Α-Dystrobrevin-1 Recruits Grb2 and α-catulin to Organize Neurotransmitter Receptors at the Neuromuscular Junction

Overview

Journal J Cell Sci

Specialty Cell Biology

Date 2016 Jan 16

PMID 26769899

Citations 11

Authors

Jacinthe Gingras

Marta Gawor

Krzysztof M Bernadzki

R Mark Grady

Peter Hallock

David J Glass

Joshua R Sanes

Tomasz J Proszynski

Affiliations

Soon will be listed here.

Abstract

Neuromuscular junctions (NMJs), the synapses made by motor neurons on muscle fibers, form during embryonic development but undergo substantial remodeling postnatally. Several lines of evidence suggest that α-dystrobrevin, a component of the dystrophin-associated glycoprotein complex (DGC), is a crucial regulator of the remodeling process and that tyrosine phosphorylation of one isoform, α-dystrobrevin-1, is required for its function at synapses. We identified a functionally important phosphorylation site on α-dystrobrevin-1, generated phosphorylation-specific antibodies to it and used them to demonstrate dramatic increases in phosphorylation during the remodeling period, as well as in nerve-dependent regulation in adults. We then identified proteins that bind to this site in a phosphorylation-dependent manner and others that bind to α-dystrobrevin-1 in a phosphorylation-independent manner. They include multiple members of the DGC, as well as α-catulin, liprin-α1, Usp9x, PI3K, Arhgef5 and Grb2. Finally, we show that two interactors, α-catulin (phosphorylation independent) and Grb2 (phosphorylation dependent) are localized to NMJs in vivo, and that they are required for proper organization of neurotransmitter receptors on myotubes.

Citing Articles

Emerging Roles of the α-Catenin Family Member α-Catulin in Development, Homeostasis and Cancer Progression.

Gielata M, Karpinska K, Pieczonka T, Kobielak A Int J Mol Sci. 2022; 23(19).

PMID: 36233261 PMC: 9569426. DOI: 10.3390/ijms231911962.

Expression and Roles of Lynx1, a Modulator of Cholinergic Transmission, in Skeletal Muscles and Neuromuscular Junctions in Mice.

Doss S, Barbat-Artigas S, Lopes M, Pradhan B, Proszynski T, Robitaille R Front Cell Dev Biol. 2022; 10:838612.

PMID: 35372356 PMC: 8967655. DOI: 10.3389/fcell.2022.838612.

Tks5 Regulates Synaptic Podosome Formation and Stabilization of the Postsynaptic Machinery at the Neuromuscular Junction.

Pezinski M, Maliszewska-Olejniczak K, Daszczuk P, Mazurek P, Niewiadomski P, Redowicz M Int J Mol Sci. 2021; 22(21).

PMID: 34769479 PMC: 8585010. DOI: 10.3390/ijms222112051.

Liprin-α-Mediated Assemblies and Their Roles in Synapse Formation.

Xie X, Liang M, Yu C, Wei Z Front Cell Dev Biol. 2021; 9:653381.

PMID: 33869211 PMC: 8044993. DOI: 10.3389/fcell.2021.653381.

The Dystrophin Node as Integrator of Cytoskeletal Organization, Lateral Force Transmission, Fiber Stability and Cellular Signaling in Skeletal Muscle.

Dowling P, Gargan S, Murphy S, Zweyer M, Sabir H, Swandulla D Proteomes. 2021; 9(1).

PMID: 33540575 PMC: 7931087. DOI: 10.3390/proteomes9010009.

References

Spangler S, Schmitz S, Kevenaar J, de Graaff E, de Wit H, Demmers J . Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. J Cell Biol. 2013; 201(6):915-28. PMC: 3678157. DOI: 10.1083/jcb.201301011. View

Choi H, Liu Y, Tennert C, Sugiura Y, Karakatsani A, Kroger S . APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. Elife. 2013; 2:e00220. PMC: 3748711. DOI: 10.7554/eLife.00220. View

Jacobson C, Cote P, Rossi S, Rotundo R, Carbonetto S . The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at neuromuscular junctions and formation of the synaptic basement membrane. J Cell Biol. 2001; 152(3):435-50. PMC: 2195998. DOI: 10.1083/jcb.152.3.435. View

