The function of Shp2 tyrosine phosphatase in the dispersal of acetylcholine receptor clusters

Qian, Yueping K.; Chan, A. M. C.; Madhavan, Raghavan; Peng, H. Benjamin

doi:10.1186/1471-2202-9-70

Cited by 22 publications

(17 citation statements)

References 68 publications

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“…However, we have not directly measured the effects of sub-maximal concentrations of n-agrin (with and without neuregulin-1) upon Shp2 activity in embryonic muscle cells. In addition, other studies have shown that NSC-87877, in the concentration range of 0.2-1 mM might also inhibit Shp1 (Qian et al, 2008). Further studies are needed to clarify the mode of this proposed inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Cdk5 and Shp2) involved in stabilizing AChR clusters (Fu et al, 2005;Ip et al, 2000;Lacazette et al, 2003;Lin et al, 2005;Qian et al, 2008;Zhao et al, 2007). There is reason to think that n-agrin-MuSK and neuregulin-1-ErbB signalling pathways converge to modulate AChR clustering (Chen et al, 2007;Lin et al, 2005;Ngo et al, 2004;Ngo et al, 2007;Qian et al, 2008;Zhao et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Positive feedback is triggered when MuSK causes the tyrosine phosphorylation of Abl 1/2 and Src-family kinases (Finn et al, 2003;Smith et al, 2001) with Abl kinases acting on MuSK to further increase MuSK phosphorylation and drive AChR clustering (Mittaud et al, 2004). Negative feedback is initiated when MuSK activates Shp2, a tyrosine phosphatase that acts to de-phosphorylate MuSK, resulting in a reduction of AChR clustering (Camilleri et al, 2007;Qian et al, 2008;Zhao et al, 2007). Hence, Abl kinases and Shp2 are in a position to regulate nagrin-MuSK-mediated AChR clustering by modulating the activity of the MuSK receptor.…”

Section: Introductionmentioning

confidence: 99%

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Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Ngo

Cole

Sunn

et al. 2012

Journal of Cell Science

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SummaryAt neuromuscular synapses, neural agrin (n-agrin) stabilizes embryonic postsynaptic acetylcholine receptor (AChR) clusters by signalling through the muscle-specific kinase (MuSK) complex. Live imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favoured by n-agrin, and possibly other synaptic signals. Neuregulin-1 is a growth factor that can act through muscle ErbB receptor kinases to enhance synaptic gene transcription. Recent studies suggest that neuregulin-1-ErbB signalling can modulate n-agrin-induced AChR clustering independently of its effects on transcription.Here we report that neuregulin-1 increased the size of developing AChR clusters when injected into muscles of embryonic mice. We investigated this phenomenon using cultured myotubes, and found that in the ongoing presence of n-agrin, neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK. This potentiation could be blocked by inhibiting Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK. Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence might function as a second-order regulator of postsynaptic AChR clustering at the neuromuscular synapse. Thus two classic synaptic signalling systems (neuregulin-1 and n-agrin) converge upon MuSK to regulate postsynaptic differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Ngo

Cole

Sunn

et al. 2012

Journal of Cell Science

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“…1). Inhibition of cellular Shp2 activity by NSC-87877 has been reported in certain cells, including epithelial/carcinoma cells, fibroblasts, endothelial cells, muscle cells, and neuronal/glioma cells [17, 28, 29, 32, 33]. Using a biology-oriented synthesis approach, Nören-Müller et al [34] discovered a tetrazolefurofuran Shp2 inhibitor furanofuran-2a (sFig.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

Chen

Pernazza

Scott

et al. 2010

Biochemical Pharmacology

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The protein tyrosine phosphatase (PTP) Shp2 (PTPN11) is an attractive target for anticancer drug discovery because it mediates growth factor signaling and its gain-of-function mutants are causally linked to leukemias. We previously synthesized SPI-112 from a lead compound of Shp2 inhibitor, NSC-117199. In this study, we demonstrated that SPI-112 bound to Shp2 by surface plasmon resonance (SPR) and displayed competitive inhibitor kinetics to Shp2. Like some other compounds in the PTP inhibitor discovery efforts, SPI-112 was not cell permeable, precluding its use in biological studies. To overcome the cell permeation issue, we prepared a methyl ester SPI-112 analog (SPI-112Me) that is predicted to be hydrolyzed to SPI-112 upon entry into cells. Fluorescence uptake assay and confocal imaging suggested that SPI-112Me was taken up by cells. Incubation of cells with SPI-112Me inhibited epidermal growth factor (EGF)-stimulated Shp2 PTP activity and Shp2-mediated paxillin dephosphorylation, Erk1/2 activation, and cell migration. SPI-112Me treatment also inhibited Erk1/2 activation by a Gab1-Shp2 chimera. Treatment of Shp2E76K mutant-transformed TF-1 myeloid cells with SPI-112Me resulted in inhibition of Shp2E76K-dependent cell survival, which is associated with inhibition of Shp2E76K PTP activity, Shp2E76K-induced Erk1/2 activation, and Bcl-XL expression. Furthermore, SPI-112Me enhanced interferon-γ (IFN-γ)-stimulated STAT1 tyrosine phosphorylation, ISRE-luciferase reporter activity, p21 expression, and the anti-proliferative effect. Thus, the SPI-112 methyl ester analog was able to inhibit cellular Shp2 PTP activity.

