PMID- 20696763
OWN - NLM
STAT- MEDLINE
DCOM- 20101207
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 42
DP  - 2010 Oct 15
TI  - Modulation of agrin-induced acetylcholine receptor clustering by extracellular 
      signal-regulated kinases 1 and 2 in cultured myotubes.
PG  - 32370-7
LID - 10.1074/jbc.M110.144774 [doi]
AB  - Agrin released by motoneurons induces and/or maintains acetylcholine receptor 
      (AChR) clustering and other aspects of postsynaptic differentiation at the 
      vertebrate neuromuscular junction. Agrin acts by binding and activating a 
      receptor complex containing LDL receptor protein 4 (Lrp4) and muscle-specific 
      kinase (MuSK). Two critical downstream components of this signaling cascade, 
      Dox-7 and rapsyn, have been identified. However, additional intracellular 
      essential elements remain unknown. Prior observations by others and us suggested 
      antagonistic interactions between agrin and neuregulin-1 (Nrg-1) signaling in 
      cultured myotubes and developing muscle fibers in vivo. A hallmark of Nrg-1 
      signaling in skeletal muscle cells is the activation of extracellular 
      signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 are also activated in most 
      cells by phorbol 12-myristate 13-acetate, a classical inhibitor of agrin-induced 
      AChR clustering in myotubes. Here, it was investigated whether agrin activates 
      ERK1/2 directly and whether such activation modulates agrin-induced AChR 
      clustering. Agrin induced a rapid but transient activation of ERK1/2 in myotubes 
      that was Lrp4/MuSK-dependent. However, blocking this ERK1/2 activation did not 
      prevent but potentiated AChR clustering induced by agrin. ERK1/2 activation was 
      dispensable for Nrg-1-mediated inhibition of the AChR clustering activity of 
      agrin, but was indispensable for such activity by phorbol 12-myristate 
      13-acetate. Together, these results suggest agrin-induced activation of ERK1/2 is 
      a negative modulator of agrin signaling in skeletal muscle cells.
FAU - Rimer, Mendell
AU  - Rimer M
AD  - Department of Neuroscience and Experimental Therapeutics, College of Medicine, 
      Texas A&M Health Science Center, College Station, Texas 77843, USA. 
      mjrimer@medicine.tamhsc.edu
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100809
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Agrin)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (LDL-Receptor Related Proteins)
RN  - 0 (Lrp4 protein, mouse)
RN  - 0 (Neuregulin-1)
RN  - 0 (Nrg1 protein, mouse)
RN  - 0 (Receptors, Cholinergic)
RN  - 0 (Receptors, LDL)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Agrin/*metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/metabolism
MH  - Humans
MH  - LDL-Receptor Related Proteins
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/*metabolism
MH  - Muscle Fibers, Skeletal/cytology/*metabolism
MH  - Muscle, Skeletal/cytology
MH  - Neuregulin-1/metabolism
MH  - Receptor Protein-Tyrosine Kinases/metabolism
MH  - Receptors, Cholinergic/*metabolism
MH  - Receptors, LDL/metabolism
MH  - Signal Transduction/physiology
MH  - Tetradecanoylphorbol Acetate/metabolism
PMC - PMC2952238
EDAT- 2010/08/11 06:00
MHDA- 2010/12/14 06:00
PMCR- 2011/10/15
CRDT- 2010/08/11 06:00
PHST- 2010/08/11 06:00 [entrez]
PHST- 2010/08/11 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2011/10/15 00:00 [pmc-release]
AID - S0021-9258(20)47286-2 [pii]
AID - M110.144774 [pii]
AID - 10.1074/jbc.M110.144774 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Oct 15;285(42):32370-7. doi: 10.1074/jbc.M110.144774. Epub 2010 
      Aug 9.