AKAP signalling complexes: focal points in space and time

Wong, Wei; Scott, John D.

doi:10.1038/nrm1527

Cited by 990 publications

(1,033 citation statements)

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“…For instance, PKA RI appears to have a weaker binding affinity to the AKAP(s) compared with PKA RII; therefore, it could be released more easily from its binding site37 In other words, the docking of RII is more static, whereas the docking of RI is more dynamic. In addition, RII subunits are typically localized to discrete sites in the cell, such as plasma membrane and cytoskeleton, while RI subunits tend to be more diffuse 38. Our findings of the change in the relative abundance of RIIα and RIα or RIIα/RIα ratio with ageing in muscle and at the NMJ suggest that an increased RIIα/RIα ratio may subsequently favour enhanced cTnT and PKA‐RIIα interaction, specifically at the NMJ in old skeletal muscle fast muscle fibres.…”

Section: Discussionmentioning

confidence: 70%

Cardiac troponin T and fast skeletal muscle denervation in ageing

Feng

Dong

et al. 2017

J cachexia sarcopenia muscle

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BackgroundAgeing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast‐twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow‐twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre‐type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle‐specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.MethodsStudies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real‐time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.ResultsLevels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region—but mainly in the fast‐twitch, not the slow‐twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ—again, preferentially in fast‐twitch but not slow‐twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ.ConclusionsCardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast‐twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age‐related decline in muscle function.

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Section: Discussionmentioning

confidence: 70%

Cardiac troponin T and fast skeletal muscle denervation in ageing

Feng

Dong

et al. 2017

J cachexia sarcopenia muscle

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“…Scaffolding proteins play an essential role in the spatial and temporal regulation of individual enzymes and provide the link between extracellular events and intracellular compartments including the nucleus (1). Scaffolding proteins, by means of protein-protein interactions, provide platforms for protein assembly.…”

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confidence: 99%

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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Scaffolding proteins are major contributors to the spatial and temporal orchestration of signaling cascades and hence cellular functions. RACK1 is a scaffolding protein that plays an important role in the regulation of, and cross-talk between, various signaling pathways. Here we report that RACK1 is a mediator of chromatin remodeling, resulting in an exon-specific expression of the brain-derived neurotrophic factor (BDNF) gene. Specifically, we found that following the activation of the cAMP pathway, nuclear RACK1 localizes at the promoter IV region of the BDNF gene by its association with histones H3 and H4, leading to the dissociation of the transcription repressor methyl-CpGbinding protein 2 (MeCP2) from the promoter, resulting in the acetylation of histone H4. These chromatin modifications lead to the activation of the promoter and to the subsequent promoter-controlled transcription of BDNF exon IV. Our findings expand our knowledge regarding the function of scaffolding proteins such as RACK1. Furthermore, this novel mechanism for the regulation of exon-specific expression of the BDNF gene by RACK1 could have implications on the neuronal functions of the growth factor including synaptic plasticity, learning, and memory.Signal transduction cascades are tightly regulated events. Scaffolding proteins play an essential role in the spatial and temporal regulation of individual enzymes and provide the link between extracellular events and intracellular compartments including the nucleus (1). Scaffolding proteins, by means of protein-protein interactions, provide platforms for protein assembly. The scaffolding protein RACK1, which was originally identified as an anchoring protein of protein kinase C ␤II (2), belongs to the WD40 family of proteins characterized by seven WD40 repeats forming a seven-blade ␤-propeller structure (3, 4). This particular structure allows RACK1 to interact with various enzymes including Fyn kinase (5), focal adhesion kinase (6), receptor protein tyrosine phosphatase (7), the cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4D5 (8), as well as the intracellular tails of receptors such as the insulin-like growth factor 1 receptor (IGF-1R) (9, 10), the inositol 1,4,5-triphosphate receptor (11), and ion channels such as the NR2B subunit of the N-methyl D-aspartate receptors (5). These interactions, and others, put RACK1 at a focal point for spatial and temporal regulation of various signaling cascades. For example, in transformed cultured cancer cells, RACK1 was shown to form a scaffolding complex that includes the IGF-1R, ␤1 integrin, and focal adhesion kinase (6,9,10,12). In addition, RACK1 is also found at the 40 S ribosomal subunit (3,13,14) and was shown to bridge protein kinase C-mediated signaling to the ribosomal translation machinery (15). RACK1 plays an important role in the central nervous system (16). For example, RACK1 links Fyn kinase to its substrate, the NR2B subunit of the N-methyl D-aspartate receptor (5, 17), and contributes to the regulation of channel activity (18)...

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“…To illustrate this approach, we first approximate the integrand (27) using a r − 1th order Lagrange polynomial at a set of interpolation points t n+1 , t n ,…, t n+2−r : (28) Then (12) becomes (29) A first order implicit approximation to (τ) of the form (30) leads to a first order implicit scheme (31) A second order implicit approximation to (τ), (32) leads to a second order implicit scheme (33) Like the implicit ETD methods based on the non-compact representation, the nonlinear function of U n+1 in the compact implicit ETD (33) is also multiplied by terms involving the approximated differential operators and their exponentials. This non-local coupling makes the implicit ETD method inefficient.…”

Section: Two-dimensionsmentioning

confidence: 99%

“…A class of proteins referred to as scaffolds are thought to play many important roles during this process [28][29][30]. Scaffold usually binds dynamically to two or more consecutively-acting components of a signaling cascade.…”

Section: 22mentioning

confidence: 99%

Compact integration factor methods in high spatial dimensions

Nie

Wan

Zhang

et al. 2008

Journal of Computational Physics

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The dominant cost for integration factor (IF) or exponential time differencing (ETD) methods is the repeated vector-matrix multiplications involving exponentials of discretization matrices of differential operators. Although the discretization matrices usually are sparse, their exponentials are not, unless the discretization matrices are diagonal. For example, a two-dimensional system of N × N spatial points, the exponential matrix is of a size of N 2 × N 2 based on direct representations. The vector-matrix multiplication is of O(N 4 ), and the storage of such matrix is usually prohibitive even for a moderate size N. In this paper, we introduce a compact representation of the discretized differential operators for the IF and ETD methods in both two-and three-dimensions. In this approach, the storage and CPU cost are significantly reduced for both IF and ETD methods such that the use of this type of methods becomes possible and attractive for two-or three-dimensional systems. For the case of two-dimensional systems, the required storage and CPU cost are reduced to O(N 2 ) and O(N 3 ), respectively. The improvement on three-dimensional systems is even more significant. We analyze and apply this technique to a class of semi-implicit integration factor method recently developed for stiff reaction-diffusion equations. Direct simulations on test equations along with applications to a morphogen system in two-dimensions and an intra-cellular signaling system in three-dimensions demonstrate an excellent efficiency of the new approach.

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AKAP signalling complexes: focal points in space and time

Cited by 990 publications

References 129 publications

Cardiac troponin T and fast skeletal muscle denervation in ageing

Cardiac troponin T and fast skeletal muscle denervation in ageing

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Compact integration factor methods in high spatial dimensions

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