Phosphoinositide 3‐kinase acts through RAC and Cdc42 during agrin‐induced acetylcholine receptor clustering

Nizhynska, Viktoria; Neumueller, Ralph; Herbst, Ruth

doi:10.1002/dneu.20371

Cited by 16 publications

(12 citation statements)

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“…Mouse muscle cryosections were stained as previously described [33]. Stained muscle sections were viewed on a confocal microscope as described above.…”

Section: Methodsmentioning

confidence: 99%

Rin-like, a novel regulator of endocytosis, acts as guanine nucleotide exchange factor for Rab5a and Rab22

Woller

Luiskandl

Popović

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RIN proteins serve as guanine nucleotide exchange factors for Rab5a. They are characterized by the presence of a RIN homology domain and a C-terminal Vps9 domain. Currently three family members have been described and analyzed. Here we report the identification of a novel RIN family member, Rin-like (Rinl), that represents a new interaction partner of the receptor tyrosine kinase MuSK, which is an essential key regulator of neuromuscular synapse development. Rinl is localized to neuromuscular synapses but shows the highest expression in thymus and spleen. Rinl preferentially binds to nucleotide-free Rab5a and catalyzes the exchange of GDP for GTP. Moreover, Rinl also binds GDP-bound Rab22 and increases the GDP/GTP exchange implicating Rinl in endocytotic processes regulated by Rab5a and Rab22. Interestingly, Rinl shows a higher catalytic rate for Rab22 compared to Rab5a. Rinl is closely associated with the cytoskeleton and thus contributes to the spatial control of Rab5a and Rab22 signaling at actin-positive compartments. Most importantly, overexpression of Rinl affects fluid-phase as well as EGFR endocytosis.

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“…Mouse muscle cryosections were stained as previously described [33]. Stained muscle sections were viewed on a confocal microscope as described above.…”

Section: Methodsmentioning

confidence: 99%

Rin-like, a novel regulator of endocytosis, acts as guanine nucleotide exchange factor for Rab5a and Rab22

Woller

Luiskandl

Popović

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Section: Agrin/lrp4/musk Signalingmentioning

confidence: 99%

“…Rho GTPases are known to be activated by guanine-nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs) in other cells, but which GEF or GAP proteins are regulated by agrin remains unclear. However, a recent study reports that the agrin-mediated activation of Rho GTPases requires PI 3-kinase (Nizhynska et al, 2007).One target of the activated Rho GTPases is the serine/threonine kinase Pak1, which is associated with Musk through Dvl (Luo et al, 2002). Pak1 might regulate actin dynamics by phosphorylating cortactin (Webb et al, 2006), an actin-binding protein present at developing NMJs (Peng et al, 1997).…”

