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PMID:17576800

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Citation

Lu, Z, Je, HS, Young, P, Gross, J, Lu, B and Feng, G (2007) Regulation of synaptic growth and maturation by a synapse-associated E3 ubiquitin ligase at the neuromuscular junction. J. Cell Biol. 177:1077-89

Abstract

The ubiquitin-proteasome pathway has been implicated in synaptic development and plasticity. However, mechanisms by which ubiquitination contributes to precise and dynamic control of synaptic development and plasticity are poorly understood. We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Regulation of cell surface levels of MuSK by PDZRN3 requires the ubiquitin ligase domain and is mediated by accelerated endocytosis. Gain- and loss-of-function studies in cultured myotubes show that regulation of MuSK by PDZRN3 plays an important role in MuSK-mediated nicotinic acetylcholine receptor clustering. Furthermore, overexpression of PDZRN3 in skeletal muscle of transgenic mice perturbs the growth and maturation of the neuromuscular junction. These results identify a synapse-associated E3 ubiquitin ligase as an important regulator of MuSK signaling.

Links

PubMed PMC2064367 Online version:10.1083/jcb.200610060

Keywords

Animals; Carrier Proteins/physiology; Endocytosis; Mice; Mice, Transgenic; Muscle Fibers, Skeletal/cytology; Muscle, Skeletal; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases/metabolism; Synapses/enzymology; Synapses/physiology; Ubiquitin-Protein Ligases/physiology; Zinc Fingers/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:UB2D2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q69ZS0

F

Seeded From UniProt

complete

MOUSE:MUSK

enables

GO:0030165: PDZ domain binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q69ZS0

F

Seeded From UniProt

complete

MOUSE:PZRN3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P62838

F

Seeded From UniProt

complete

MOUSE:PZRN3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q61006

F

Seeded From UniProt

complete

MOUSE:PZRN3

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:103581)

Seeded From UniProt

complete

MOUSE:PZRN3

involved_in

GO:0016567: protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PZRN3

located_in

GO:0031594: neuromuscular junction

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PZRN3

involved_in

GO:0007528: neuromuscular junction development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PZRN3

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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