Interactions between β2-syntrophin and a family of microtubule-associated serine/threonine kinases

Lumeng, Carey N.; Phelps, Stephanie F.; Crawford, Gregory E.; Walden, Paul D.; Barald, Kate E; Chamberlain, Jeffrey S.

doi:10.1038/10165

Cited by 142 publications

(111 citation statements)

References 46 publications

(46 reference statements)

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“…In addition, recent studies (1)(2)(3)(4)(5)(6)(7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.…”

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confidence: 99%

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DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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Mice rendered null for ␣-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, ␣-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAM-AGE associates directly with ␣-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of ␣-dystrobrevin but not ␤-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279 -288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.The dystrophin glycoprotein complex links the actin cytoskeleton to the extracellular matrix in skeletal muscle. In addition, recent studies (1-7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way. Dystrobrevin has no enzymatic activity of its own; therefore, the involvement of dystrobrevin in signaling pathways is dependent on its interaction with other proteins.The dystrobrevins are transcribed from two separate genes, designated ␣ and ␤, that shar...

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“…Of these, the syntrophins are the best characterized and are involved in signaling by recruiting neuronal nitric-oxide synthase (1,24), ion channels (6), and kinases (3,5) to the dystrophin complex. Whether syncoilin, desmuslin, or dysbindin contributes to the signaling function of dystrobrevin and the dystrophin complex remains to be seen.…”

mentioning

confidence: 99%

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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“…At neuromuscular synapses MAST205 interacts with ␤-2 syntrophin (1,2). In addition to a well conserved protein kinase C/A kinase domain, MAST205 has a PDZ domain, a protein-protein recognition module (3).…”

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Interaction of TRAF6 with MAST205 Regulates NF-κB Activation and MAST205 Stability

Xiong

Chen

et al. 2004

Journal of Biological Chemistry

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The binding of immune complexes to macrophage Fc␥ receptor results in a subsequent inhibition of lipopolysaccharide-stimulated interleukin-12 synthesis without affecting the induction of tumor necrosis factor-␣. RNA interference targeting MAST205, a 205-kDa serine/ threonine kinase, and transfection of dominant negative MAST205 mutants also mimic this type II macrophage phenotype. Our previous epistasis experiments suggested that the position of MAST205 in the TLR4 signal pathway was proximal to the I B kinase complex. We now report that MAST205 forms a complex with TRAF6, resulting in the inhibition of TRAF6 NF-B activation. We have identified a peptide (residues 218 -233) from the N terminus of MAST205 that, when coupled to a protein transduction domain, inhibits the lipopolysaccharidestimulated activation of NF-B, modulates the size of the MAST205⅐TRAF6 complex, and inhibits ubiquitination of TRAF6. A dominant negative N-terminal MAST205 deletion mutant also inhibits TRAF6 ubiquitination. The domain required for degradation of MAST205 after Fc␥ receptor activation resides within the N-terminal 261 residues, and degradation is triggered by protein kinase C isoform phosphorylation of Ser/Thr residues. These results suggest that MAST205 functions as a scaffolding protein controlling TRAF6 activity and, therefore, plays an important role in regulating inflammatory responses.MAST205 1 is a 205-kDa Ser/Thr kinase that is widely expressed at low levels and highly expressed in spermatids, where MAST205 associates with microtubules. At neuromuscular synapses MAST205 interacts with ␤-2 syntrophin (1, 2). In addition to a well conserved protein kinase C/A kinase domain, MAST205 has a PDZ domain, a protein-protein recognition module (3). The role of MAST205 in cellular physiology, however, has yet to be determined. We have found that MAST205 plays a central role in the regulation of LPS-induced cytokine responses of macrophages (4). In this paper we analyze in greater detail the position of MAST205 in LPS-induced signal pathways and the factors regulating stability of the protein.Macrophages respond to LPS by secreting proinflammatory cytokines such as tumor necrosis factor-␣, IL-1, IL-6, IL-8, and IL-12. IL-12, in particular, is required for the induction of a T helper 1 response that facilitates the clearance of intracellular pathogens. The signal cascade leading to the inflammatory response is complex, reflecting both the importance of controlling the synthesis of potentially harmful cytokines and metabolites, such as reactive oxygen intermediates, and the need to tailor the response depending on the pathogen (5). The inflammatory response is also influenced by previous physiological stimuli to the responding cells, which has lent credence to the concept of macrophage subsets. For example, LPS-stimulated synthesis of IL-12 by macrophages, which is required for the induction of interferon-␥ from NK cells (6), is inhibited by immune complex activation of Fc␥R. As a result, such type II macrophages (7) as antigen present...

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“…Dystrophin/utrophin bind other intracellular members of the DGC: dystrobrevin (which in turn binds neuronal nitric oxide synthase / nNOS, dysbindin , syncoilin and DAMAGE (Albrecht and Froehner, 2004a)), and syntrophin (binds Calmodulin, Na + channels (Gee et al, 1998b), the potassium channel Kir4.1 (Connors et al, 2004a), Grb2, ErbB4, MAST/SAST (Yano et al, 2003;Lumeng et al, 1999b) and might also be responsible for the correct localisation of aquaporin-4 (Neely et al, 2001)). Localisation: Dystrobrevin has been found to be expressed in the developing and adult brain (Lien et al, 2004;Enigk and Maimone, 1999) and retina (Blank et al, 2002).…”

Section: Utrophinmentioning

confidence: 99%

Review: Dystroglycan in the Nervous System

Samwald

2007

Nature Precedings

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Dystroglycan is part of a large complex of proteins, the dystrophin-glycoprotein complex, which has been implicated in the pathogenesis of muscular dystrophies for a long time. Besides muscular degeneration many patients manifest symptoms of neurological and cognitive dysfunction. Recent findings suggest that dystroglycan is implicated in brain development, synapse formation and plasticity, nerve-glia interactions and maintenance of the blood-brain barrier. Most research so far has focused on the functions of dystroglycan in muscle and neuromuscular junctions, while its role in the brain and interneuronal synapses has been neglected. This review will give an overview of the biochemistry of dystroglycan, its interaction with other proteins as well as its confirmed and hypothetical functions in the nervous system.

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Interactions between β2-syntrophin and a family of microtubule-associated serine/threonine kinases

Cited by 142 publications

References 46 publications

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Interaction of TRAF6 with MAST205 Regulates NF-κB Activation and MAST205 Stability

Review: Dystroglycan in the Nervous System

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