Analysis of a Shc Family Adaptor Protein, ShcD/Shc4, That Associates with Muscle-Specific Kinase

Jones, Nina; Hardy, W. Rod; Friese, Matthew B.; Jørgensen, Claus; Smith, Matthew J.; Woody, N.M.; Burden, Steven J.; Pawson, Tony

doi:10.1128/mcb.00184-07

Cited by 54 publications

(73 citation statements)

References 60 publications

(80 reference statements)

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“…In contrast, the Shc family proteins serve as phosphotyrosine adaptor molecules in various receptor-mediated signaling pathways. The Shc family of docking proteins, ShcD/Shc4, expressed in adult brain and skeletal muscle, may play a role in mediating downstream signaling of a muscle-specific kinase receptor 29 . FLJ23834 is a putative calcium-dependent cell adhesion protein, and its function has not been established.…”

Section: Discussionmentioning

confidence: 99%

Linkage and Association Studies of Joint Morbidity from Rheumatoid Arthritis

Min

Min²,

Sung³

et al. 2009

J Rheumatol

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ABSTRACT. Objective. To investigate the relationship between genetic variations of rheumatoid arthritis (RA) susceptibility in terms of joint morbidity. Methods. We used data from Genetic Analysis Workshop 15. The Illumina linkage panel IV included 5858 single-nucleotide polymorphisms (SNP), with 5744 SNP passing quality control filters. The phenotypic variables analyzed were the level of rheumatoid factor (RF) and score on the Joint Alignment and Motion (JAM) scale. We modified the scale, dividing by RF values relevant to disease severity. Linkage analysis for affected sibling pairs was done using the MERLIN program, and family-based association tests were carried out using PLINK and FBAT software.Results. We found a high peak (LOD = 3.29; NPL Z = 4.07) near the HLA-DRB1 region on chromosome 6. The linkage at 6p24 at rs1410766 [LOD = 2.66; nonparametric linkage (NPL) Z = 3.23] was statistically significant. Two other regions also showed possible linkage peaks: chromosome 7q30 at rs322812 (LOD = 2.47; NPL Z = 3.39) and chromosome 15p34 at rs347117 (LOD = 1.95; NPL Z = 2.80). For the family-based association study, 7 SNP related to clinical RA severity were detected. Conclusion. Genetic variations may lead to an enhanced risk of joint damage and increased levels of RF. Further studies are needed to elucidate the roles of other genes involved in RA and to explore whether the clinical signs of RA are associated with particular genetic variations. (First Release

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Section: Discussionmentioning

confidence: 99%

Linkage and Association Studies of Joint Morbidity from Rheumatoid Arthritis

Min

Min²,

Sung³

et al. 2009

J Rheumatol

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“…3; Box 2). This process appears to involve Src homologous collagen D (ShcD; also known as Shc4) (Jones et al, 2007) and several kinases, including Src family kinases (Borges and Ferns, 2001;Mittaud et al, 2001;Mohamed et al, 2001) and casein kinase 2 (CK2) (Cheusova et al, 2006). Mutant mice that lack these kinases form morphologically normal NMJs, but AChR clusters become unstable (Cheusova et al, 2006;Smith et al, 2001).…”

Section: Box 2 a Musk Organizing Scaffoldmentioning

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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“…2A). Histological examination of the enlarged spleens from Rai Ϫ/Ϫ mice revealed white pulp hyperplasia, characterized by the presence of frequent florid germinal centers 3 Abbreviations used in this paper: TNCB, 2,4,6-trinitrochlorobenzene; DTH, delayed-type hypersensivity reaction. ( Fig.…”

Section: Splenomegaly and Spontaneous T And B Cell Activation In Raimentioning

confidence: 99%

“…T he Shc protein family includes four members, ShcA, ShcB/Sli, ShcC/Rai, and ShcD/RaLP, sharing a highly conserved domain organization characterized by the (CH2)-PTB-CH1-SH2 modularity (1)(2)(3). Despite their structural similarity, Shc proteins differ in tissue specificity, and genetic and biological evidence indicates that they subserve highly specific functions in the control of key cellular processes, including cell proliferation, survival, apoptosis, migration, and anoikis (1, 4 -6).…”

mentioning

confidence: 99%

Rai Acts as a Negative Regulator of Autoimmunity by Inhibiting Antigen Receptor Signaling and Lymphocyte Activation

Savino

Ortensi

Ferro

et al. 2009

The Journal of Immunology

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Rai (ShcC) belongs to the family of Shc adaptor proteins and is expressed in neuronal cells, where it acts as a survival factor activating the PI3K/Akt survival pathway. In vivo, Rai protects the brain from ischemic damage. In this study, we show that Rai is expressed in T and B lymphocytes. Based on the finding that Rai−/− mice consistently develop splenomegaly, the role of Rai in lymphocyte homeostasis and proliferation was addressed. Surprisingly, as opposed to neurons, Rai was found to impair lymphocyte survival. Furthermore, Rai deficiency results in a reduction in the frequency of peripheral T cells with a concomitant increase in the frequency of B cells. Rai−/− lymphocytes display enhanced proliferative responses to Ag receptor engagement in vitro, which correlates with enhanced signaling by the TCR and BCR, and more robust responses to allergen sensitization in vivo. A high proportion of Rai−/− mice develop a lupus-like autoimmune syndrome characterized by splenomegaly, spontaneous peripheral T and B cell activation, autoantibody production, and deposition of immune complexes in the kidney glomeruli, resulting in autoimmune glomerulonephritis. The data identify Rai as a negative regulator of lymphocyte survival and activation and show that loss of this protein results in breaking of immunological tolerance and development of systemic autoimmunity.

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Analysis of a Shc Family Adaptor Protein, ShcD/Shc4, That Associates with Muscle-Specific Kinase

Cited by 54 publications

References 60 publications

Linkage and Association Studies of Joint Morbidity from Rheumatoid Arthritis

Linkage and Association Studies of Joint Morbidity from Rheumatoid Arthritis

To build a synapse: signaling pathways in neuromuscular junction assembly

Rai Acts as a Negative Regulator of Autoimmunity by Inhibiting Antigen Receptor Signaling and Lymphocyte Activation

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