Newey S, Gramolini A, Wu J, Holzfeind P, Jasmin B, Davies K . A novel mechanism for modulating synaptic gene expression: differential localization of alpha-dystrobrevin transcripts in skeletal muscle. Mol Cell Neurosci. 2001; 17(1):127-40. DOI: 10.1006/mcne.2000.0918. View

Smith C, Mittaud P, Prescott E, Fuhrer C, Burden S . Src, Fyn, and Yes are not required for neuromuscular synapse formation but are necessary for stabilization of agrin-induced clusters of acetylcholine receptors. J Neurosci. 2001; 21(9):3151-60. PMC: 6762551. View

McMahon J, Signori E, Wells K, Fazio V, Wells D . Optimisation of electrotransfer of plasmid into skeletal muscle by pretreatment with hyaluronidase -- increased expression with reduced muscle damage. Gene Ther. 2001; 8(16):1264-70. DOI: 10.1038/sj.gt.3301522. View

Oak S, Russo K, Petrucci T, Jarrett H . Mouse alpha1-syntrophin binding to Grb2: further evidence of a role for syntrophin in cell signaling. Biochemistry. 2001; 40(37):11270-8. DOI: 10.1021/bi010490n. View

Mariotti A, Kedeshian P, Dans M, Curatola A, Gagnoux-Palacios L, Giancotti F . EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J Cell Biol. 2001; 155(3):447-58. PMC: 2150849. DOI: 10.1083/jcb.200105017. View

Sanes J, Lichtman J . Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci. 2001; 2(11):791-805. DOI: 10.1038/35097557. View

10.

Kaufmann N, DeProto J, Ranjan R, Wan H, Van Vactor D . Drosophila liprin-alpha and the receptor phosphatase Dlar control synapse morphogenesis. Neuron. 2002; 34(1):27-38. DOI: 10.1016/s0896-6273(02)00643-8. View

11.

Greer P . Closing in on the biological functions of Fps/Fes and Fer. Nat Rev Mol Cell Biol. 2002; 3(4):278-89. DOI: 10.1038/nrm783. View

12.

Darabid H, Perez-Gonzalez A, Robitaille R . Neuromuscular synaptogenesis: coordinating partners with multiple functions. Nat Rev Neurosci. 2014; 15(11):703-18. View

13.

Bernadzki K, Rojek K, Proszynski T . Podosomes in muscle cells and their role in the remodeling of neuromuscular postsynaptic machinery. Eur J Cell Biol. 2014; 93(10-12):478-85. DOI: 10.1016/j.ejcb.2014.06.002. View

14.

Gout I, Dhand R, Panayotou G, Fry M, Hiles I, Otsu M . Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system. Biochem J. 1992; 288 ( Pt 2):395-405. PMC: 1132024. DOI: 10.1042/bj2880395. View

15.

Ervasti J, Campbell K . A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol. 1993; 122(4):809-23. PMC: 2119587. DOI: 10.1083/jcb.122.4.809. View

16.

Kapeller R, Prasad K, Janssen O, Hou W, Schaffhausen B, Rudd C . Identification of two SH3-binding motifs in the regulatory subunit of phosphatidylinositol 3-kinase. J Biol Chem. 1994; 269(3):1927-33. View

17.

Grady R, Grange R, Lau K, Maimone M, Nichol M, Stull J . Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nat Cell Biol. 1999; 1(4):215-20. DOI: 10.1038/12034. View

18.

Grady R, Zhou H, Cunningham J, Henry M, Campbell K, Sanes J . Maturation and maintenance of the neuromuscular synapse: genetic evidence for roles of the dystrophin--glycoprotein complex. Neuron. 2000; 25(2):279-93. DOI: 10.1016/s0896-6273(00)80894-6. View

19.

Grady R, Akaaboune M, Cohen A, Maimone M, Lichtman J, Sanes J . Tyrosine-phosphorylated and nonphosphorylated isoforms of alpha-dystrobrevin: roles in skeletal muscle and its neuromuscular and myotendinous junctions. J Cell Biol. 2003; 160(5):741-52. PMC: 2173352. DOI: 10.1083/jcb.200209045. View

20.

Vadlamudi R, Sahin A, Adam L, Wang R, Kumar R . Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. FEBS Lett. 2003; 543(1-3):76-80. DOI: 10.1016/s0014-5793(03)00404-6. View