mentioning

confidence: 99%

To build a synapse: signaling pathways in neuromuscular junction assembly

2010

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SummarySynapses, as fundamental units of the neural circuitry, enable complex behaviors. The neuromuscular junction (NMJ) is a synapse type that forms between motoneurons and skeletal muscle fibers and that exhibits a high degree of subcellular specialization. Aided by genetic techniques and suitable animal models, studies in the past decade have brought significant progress in identifying NMJ components and assembly mechanisms. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues, which shed light on synaptogenesis in the brain and contribute to a better understanding of muscular dystrophy. Key words: Neural development, Neuromuscular junction, Retrograde signaling, Synapse formation IntroductionThe brain contains billions of nerve cells, or neurons, which receive and integrate signals from the environment, and which govern the body's responses. Nervous system activity is made possible by synapses, contacts formed either between neurons or between a neuron and a target cell. Synapses are asymmetric structures in which neurotransmitter molecules are released from the presynaptic membrane and activate receptors on the postsynaptic membrane, thus establishing neuronal communication. As such, synapses are fundamental units of neural circuitry and enable complex behaviors. The neuromuscular junction (NMJ) is a type of synapse formed between motoneurons and skeletal muscle fibers. Large and easily accessed experimentally, this peripheral synapse has contributed greatly to the understanding of the general principles of synaptogenesis and to the development of potential therapeutic strategies for muscular disorders. The NMJ uses different neurotransmitters in different species; for example, acetylcholine (ACh) in vertebrates and glutamate in Drosophila, both of which are excitatory and cause muscle contraction. In Caenorhabditis elegans, there are two types of NMJs: at excitatory NMJs, ACh causes muscle contraction, whereas inhibitory NMJs release g-aminobutyric acid (GABA) to cause muscle relaxation. Motor nerve terminals differentiate to form presynaptic active zones, where synaptic vesicles dock and release neurotransmitters. On the apposed postsynaptic membranes, neurotransmitter receptors are packed at high densities. Aided by genetic techniques and by the use of suitable animal models, including rodents, zebrafish, Drosophila and C. elegans, studies in the past decade have brought significant progress, not only in identifying components present in pre-and postsynaptic membranes, but also in understanding the mechanisms that underpin NMJ assembly. This review highlights recent advances in the study of NMJ development, focusing on signaling pathways that are activated by diffusible cues from motor nerves and muscle fibers. Readers are referred to other outstanding reviews for a broad view of NMJ development (see Froehner, 1993;Hall and Sanes, 1993;Kummer et al., 2006;Salpeter and Loring, 1985;Schaeffer et al., 2001). NMJ formati...

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“…New F-actin synthesis occurs at AChR clustering sites in muscle cells [19], [20] and likely depends on the combined activity of Rho GTPases and their regulators and effectors that function in agrin/MuSK signaling [21], [23], [24], [25]. Rho GTPases are potent stimulators of the Arp2/3 complex, which enhances actin polymerization in many types of cells [31].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, AChR clustering involves signaling by Rho-family GTPases [21], which regulate diverse actin polymerization-driven processes [22], p21-activated kinase 1, an effector of the GTPase Cdc42 [23], and geranylgeranyl transferase, an enzyme which enhances the membrane association and activation of GTPases [24]. Conversely, inhibition of PI3 kinase signaling in myotubes reduces agrin-dependent activation of Rac and Cdc42 GTPases and impedes AChR clustering [25].…”

Section: Introductionmentioning

confidence: 99%

The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction

et al. 2009

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BackgroundPostsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.Methodology/Principal FindingsIn this study we used biochemical, cell biological and molecular assays to investigate a possible role in AChR clustering of cortactin, a protein which is a tyrosine kinase substrate and a regulator of F-actin assembly and which has also been previously localized at AChR clustering sites. We report that cortactin was co-enriched at AChR clusters in situ with its target the Arp2/3 complex, which is a key stimulator of actin polymerization in cells. Cortactin was further preferentially tyrosine phosphorylated at AChR clustering sites and treatment of myotubes with agrin significantly enhanced the tyrosine phosphorylation of cortactin. Importantly, forced expression in myotubes of a tyrosine phosphorylation-defective cortactin mutant (but not wild-type cortactin) suppressed agrin-dependent AChR clustering, as did the reduction of endogenous cortactin levels using RNA interference, and introduction of the mutant cortactin into muscle cells potently inhibited synaptic AChR aggregation in response to innervation.ConclusionOur results suggest a novel function of phosphorylation-dependent cortactin signaling downstream from agrin/MuSK in facilitating AChR clustering at the developing NMJ.

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Phosphoinositide 3‐kinase acts through RAC and Cdc42 during agrin‐induced acetylcholine receptor clustering

Cited by 16 publications

References 55 publications

Rin-like, a novel regulator of endocytosis, acts as guanine nucleotide exchange factor for Rab5a and Rab22

Rin-like, a novel regulator of endocytosis, acts as guanine nucleotide exchange factor for Rab5a and Rab22

To build a synapse: signaling pathways in neuromuscular junction assembly

The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction

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