title: The function of Shp2 tyrosine phosphatase in the dispersal of acetylcholine receptor clusters.
abstract: BACKGROUND
  A crucial event in the development of the vertebrate neuromuscular junction (NMJ) is the postsynaptic enrichment of muscle acetylcholine (ACh) receptors (AChRs). This process involves two distinct steps: the local clustering of AChRs at synapses, which depends on the activation of the muscle-specific receptor tyrosine kinase MuSK by neural agrin, and the global dispersal of aneural or "pre-patterned" AChR aggregates, which is triggered by ACh or by synaptogenic stimuli. We and others have previously shown that tyrosine phosphatases, such as the SH2 domain-containing phosphatase Shp2, regulate AChR cluster formation in muscle cells, and that tyrosine phosphatases also mediate the dispersal of pre-patterned AChR clusters by synaptogenic stimuli, although the specific phosphatases involved in this latter step remain unknown.
  
  
  RESULTS
  Using an assay system that allows AChR cluster assembly and disassembly to be studied separately and quantitatively, we describe a previously unrecognized role of the tyrosine phosphatase Shp2 in AChR cluster disassembly. Shp2 was robustly expressed in embryonic Xenopus muscle in vivo and in cultured myotomal muscle cells, and treatment of the muscle cultures with an inhibitor of Shp2 (NSC-87877) blocked the dispersal of pre-patterned AChR clusters by synaptogenic stimuli. In contrast, over-expression in muscle cells of either wild-type or constitutively active Shp2 accelerated cluster dispersal. Significantly, forced expression in muscle of the Shp2-activator SIRPalpha1 (signal regulatory protein alpha1) also enhanced the disassembly of AChR clusters, whereas the expression of a truncated SIRPalpha1 mutant that suppresses Shp2 signaling inhibited cluster disassembly.
  
  
  CONCLUSIONS
  Our results suggest that Shp2 activation by synaptogenic stimuli, through signaling intermediates such as SIRPalpha1, promotes the dispersal of pre-patterned AChR clusters to facilitate the selective accumulation of AChRs at developing NMJs.
authors.affiliation: Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China. boqyp@ust.hk
authors.forename: Yueping K
authors.initials: YK
authors.lastname: Qian
authors.forename: Ariel W S
authors.initials: AW
authors.lastname: Chan
authors.forename: Raghavan
authors.initials: R
authors.lastname: Madhavan
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Peng
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002038:Bungarotoxins / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization / Q000379:methods; D008845:Microinjections / Q000379:methods; D008856:Microscopy, Fluorescence; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D018075:RNA, Complementary / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012235:Rhodamines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014981:Xenopus
chemical_list: D000943:Antigens, Differentiation; D002038:Bungarotoxins; C512715:NSC-87877; D011804:Quinolines; D018075:RNA, Complementary; D011950:Receptors, Cholinergic; D011971:Receptors, Immunologic; D012235:Rhodamines; C501920:SIRPA protein, human; C494031:rhodamine-alpha-bungarotoxin; D049452:Green Fluorescent Proteins; D020794:Receptor Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11