylase-1 (HD1) to a promoter using the GAL4 DNA binding domain inhibited transcription. Furthermore, PR transactivation was repressed by recruiting HD1 into the PR-DNA complex by fusing HD1 to a PR ligand-binding domain-interacting portion of SRC-1. Collectively, these results suggest that targeted histone acetylation by recruited HAT cofactors and histone deacetylation are important factors affecting PR transactivation. Recruitment of coactivators and HATs by the liganded PR in vivo may result in (i) remodeling of transcriptionally repressed chromatin to facilitate assembly and (ii) enhanced stabilization of the preinitiation complex by the activation functions of coactivators and the liganded PR itself.
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PMID:Steroid receptor induction of gene transcription: a two-step model. 922 81

The molecular signaling mechanisms by which muscle contractions lead to changes in glucose metabolism and gene expression remain largely undefined. We assessed whether exercise activates MAP kinase proteins (ERK1/2, SEK1, and p38 MAP kinase) as well as Akt and PYK2 in skeletal muscle from healthy volunteers obtained during and after one-leg cycle ergometry at approximately 70% VO2max. Exercise led to a marked increase in ERK1/2 phosphorylation, which rapidly decreased to resting levels upon recovery. Exercise increased phosphorylation of SEK1 and p38 MAP kinase to a lesser extent than ERK1/2. In contrast to ERK1/2, p38 MAP kinase phosphorylation was increased in nonexercised muscle upon cessation of exercise. Phosphorylation of the transcription factor CREB was increased in nonexercised muscle upon cessation of exercise. Exercise did not activate Akt or increase tyrosine phosphorylation of PYK2. Thus, exercise has divergent effects on parallel MAP kinase pathways, of which only p38 demonstrated a systemic response. However, our data do not support a role of Akt or PYK2 in exercise/contraction-induced signaling in human skeletal. Activation of the different MAP kinase pathways by physical exercise appears to be important in the regulation of transcriptional events in skeletal muscle.
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PMID:Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle. 976 81

The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. Recent studies showing that CREB and its paralog CREM are required for survival of certain cell types prompted us to examine whether CREB is a nuclear target for activation via the growth factor-dependent Ser/Thr kinase Akt/PKB. When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. Akt/PKB induced CREB activity only in response to serum stimulation, and this effect was suppressed by the phosphatidylinositol 3-kinase inhibitor LY 294002. Our results support the notion that Akt/PKB promotes cell survival, at least in part, by stimulating the expression of cellular genes via the CREB/CBP nuclear transduction pathway.
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PMID:CREB is a regulatory target for the protein kinase Akt/PKB. 982 64

CREB-binding proteins (CBP) and p300 are essential transcriptional coactivators for a large number of regulated DNA-binding transcription factors, including CREB, nuclear receptors, and STATs. CBP and p300 function in part by mediating the assembly of multiprotein complexes that contain additional cofactors such as p300/CBP interacting protein (p/CIP), a member of the p160/SRC family of coactivators, and the p300/CBP associated factor p/CAF. In addition to serving as molecular scaffolds, CBP and p300 each possess intrinsic acetyltransferase activities that are required for their function as coactivators. Here we report that the adenovirus E1A protein inhibits the acetyltransferase activity of CBP on binding to the C/H3 domain, whereas binding of CREB, or a CREB/E1A fusion protein to the KIX domain, fails to inhibit CBP acetyltransferase activity. Surprisingly, p/CIP can either inhibit or stimulate CBP acetyltransferase activity depending on the specific substrate evaluated and the functional domains present in the p/CIP protein. While the CBP interaction domain of p/CIP inhibits acetylation of histones H3, H4, or high mobility group by CBP, it enhances acetylation of other substrates, such as Pit-1. These observations suggest that the acetyltransferase activities of CBP/p300 and p/CAF can be differentially modulated by factors binding to distinct regions of CBP/p300. Because these interactions are likely to result in differential effects on the coactivator functions of CBP/p300 for different classes of transcription factors, regulation of CBP/p300 acetyltransferase activity may represent a mechanism for integration of diverse signaling pathways.
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PMID:Factor-specific modulation of CREB-binding protein acetyltransferase activity. 1009 92

The serine/threonine kinase Akt (also known as protein kinase B, PKB) is activated by numerous growth-factor and immune receptors through lipid products of phosphatidylinositol (PI) 3-kinase. Akt can couple to pathways that regulate glucose metabolism or cell survival [1]. Akt can also regulate several transcription factors, including E2F, CREB, and the Forkhead family member Daf-16 [2] [3] [4]. Here, we show that Akt can regulate signaling pathways that lead to induction of the NF-kappaB family of transcription factors in the Jurkat T-cell line. This induction occurs, at least in part, at the level of degradation of the NF-kappaB inhibitor IkappaB, and is specific for NF-kappaB, as other inducible transcription factors are not affected by Akt overexpression. Furthermore, the effect requires the kinase activity and pleckstrin homology (PH) domain of Akt. Also, Akt does not act alone to induce cytokine promoters and NF-kappaB reporters, because signals from other pathways are required to observe the effect. These studies uncover a previously unappreciated connection between Akt and NF-kappaB induction that could have implications for the control of T-cell growth and survival.
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PMID:Induction of NF-kappaB by the Akt/PKB kinase. 1035 2

