共查询到20条相似文献,搜索用时 15 毫秒
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Regulation of transcription factors by protein degradation 总被引:4,自引:0,他引:4
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The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis, and is implicated
in human disease. Wnts transduce signals via transmembrane receptors of the Frizzled (Fzd/Fz) family and the low density lipoprotein
receptor-related protein 5/6 (Lrp5/6). A key mechanism in their signal transduction is that Wnts induce Lrp6 signalosomes,
which become phosphorylated at multiple conserved sites, notably at PPSPXS motifs. Lrp6 phosphorylation is crucial to β-catenin
stabilization and pathway activation by promoting Axin and Gsk3 recruitment to phosphorylated sites. Here, we summarize how
proline-directed kinases (Gsk3, PKA, Pftk1, Grk5/6) and non-proline-directed kinases (CK1 family) act upon Lrp6, how the phosphorylation
is regulated by ligand binding and mitosis, and how Lrp6 phosphorylation leads to β-catenin stabilization. 相似文献
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Regulation of receptor function by cholesterol 总被引:8,自引:0,他引:8
Cholesterol influences many of the biophysical properties of membranes and is nonrandomly distributed between cellular organelles, subdomains of membranes, and leaflets of the membrane bilayer. In combination with the high dynamics of cholesterol distribution, this offers many possibilities for regulation of membrane-embedded receptors. Depending on the receptor, cholesterol can have a strong influence on the affinity state, on the binding capacity, and on signal transduction. Most important, cholesterol may stabilize receptors in defined conformations related to their biological functions. This may occur by direct molecular interaction between cholesterol and receptors. In this review, we discuss the functional dependence of the nicotinic acetylcholine receptor as well as different G protein-coupled receptors on the presence of cholesterol. 相似文献
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Mitochondrial dysfunction and protein kinase C (PKC) activation are consistently found in diabetic cardiomyopathy but their
relationship remains unclear. This study identified mitochondrial aconitase as a downstream target of PKC activation using
immunoblotting and mass spectrometry, and then characterized phosphorylation-induced changes in its activity in hearts from
type 1 diabetic rats. PKCβ2 co-immunoprecipitated with phosphorylated aconitase from mitochondria isolated from diabetic hearts. Augmented phosphorylation
of mitochondrial aconitase in diabetic hearts was found to be associated with an increase in its reverse activity (isocitrate
to aconitate), while the rate of the forward activity was unchanged. Similar results were obtained on phosphorylation of mitochondrial
aconitase by PKCβ2 in vitro. These results demonstrate the regulation of mitochondrial aconitase activity by PKC-dependent phosphorylation. This may
influence the activity of the tricarboxylic acid cycle, and contribute to impaired mitochondrial function and energy metabolism
in diabetic hearts.
Received 31 October 2008; received after revision 17 December 2008; accepted 2 January 2009 相似文献
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Regulation of mitochondrial oxidative phosphorylation by second messenger-mediated signal transduction mechanisms 总被引:2,自引:0,他引:2
Boneh A 《Cellular and molecular life sciences : CMLS》2006,63(11):1236-1248
The mitochondrial oxidative phosphorylation system is responsible for providing the bulk of cellular ATP molecules. There
is a growing body of information regarding the regulation of this process by a number of second messenger-mediated signal
transduction mechanisms, although direct studies aimed at elucidating this regulation are limited. The main second messengers
affecting mitochondrial signal transduction are cAMP and calcium. Other second messengers include ceramide and reactive oxygen
species as well as nitric oxide and reactive nitrogen species. This review focuses on available data on the regulation of
the mitochondrial oxidative phosphorylation system by signal transduction mechanisms and is organised according to the second
messengers involved, because of their pivotal role in mitochondrial function. Future perspectives for further investigations
regarding these mechanisms in the regulation of the oxidative phosphorylation system are formulated.
Received 11 December 2005; received after revision 14 January 2006; accepted 6 February 2006 相似文献
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Protein kinase C (PKC) is an important signaling molecule in the heart, but its targets remain unclear. Using a PKC substrate
antibody, we detected a 40-kDa phosphorylated cardiac protein that was subsequently identified by tandem mass spectroscopy
as muscle creatine kinase (M-CK) with phosphorylation at serine 128. The forward reaction using ATP to generate phosphocreatine
was reduced, while the reverse reaction using phosphocreatine to generate ATP was increased following dephosphorylation of
immunoprecipitated M-CK with protein phosphatase 2A (PP2A) or PP2C. Despite higher PKC levels in diabetic hearts, decreased
phosphorylation of M-CK was more prominent than the reduction in its expression. Changes in CK activity in diabetic hearts
were similar to those found following dephosphorylation of M-CK from control hearts. The decrease in phosphorylation may act
as a compensatory mechanism to maintain CK activity at an appropriate level for cytosolic ATP regeneration in the diabetic
heart.
Received 15 September 2008; received after revision 30 September 2008; accepted 13 October 2008 相似文献
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Regulation of insulin receptor function 总被引:1,自引:0,他引:1
Youngren JF 《Cellular and molecular life sciences : CMLS》2007,64(7-8):873-891
Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular
disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation
events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin
resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase
activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation
of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding
to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational
changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human
disease, is reviewed in this article.
Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007 相似文献