A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering

Campanelli, James T.; Roberds, Steven L.; Campbell, Kevin P.; Scheller, Richard H.

doi:10.1016/0092-8674(94)90051-5

Cited by 356 publications

(235 citation statements)

References 57 publications

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“…The binding region to ␣-dystroglycan also partially overlaps with the region necessary for AChR aggregation (52)(53)(54). Several lines of evidence suggest that the binding affinity of agrin to ␣-dystroglycan is regulated by amino acid inserts at the A-and the B-site (37,55).…”

Section: Agrin Binding To ␣-Dystroglycan Is Modulated By Inserts At Amentioning

confidence: 99%

Activation of Muscle-specific Receptor Tyrosine Kinase and Binding to Dystroglycan Are Regulated by Alternative mRNA Splicing of Agrin

Scotton

Bleckmann

Stebler

et al. 2006

Journal of Biological Chemistry

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Agrin induces the aggregation of postsynaptic proteins at the neuromuscular junction (NMJ). This activity requires the receptor-tyrosine kinase MuSK. Agrin isoforms differ in short amino acid stretches at two sites, called A and B, that are localized in the two most C-terminal laminin G (LG) domains. Importantly, agrin isoforms greatly differ in their activities of inducing MuSK phosphorylation and of binding to ␣-dystroglycan. By using site-directed mutagenesis, we characterized the amino acids important for these activities of agrin. We find that the conserved tripeptide asparagineglutamate-isoleucine in the eight-amino acid long insert at the B-site is necessary and sufficient for full MuSK phosphorylation activity. However, even if all eight amino acids were replaced by alanines, this agrin mutant still has significantly higher MuSK phosphorylation activity than the splice version lacking any insert. We also show that binding to ␣-dystroglycan requires at least two LG domains and that amino acid inserts at the A and the B splice sites negatively affect binding.

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Section: Agrin Binding To ␣-Dystroglycan Is Modulated By Inserts At Amentioning

confidence: 99%

Activation of Muscle-specific Receptor Tyrosine Kinase and Binding to Dystroglycan Are Regulated by Alternative mRNA Splicing of Agrin

Scotton

Bleckmann

Stebler

et al. 2006

Journal of Biological Chemistry

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“…The glycan chains of the central mucin domain of ␣-dystroglycan are known to mediate binding to components such as laminin (Ervasti and Campbell, 1993), perlecan (Peng et al, 1998) agrin (Bowe et al, 1994;Campanelli et al, 1994;Gee et al, 1994), neurexin in the brain (Sugita et al, 2001) and pikachurin in the eye (Sato et al, 2008). Aberrant glycosylation of ␣-dystroglycan is thought to be central to the pathogenesis of the muscular dystrophy and the brain abnormalities manifested by patients (cobblestone lissencephaly) and animal models with severe forms of dystroglycanopathy (Michele et al, 2002;Michele and Campbell, 2003;Hewitt, 2009;Yoshida-Moriguchi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Fukutin-Related Protein Alters the Deposition of Laminin in the Eye and Brain

Ackroyd¹,

Whitmore²,

Prior³

et al. 2011

J. Neurosci.

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Mutations in fukutin-related protein (FKRP) are responsible for a common group of muscular dystrophies ranging from adult onset limb girdle muscular dystrophies to severe congenital forms with associated structural brain involvement. The defining feature of this group of disorders is the hypoglycosylation of ␣-dystroglycan and its inability to effectively bind extracellular matrix ligands such as laminin ␣2. However, ␣-dystroglycan has the potential to interact with a number of laminin isoforms many of which are basement membrane/ tissue specific and developmentally regulated. To further investigate this we evaluated laminin ␣-chain expression in the cerebral cortex and eye of our FKRP knock-down mouse (FKRP KD ). These mice showed a marked disturbance in the deposition of laminin ␣-chains including ␣1, ␣2, ␣4, and ␣5, although only laminin ␣1-and ␥1-chain mRNA expression was significantly upregulated relative to controls. Moreover, there was a diffuse pattern of laminin deposition below the pial surface which correlated with an abrupt termination of many of the radial glial cells. This along with the pial basement membrane defects, contributed to the abnormal positioning of both early-and late-born neurons. Defects in the inner limiting membrane of the eye were associated with a reduction of laminin ␣1 demonstrating the involvement of the ␣-dystroglycan:laminin ␣1 axis in the disease process. These observations demonstrate for the first time that a reduction in Fkrp influences the ability of tissue-specific forms of ␣-dystroglycan to direct the deposition of several laminin isoforms in the formation of different basement membranes.

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“…The dystrophin-related protein (also named utrophin), which is 80% homologous with dystrophin but encoded by a gene mapped on 6q24 [22], has the same link with this protein complex but its main localization is at the neuromuscular junction in skeletal muscle [23]. According to recent studies [24][25][26][27], dystroglycan localized with utrophin in this structure could be an agrin receptor and would thus play a key role in synapse formation via acetyl choline receptor clustering. Torpedo electrocytes were the first tissues in which interactions between agrin and dystroglycan were tentatively identified [28].…”

Section: Introductionmentioning

confidence: 99%

Presence of long and short dystrophin and/or utrophin products in Torpedo marmorata peripheral nerves

et al. 1996

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Peripheral nerves from rabbit and Torpedo marmorata were comparatively analyzed for the presence of short dystrophin products. Western blot analyses of Torpedo marmorata peripheral nerve extracts revealed the existence of three proteins belonging to the dystrophin family: a M, 400 kDa protein band detected with dystrophin/utrophin, dystrophin-specific and Torpedo utrophin-specific antibodies, a molecule identified as Dpll6 and, for the frst time at the protein level, a new protein probably corresponding to Upll6. All of these products were carefully identified according to the specificities of the monoclonal antibodies used. In immunofluorescence studies, clear staining of the thin rim surrounding each Schwann cell-axon unit was observed in both Torpedo marmorata and rabbit peripheral nerves, showing colocalization of all of these molecules. Their potential functions were discussed in comparison to similar products found in rabbit peripheral nerves.

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A role for dystrophin-associated glycoproteins and utrophin in agrin-induced AChR clustering

Cited by 356 publications

References 57 publications

Activation of Muscle-specific Receptor Tyrosine Kinase and Binding to Dystroglycan Are Regulated by Alternative mRNA Splicing of Agrin

Activation of Muscle-specific Receptor Tyrosine Kinase and Binding to Dystroglycan Are Regulated by Alternative mRNA Splicing of Agrin

Fukutin-Related Protein Alters the Deposition of Laminin in the Eye and Brain

Presence of long and short dystrophin and/or utrophin products in Torpedo marmorata peripheral nerves

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