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“…The degree of AChR clustering can be altered by the level of activation (phosphorylation) of MuSK, with Ab1 kinases acting to increase the level of MuSK phosphorylation and consequently lead to more AChR clustering (Mittaud et al, 2004). More recently, Ngo et al (2012) (Madhavan & Peng, 2005;Madhavan et al, 2005;Qian et al, 2008). Both MuSK and the receptor associated protein, rapsyn are required for the clustering of AChR at the postsynaptic membrane Qu et al, 1996;Lin et al, 2001;Sanes & Lichtman, 2001).…”

Section: The Postsynaptic Membranementioning

confidence: 99%

The functional role of laminins-α4 and -β2 in development of the neuromuscular junction

Chand¹

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The precise development and organisation of the neuromuscular junction (NMJ) is critical for the production of efficient neurotransmission signals. Disruption of these specialisations may result in severely altered transmission properties at the NMJ.Signalling and adhesion molecules have long been established to be key mediators in the distribution of synaptic specialisations. The basal lamina acts to maintain stability of the associated tissue and contains a number of these signalling and adhesion molecules. The laminins, a family of large multimeric proteins, are one of the key components of the basal lamina that act as specific cell regulators and provide mechanical stability. Laminins have been shown to form an interconnecting network that assists in stabilisation of the basal lamina and provides attachment sites for other basal lamina components. The synapse specific laminin chains, -α4, -α5, and -β2, play an essential role in differentiation and organisation of the NMJ. These chains form the laminin isoforms, laminin-221 (α2β2γ1), laminin-421 (α4β2γ1), and laminin-521 (α5β2γ1).Laminin-β2, found in each of the three synapse specific isoforms, has been shown to organise presynaptic specialisations at the developing NMJ. In vitro laminin-β2 is able to interact directly with N-type and P/Q-type voltage-gated calcium This study examined the role of laminin-β2 in the organisation of N-and P/Q-type VGCCs at active zones of developing postnatal day 8 (P8) and matured, postnatal day 18 (P18) NMJs.The contribution of each channel to the release of transmitter was assessed using intracellular electrode recordings of end-plate potentials (EPPs). The VGCC toxins, ω-conotoxin-GVIA and ω-agatoxin-IVA, were used to specifically target N-and P/Q-type NMJs displayed significantly higher levels of synaptic depression under high frequency stimuli and altered paired pulse facilitation compared to wild-type littermates. Analysis of the binomial parameters of neurotransmitter release demonstrated a decrease in quantal release as a result of a decrease in the number of active release sites, but not in the average probability of transmitter release from these sites. Our functional findings suggest alterations in the short-term plasticity of the NMJ and possibly defective recycling of ii synaptic vesicles and/or the calcium handling at lama4 -/-NMJs. We propose that alterations to synapsin I and its associated molecules may be partly responsible for the changes in neurotransmission observed at lama4 -/-NMJs. Our findings demonstrate altered distribution and expression of presynaptic components associated with active zones, specifically an increase in the number of synaptic vesicles and a decrease in the density of the fluorescently labelled Bassoon at the active zone region. Our results suggest that the fewer active release sites may compensate for the deficits of the lama4 -/-NMJs by alterations to pre-and postsynaptic specialisations.In conclusion, this thesis has identified that laminins-α4 and -β2 play fundamental role...

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The function of Shp2 tyrosine phosphatase in the dispersal of acetylcholine receptor clusters

Cited by 22 publications

References 68 publications

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Neuregulin-1 Potentiates Agrin-Induced Acetylcholine Receptor Clustering via Muscle Specific Kinase Phosphorylation

Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112

The functional role of laminins-α4 and -β2 in development of the neuromuscular junction

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