The Ca2+-calmodulin-dependent protein kinase (CaM kinase) cascade includes three kinases: CaM-kinase kinase (CaMKK); and the CaM kinases CaMKI and CaMKIV, which are phosphorylated and activated by CaMKK. Members of this cascade respond to elevation of intracellular Ca2+ levels and are particularly abundant in brain and in T cells. CaMKK and CaMKIV localize both to the nucleus and to the cytoplasm, whereas CaMKI is only cytosolic. Nuclear CaMKIV regulates transcription through phosphorylation of several transcription factors, including CREB. In the cytoplasm, there is extensive cross-talk between CaMKK, CaMKIV and other signaling cascades, including those that involve the cAMP-dependent kinase (PKA), MAP kinases and protein kinase B (PKB; also known as Akt). Activation of PKB by CaMKK appears to be important in protection of neurons from programmed cell death during development.
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PMID:The Ca-calmodulin-dependent protein kinase cascade. 1036 52

The CDC37 gene was isolated from a round-spotted pufferfish genomic library and characterized. This gene is composed of nine exons spanning 3.5 kb. Exon 1 contains the 5'-untranslated region and exon 2 contains the putative translation initiation site. By 5'-RACE (rapid amplication of cDNA ends) and sequence analysis, we deduced the promoter region for the CDC37 gene and found that it does not contain typical TATA or CCAAT box. The 1.8 kb DNA fragment upstream of the putative transcription initiation site contains numerous potential binding sites for transcription factors including CREB, E2A, Ets-1, GATA, NF-IL6 and PEA3. When this DNA fragment was placed upstream of the chloramphenicol acetyltransferase (CAT) reporter gene and transfected into a carp CF cell line, it could drive the synthesis of CAT enzyme four times more efficiently than the promoterless pCAT-Basic did. In addition, the CDC37 gene is linked to the TYK2 gene in a tail-to-head manner with a small intergenic region of 292 bp.
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PMID:Genomic organization and the promoter region of the round-spotted pufferfish (Tetraodon fluviatilis) CDC37 gene. 1107 77

The glycoprotein hormones, ACTH, TSH, FSH, and LH regulate diverse functions in endocrine cells. Although cAMP and PKA have long been shown to mediate specific intracellular signaling events including the transcription of specific genes via the CREB-CBP complex, recent observations have indicated that PKA does not account for all of the intracellular targets of cAMP. For example, TSH stimulation of thyroid cell proliferation is not completely blocked by PKA inhibitors. TSH and FSH can stimulate PKB phosphorylation by a PKAindependent but PI3-K/PDK1-dependent pathway. An FSH inducible kinase, Sgk, has recently been shown to be a close relative of PKB. Sgk is also a target of PI3-K-PDK1 pathway, indicating that some effects previously ascribed to PKB may be mediated by this inducible kinase. The identification of novel cAMP-binding proteins that exhibit guanine nucleotide exchange (GEF) activity (cAMP-GEFS; Epacs) has open new doors for cAMP action that include activation of small GTPases such as Rap1a, Rap2, and possibly Ras. These GTPases are known activators of downstream kinase cascades, including p38MAPK and Erk1/2 as well as PI3-K. Thus, FSH and TSH activation of PKB and Sgk may occur via this alternative cAMP pathway that involves cAMP-GEFs and the activation of the PI3-K/PDK1 pathway.
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PMID:New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. 1115 28

Little is known regarding hepatic insulin-like growth factor-1 IGF-I signaling with aging despite the observation that other tissues demonstrate resistance to IGF-I with aging and declines in liver mass accompany aging. Our aim was to determine if the IGF-I-induced signaling process changes with aging. Young (5 months) and old (24 months) C57BL/6 mice hepatic tissues and blood samples were taken 20 min after an intraperitoneal injection of desIGF-I. Age had no significant effect on plasma glucose, insulin and total IGF-I levels. IRS-1 protein was significantly decreased (33%) with aging. Basal phosphorylation of IRS-1, PKB and ERK were unaffected whereas basal phosphorylation of CREB and FKHR were significantly increased (37 and 33%, respectively) with aging. desIGF-I caused a significant decrease in plasma glucose concentrations in both young (53%) and old (44%) mice. desIGF-I administration significantly increased the phosphorylation of IRS-1 in both young (104%) and old (89%) hepatic tissues. Similarly, the phosphorylation of PKB was dramatically enhanced in both young (527%) and old (350%) hepatic tissues after desIGF-I stimulation. By contrast, desIGF-I administration had no significant effects on the phosphorylation of ERK and phosphorylation of transcription factors CREB and FKHR in both young and old hepatic tissues. These data suggest that aging dose not impair IGF-I signaling in hepatic tissues.
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PMID:Effects of aging on hepatic IGF-I signaling. 1185 24


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